17

The Breast
chapter Catherine C. Parker, Senthil Damodaran,
Kirby I. Bland, and Kelly K. Hunt

A Brief History of Breast Hormonal and Nonhormonal Local-Regional Recurrence / 587

Cancer Therapy
Embryology and Functional
Anatomy of the Breast
Embryology / 543
Functional Anatomy / 544
Physiology of the Breast
Breast Development and Function / 547
Pregnancy, Lactation,
and Senescence / 548
Gynecomastia / 549
Infectious and Inflammatory
Disorders of the Breast
Bacterial Infection / 550
Mycotic Infections / 550
Hidradenitis Suppurativa / 550
Mondor’s Disease / 550
Common Benign Disorders and
Diseases of the Breast
Aberrations of Normal Development and
Involution / 551
Pathology of Nonproliferative
Disorders / 552
Pathology of Proliferative Disorders
Without Atypia / 553
Pathology of Atypical Proliferative
Diseases / 553
Treatment of Selected Benign Breast
Disorders and Diseases / 554
Risk Factors for Breast Cancer
541 Risk Factors / 555
Risk Assessment Models / 555
543 Risk Management / 556
BRCA Mutations / 558
Epidemiology and Natural
547 History of Breast Cancer
Epidemiology / 561
Natural History / 562
Histopathology of Breast Cancer 563
Carcinoma In Situ / 563
Invasive Breast Carcinoma / 565
550 Diagnosis of Breast Cancer
Examination / 567
Imaging Techniques / 567
Breast Biopsy / 574
Breast Cancer Staging and
Biomarkers
551
Breast Cancer Staging / 575
Biomarkers / 575
Overview of Breast Cancer
Therapy
In Situ Breast Cancer (Stage 0) / 580
Early Invasive Breast Cancer
(Stage I, IIA, or IIB) / 582
Advanced Local-Regional Breast Cancer
(Stage IIIA or IIIB) / 585
Internal Mammary Lymph Nodes / 587
Distant Metastases (Stage IV) / 587
555
Breast Cancer Prognosis / 587
Surgical Techniques in
Breast Cancer Therapy 588
Excisional Biopsy With Needle
Localization / 588
561 Sentinel Lymph Node Dissection / 590
Breast Conservation / 591
Mastectomy and Axillary Dissection / 591
Modified Radical Mastectomy / 592
Reconstruction of the
Breast and Chest Wall / 593
567 Nonsurgical Breast
Cancer Therapies 594
Radiation Therapy / 594
Chemotherapy Adjuvant / 594
Antiestrogen Therapy / 597
Ablative Endocrine Therapy / 598
575
Anti-HER2 Therapy / 598
Special Clinical Situations 599
Nipple Discharge / 599
Axillary Lymph Node Metastases
580
in the Setting of an Unknown
Primary Cancer / 600
Breast Cancer During Pregnancy / 600
Male Breast Cancer / 600
Phyllodes Tumors / 600
Inflammatory Breast Carcinoma / 601
Rare Breast Cancers / 602

A BRIEF HISTORY OF BREAST CANCER THERAPY exactly resembling the animal the crab. Just as the crab has legs
on both sides of his body, so in this disease the veins extending
Breast cancer has captured the attention of surgeons throughout
out from the unnatural growth take the shape of a crab’s legs.
the ages. The Smith Surgical Papyrus (3000–2500 b.c.) is the
We have often cured this disease in its early stages, but after
earliest known document to refer to breast cancer. The cancer
it has reached a large size, no one has cured it. In all operations
was in a man, but the description encompassed most of the
we attempt to excise the tumor in a circle where it borders on
common clinical features. In reference to this cancer, the author
the healthy tissue.”3
concluded, “There is no treatment.”1 There were few other
The Galenic system of medicine ascribed cancers to an
historical references to breast cancer until the first century. In
excess of black bile and concluded that excision of a local
De Medicina, Celsus commented on the value of operations for
bodily outbreak could not cure the systemic imbalance. Theories
early breast cancer: “None of these may be removed but the
espoused by Galen dominated medicine until the Renaissance.
cacoethes (early cancer), the rest are irritated by every method
In 1652, Tulp introduced the idea that cancer was contagious
of cure. The more violent the operations are, the more angry
when he reported an elderly woman and her housemaid who
they grow.”2 In the second century, Galen inscribed his classical
both developed breast cancer (N. Tulp, Observationes medi-
clinical observation: “We have often seen in the breast a tumor
cae 1652). This single incidence was accepted as conclusive
 Key Points
1 The breast receives its principal blood supply from per-
forating branches of the internal mammary artery, lateral
branches of the posterior intercostal arteries, and branches
from the axillary artery, including the highest thoracic, lat-
eral thoracic, and pectoral branches of the thoracoacromial
artery.
2 The axillary lymph nodes usually receive >75% of the
lymph drainage from the breast, and the rest flows through
the lymph vessels that accompany the perforating branches
of the internal mammary artery and enters the parasternal
(internal mammary) group of lymph nodes.
3 Breast development and function are initiated by a variety
of hormonal stimuli, with the major trophic effects being
modulated by estrogen, progesterone, and prolactin.
4 Benign breast disorders and diseases are related to the nor-
mal processes of reproductive life and to involution, and
there is a spectrum of breast conditions that ranges from
normal to disorder to disease (aberrations of normal devel-
opment and involution classification).
5 To calculate breast cancer risk using the Gail model, a
woman’s risk factors are translated into an overall risk
score by multiplying her relative risks from several cat-
egories. This risk score is then compared with an adjusted
population risk of breast cancer to determine the wom-
an’s individual risk. This model is not appropriate for use
evidence and started an idea which persisted into the 20th
century among some lay people. The majority of respected sur-
geons considered operative intervention to be a futile and ill-
advised endeavor. The Renaissance and the wars of the 16th and
17th centuries brought developments in surgery, particularly in
anatomical understanding. However, there were no new theories
espoused in relation to cancer. Beginning with Morgagni, surgi-
cal resections were more frequently undertaken, including some
early attempts at mastectomy and axillary dissection. The 17th
century saw the start of the Age of Enlightenment, which lasted
until the 19th century. In terms of medicine, this resulted in the
abandonment of Galen’s humoral pathology, which was repudi-
ated by Le Dran, and the subsequent rise in cellular pathology
as espoused by Virchow. Le Dran stated that breast cancer was
a local disease that spread by way of lymph vessels to axillary
lymph nodes. When operating on a woman with breast cancer,
he routinely removed any enlarged axillary lymph nodes.4
In the 19th century, Moore, of the Middlesex Hospital,
London, emphasized complete resection of the breast for cancer
and stated that palpable axillary lymph nodes also should be
removed.5 In a presentation before the British Medical Asso-
ciation in 1877, Banks supported Moore’s concepts and advo-
cated the resection of axillary lymph nodes even when palpable
lymphadenopathy was not evident, recognizing that occult
involvement of axillary lymph nodes was frequently present. In
1894, Halsted and Meyer reported their operations for treatment
of breast cancer.6 By demonstrating superior local-regional con-
trol rates after radical resection, these surgeons established radi-
cal mastectomy as state-of-the-art treatment for that era. Halsted
and Meyer advocated complete dissection of axillary lymph
542 node levels I to III. Both routinely resected the long thoracic
in women with a known BRCA1 or BRCA2 mutation or
women with lobular or ductal carcinoma in situ.
6 Routine use of screening mammography in women ≥50
years of age reduces mortality from breast cancer by 25%.
Magnetic resonance imaging (MRI) screening is recom-
mended in women with BRCA mutations and may be con-
sidered in women with a greater than 20% to 25% lifetime
risk of developing breast cancer.
7 Core-needle biopsy is the preferred method for diagnosis
of palpable or nonpalpable breast abnormalities.
8 When a diagnosis of breast cancer is made, the surgeon
should determine the clinical stage, histologic characteris-
tics, and appropriate biomarker levels before initiating
local therapy.
9 Sentinel node dissection is the preferred method for stag-
ing of the regional lymph nodes in women with clinically
node-negative invasive breast cancer. Axillary dissection
may be avoided in women with one to two positive senti-
nel nodes who are treated with breast conserving surgery,
whole breast radiation, and systemic therapy.
10 Local-regional and systemic therapy decisions for an indi-
vidual patient with breast cancer are best made using a
multidisciplinary treatment approach. The sequencing of
therapies is dependent on patient and tumor related factors
including breast cancer subtype.
nerve and the thoracodorsal neurovascular bundle with the axil-
lary contents. In 1943, Haagensen and Stout described the grave
signs of breast cancer, which included: (a) edema of the skin
of the breast, (b) skin ulceration, (c) chest wall fixation, (d) an
axillary lymph node >2.5 cm in diameter, and (e) fixed axillary
lymph nodes. Women with two or more signs had a 42% local
recurrence rate and only a 2% 5-year disease-free survival rate.7
Based on these findings, they declared that women with grave
signs were beyond cure by radical surgery. In 1948, Patey and
Dyson of the Middlesex Hospital, London, advocated a modi-
fied radical mastectomy for the management of advanced oper-
able breast cancer, explaining, “Until an effective general agent
for treatment of carcinoma of the breast is developed, a high
proportion of these cases are doomed to die.”8 Their technique
included removal of the breast and axillary lymph nodes with
preservation of the pectoralis major muscle. They showed that
removal of the pectoralis minor muscle allowed access to and
clearance of axillary lymph node levels I to III.
During the 1970s, there was a transition from the Halsted
radical mastectomy to the modified radical mastectomy as the
surgical procedure most frequently used by American surgeons
to treat breast cancer. This transition acknowledged that: (a)
fewer patients were presenting with advanced local disease
with or without the grave signs described by Haagensen, (b)
extirpation of the pectoralis major muscle was not essential for
local-regional control in stages I and II breast cancer, and (c)
neither the modified radical mastectomy nor the Halsted radi-
cal mastectomy consistently achieved local-regional control of
stage III breast cancer. Radiation therapy was incorporated into
the management of advanced breast cancer and demonstrated
improvements in local-regional control. The National Surgical
Adjuvant Breast and Bowel Project (NSABP) conducted a ran-
domized trial in the early 1970s to determine the impact of local
and regional treatments on survival in operable breast cancer.
In the B-04 trial, 1665 women were enrolled and stratified by
clinical assessment of the axillary lymph nodes. The clinically
node-negative women were randomized into three treatment
groups: (a) Halsted radical mastectomy; (b) total mastectomy
plus radiation therapy; and (c) total mastectomy alone. Clini-
cally node-positive women were randomized to Halsted radical
mastectomy or total mastectomy plus radiation therapy. This
trial accrued patients between 1971 and 1974, an era that pre-
dated widespread availability of effective systemic therapy for
breast cancer and therefore reflect survival associated with local-
regional therapy alone. There were no differences in survival
between the three groups of node-negative women or between
the two groups of node-positive women. These overall survival
equivalence patterns persisted at 25 years of follow-up.9
The next major advance in the surgical management
of breast cancer was the development of breast conserving
surgery. Breast conserving surgery and radium treatment
was first reported by Geoffrey Keynes of St Bartholomew’s
Hospital, London in the British Medical Journal in 1937.10
Several decades later, the NSABP launched the B-06 trial, a
phase 3 study that randomized 1851 patients to total mastec-
tomy, lumpectomy alone, or lumpectomy with breast irradia-
tion. The results showed no difference in disease-free, distant
disease-free, and overall survival among the three groups; how-
ever, the omission of radiation therapy resulted in significantly
higher rates of ipsilateral breast tumor recurrence in those who
received lumpectomy alone.11 The B-06 trial excluded patients
who had palpable axillary lymph nodes, and those patients
randomized to breast conserving surgery had frozen sections
performed. If on frozen section the margins were involved, the
surgeon proceeded to perform a mastectomy, but the patient
was included in the analysis as having had a breast conserv-
ing operation. Furthermore, in B-06, local in-breast recurrences
were regarded as “nonevents” in terms of disease-free survival.
Both the NSABP B-04 and B-06 trials were taken to refute the
Halstedian concept that cancer spread throughout a region of the
breast to lymphatics and then on to distant sites. Bernard Fisher
proposed the “alternative hypothesis” that breast cancer was a
systemic disease at diagnosis and that tumor cells had access to
both the blood and lymphatic systems and that regional lymph
nodes were a marker of systemic disease and not a barrier to
the dissemination of cancer cells. He proposed that host factors
were important in the development of metastasis and that varia-
tions in the local-regional approach to breast cancer treatment
were not likely to substantially impact survival. This idea was
dominant for a number of years but has been challenged by the
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
overview analysis, which reported that “the avoidance of recur-
rence in a conserved breast . . . avoids about one breast cancer
death over the next 15 years for every four such recurrences
avoided,”12 indicating that not all breast cancer is a systemic
disease at presentation.
During the 1970s, clinical trials were initiated to determine
the value of systemic therapy in the postoperative setting as an
adjuvant to surgery. The EBCTCG was established in 1985 to
coordinate the meta-analysis of data from randomized clinical
trials in order to examine the impact of adjuvant treatments
for breast cancer on recurrence and mortality. The EBCTCG
overview has demonstrated that anthracycline containing
regimens are superior to cyclophosphamide, methotrexate, and 543
5-fluorouracil (CMF), and more recently, that the addition of a
taxane to an anthracycline-based regimen reduces breast cancer
mortality by one-third.11 The overview has also demonstrated
that tamoxifen is of benefit only in patients with estrogen recep-
tor (ER) positive breast cancer and that tamoxifen may decrease
mortality from breast cancer by as much as 30%.13 Importantly,
the EBCTCG data have shown that proportional reduction in
risk was not significantly affected by standard clinical and
pathologic factors such as tumor size, ER status, and nodal
CHAPTER 17 THE BREAST
status.14 This underscores the importance of stratification of risk
in determining adjuvant therapy decisions in order to minimize
the toxicities of therapies in those unlikely to benefit, yet real-
ize the substantial benefits gained in local-regional control and
survival in those at higher risk.
Many early randomized clinical trials considered all
patients similarly in terms of treatment viewing breast cancer as
more of a homogeneous disease. Breast cancer has traditionally
been defined by pathologic determinants using conventional
light microscopy and basic histologic techniques. In the 1980s,
immunohistochemistry allowed assessment of the expression
of individual tumor markers (most commonly proteins) while
DNA was initially assessed in terms of its ploidy status. Sub-
sequently, breast cancer specimens have been interrogated at
the level of the DNA by labeling genes of interest and allow-
ing fluorescent dyes to quantify the abundance of a particular
gene and comparing a large number of genes simultaneously in
a single breast cancer specimen. Gene expression arrays have
shown that breast cancers cluster according to their intrinsic
gene expression patterns into at least five intrinsic subtypes and
these intrinsic subtypes correlate with breast cancer outcomes.15
Breast cancers are now classified by molecular subtypes and
these are being used for risk stratification and decision making
in terms of local-regional and systemic therapies.
Currently, 50% of American women will consult a sur-
geon regarding breast disease, 25% will undergo breast biopsy
for diagnosis of an abnormality, and 12% will develop some
variant of breast cancer. Considerable progress has been made
in the integration of surgery, radiation therapy, and systemic
therapy to control local-regional disease, enhance survival, and
improve the quality of life of breast cancer survivors. Surgeons
are traditionally the first physician consulted for breast care, and
it is critical for them to be well trained in all aspects of the breast
from embryologic development, to growth and development,
to benign and malignant disease processes. This will allow the
greatest opportunity to achieve optimal outcomes for patients
and their families.
EMBRYOLOGY AND FUNCTIONAL
ANATOMY OF THE BREAST
Embryology
At the fifth or sixth week of fetal development, two ventral
bands of thickened ectoderm (mammary ridges, milk lines)
are evident in the embryo.16 In most mammals, paired breasts
develop along these ridges, which extend from the base of
the forelimb (future axilla) to the region of the hind limb
(inguinal area). These ridges are not prominent in the human
embryo and disappear after a short time, except for small
portions that may persist in the pectoral region. Accessory
breasts (polymastia) or accessory nipples (polythelia) may
544 and dysgenesis) and Fleischer’s syndrome (displacement of the
nipples and bilateral renal hypoplasia) may have polymastia as
a component. Accessory axillary breast tissue is uncommon and
usually is bilateral.
Functional Anatomy
The breast is composed of 15 to 20 lobes (Fig. 17-2), which
are each composed of several lobules.17 Fibrous bands of con-
nective tissue travel through the breast (Cooper’s suspensory
ligaments), insert perpendicularly into the dermis, and provide
structural support. The mature female breast extends from the
level of the second or third rib to the inframammary fold at
PART II

the sixth or seventh rib. It extends transversely from the lateral

border of the sternum to the anterior axillary line. The deep or
posterior surface of the breast rests on the fascia of the pecto-
ralis major, serratus anterior, and external oblique abdominal
muscles, and the upper extent of the rectus sheath. The retro-
SPECIFIC CONSIDERATIONS

mammary bursa may be identified on the posterior aspect of the

breast between the investing fascia of the breast and the fascia of
the pectoralis major muscles. The axillary tail of Spence extends
laterally across the anterior axillary fold. The upper outer quad-
rant of the breast contains a greater volume of tissue than do the
other quadrants. The breast has a protuberant conical form. The
Figure 17-1. The mammary milk line. (Visual Art: © 2013.
base of the cone is roughly circular, measuring 10 to 12 cm in
The University of Texas MD Anderson Cancer Center.)
diameter. Considerable variations in the size, contour, and den-
sity of the breast are evident among individuals. The nulliparous
breast has a hemispheric configuration with distinct flattening
occur along the milk line (Fig. 17-1) when normal regression above the nipple. With the hormonal stimulation that accom-
fails. Each breast develops when an ingrowth of ectoderm panies pregnancy and lactation, the breast becomes larger and
forms a primary tissue bud in the mesenchyme. The primary increases in volume and density, whereas with senescence, it
bud, in turn, initiates the development of 15 to 20 secondary assumes a flattened, flaccid, and more pendulous configuration
buds. Epithelial cords develop from the secondary buds and with decreased volume.
extend into the surrounding mesenchyme. Major (lactiferous) Nipple-Areola Complex. The epidermis of the nipple-are-
ducts develop, which open into a shallow mammary pit. Dur- ola complex is pigmented and is variably corrugated. During
ing infancy, a proliferation of mesenchyme transforms the puberty, the pigment becomes darker and the nipple assumes
mammary pit into a nipple. If there is failure of a pit to elevate an elevated configuration. Throughout pregnancy, the areola
above skin level, an inverted nipple results. This congenital
malformation occurs in 4% of infants. At birth, the breasts are
identical in males and females, demonstrating only the pres-
ence of major ducts. Enlargement of the breast may be evi-
dent, and a secretion, historically referred to as witch’s milk,
may be produced. These transitory events occur in response
to maternal hormones that cross the placenta.
The breast remains undeveloped in the female until
puberty, when it enlarges in response to ovarian estrogen and
progesterone, which initiate proliferation of the epithelial
and connective tissue elements. However, the breasts remain
incompletely developed until pregnancy occurs. Absence of
the breast (amastia) is rare and results from an arrest in mam-
mary ridge development that occurs during the sixth fetal week.
Poland’s syndrome consists of hypoplasia or complete absence
of the breast, costal cartilage and rib defects, hypoplasia of the
subcutaneous tissues of the chest wall, and brachysyndactyly.
Breast hypoplasia also may be iatrogenically induced before
puberty by trauma, infection, or radiation therapy. Symmastia
is a rare anomaly recognized as webbing between the breasts
across the midline. Accessory nipples (polythelia) occur in
<1% of infants and may be associated with abnormalities of Figure 17-2. Anatomy of the breast. Tangential and cross-
the urinary and cardiovascular systems. Supernumerary breasts sectional (sagittal) views of the breast and associated chest wall.
may occur in any configuration along the mammary milk line (Reproduced with permission from Bland KI, Copeland EMI: The
but most frequently occur between the normal nipple location Breast: Comprehensive Management of Benign and Malignant
and the symphysis pubis. Turner’s syndrome (ovarian agenesis Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)
enlarges and pigmentation is further enhanced. The areola con-
tains sebaceous glands, sweat glands, and accessory glands,
which produce small elevations on the surface of the areola
(Montgomery’s tubercles). Smooth muscle bundle fibers, which
lie circumferentially in the dense connective tissue and longi-
tudinally along the major ducts, extend upward into the nipple,
where they are responsible for the nipple erection that occurs
with various sensory stimuli. The dermal papilla at the tip of
the nipple contains numerous sensory nerve endings and Meiss-
ner’s corpuscles. This rich sensory innervation is of functional
importance because the sucking of the infant initiates a chain of
neurohumoral events that results in milk letdown.
Inactive and Active Breast. Each lobe of the breast termi-
nates in a major (lactiferous) duct (2–4 mm in diameter), which
opens through a constricted orifice (0.4–0.7 mm in diameter)
into the ampulla of the nipple (see Fig. 17-2). Immediately
below the nipple-areola complex, each major duct has a dilated
portion (lactiferous sinus), which is lined with stratified squa-
mous epithelium. Major ducts are lined with two layers of
cuboidal cells, whereas minor ducts are lined with a single layer
of columnar or cuboidal cells. Myoepithelial cells of ectoder-
mal origin reside between the epithelial cells in the basal lamina
and contain myofibrils. In the inactive breast, the epithelium is
sparse and consists primarily of ductal epithelium (Fig. 17-3).
In the early phase of the menstrual cycle, minor ducts are cord-
like with small lumina. With estrogen stimulation at the time of
ovulation, alveolar epithelium increases in height, duct lumina
become more prominent, and some secretions accumulate.
When the hormonal stimulation decreases, the alveolar epithe-
lium regresses.
With pregnancy, the breast undergoes proliferative and
developmental maturation. As the breast enlarges in response
to hormonal stimulation, lymphocytes, plasma cells, and eosin-
ophils accumulate within the connective tissues. The minor
ducts branch and alveoli develop. Development of the alveoli
is asymmetric, and variations in the degree of development
may occur within a single lobule (Fig. 17-4). With parturition,
enlargement of the breasts occurs via hypertrophy of alveolar
Figure 17-3. Inactive human breast (100x). The epithelium, which
is primarily ductal, is embedded in loose connective tissue. Dense
connective tissue surrounds the terminal duct lobular units (TDLU).
(Used with permission from Dr. Sindhu Menon, Consultant Histo-
pathologist and Dr. Rahul Deb, Consultant Histopathologist and
Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)
545
CHAPTER 17 THE BREAST
Figure 17-4. Active human breast: pregnancy and lactation (160x).
The alveolar epithelium becomes conspicuous during the early pro-
liferative period. The alveolus is surrounded by cellular connective
tissue. (Used with permission from Dr. Sindhu Menon, Consultant
Histopathologist and Dr. Rahul Deb, Consultant Histopathologist
and Lead Breast Pathologist, Royal Derby Hospital, Derby, UK.)
epithelium and accumulation of secretory products in the lumina
of the minor ducts. Alveolar epithelium contains abundant endo-
plasmic reticulum, large mitochondria, Golgi complexes, and
dense lysosomes. Two distinct substances are produced by the
alveolar epithelium: (a) the protein component of milk, which is
synthesized in the endoplasmic reticulum (merocrine secretion);
and (b) the lipid component of milk (apocrine secretion), which
forms as free lipid droplets in the cytoplasm. Milk released in
the first few days after parturition is called colostrum and has
low lipid content but contains considerable quantities of anti-
bodies. The lymphocytes and plasma cells that accumulate
within the connective tissues of the breast are the source of the
antibody component. With subsequent reduction in the number
of these cells, the production of colostrum decreases and lipid-
rich milk is released.
Blood Supply, Innervation, and Lymphatics. The breast
receives its principal blood supply from: (a) perforating branches
of the internal mammary artery; (b) lateral branches of the poste-
rior intercostal arteries; and (c) branches from the axillary artery,
including the highest thoracic, lateral thoracic, and pectoral
branches of the thoracoacromial artery (Fig. 17-5). The second,
1 third, and fourth anterior intercostal perforators and
branches of the internal mammary artery arborize in the
breast as the medial mammary arteries. The lateral thoracic artery
gives off branches to the serratus anterior, pectoralis major and
pectoralis minor, and subscapularis muscles. It also gives rise to
lateral mammary branches. The veins of the breast and chest wall
follow the course of the arteries, with venous drainage being
toward the axilla. The three principal groups of veins are: (a) per-
forating branches of the internal thoracic vein, (b) perforating
branches of the posterior intercostal veins, and (c) tributaries of
the axillary vein. Batson’s vertebral venous plexus, which invests
the vertebrae and extends from the base of the skull to the sacrum,
may provide a route for breast cancer metastases to the vertebrae,
skull, pelvic bones, and central nervous system. Lymph vessels
generally parallel the course of blood vessels.
546
PART II
SPECIFIC CONSIDERATIONS

Figure 17-5. Arterial supply to the breast, axilla, and chest wall.
(Reproduced with permission from Bland KI, Copeland EMI: The
Breast: Comprehensive Management of Benign and Malignant
Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)

Lateral cutaneous branches of the third through sixth inter- Figure 17-6. Lymphatic pathways of the breast. Arrows indicate
costal nerves provide sensory innervation of the breast (lateral the direction of lymph flow. (Visual Art: © 2013. The University of
mammary branches) and of the anterolateral chest wall. These Texas MD Anderson Cancer Center.)
branches exit the intercostal spaces between slips of the serratus
anterior muscle. Cutaneous branches that arise from the cervical interpectoral group (Rotter’s lymph nodes), which consists of
plexus, specifically the anterior branches of the supraclavicular one to four lymph nodes that are interposed between the pec-
nerve, supply a limited area of skin over the upper portion of toralis major and pectoralis minor muscles and receive lymph
the breast. The intercostobrachial nerve is the lateral cutane- drainage directly from the breast. The lymph fluid that passes
ous branch of the second intercostal nerve and may be visual-
ized during surgical dissection of the axilla. Resection of the
intercostobrachial nerve causes loss of sensation over the medial
aspect of the upper arm.
The boundaries for lymph drainage of the axilla are not
well demarcated, and there is considerable variation in the posi-
tion of the axillary lymph nodes. The six axillary lymph node
groups recognized by surgeons (Figs. 17-6 and 17-7) are: (a) the
axillary vein group (lateral), which consists of four to six lymph
nodes that lie medial or posterior to the vein and receive most
of the lymph drainage from the upper extremity; (b) the external
mammary group (anterior or pectoral group), which consists of
five to six lymph nodes that lie along the lower border of the
pectoralis minor muscle contiguous with the lateral thoracic
vessels and receive most of the lymph drainage from the lat-
eral aspect of the breast; (c) the scapular group (posterior or
subscapular), which consists of five to seven lymph nodes that
lie along the posterior wall of the axilla at the lateral border of
the scapula contiguous with the subscapular vessels and receive
lymph drainage principally from the lower posterior neck, the
posterior trunk, and the posterior shoulder; (d) the central group,
which consists of three or four sets of lymph nodes that are
embedded in the fat of the axilla lying immediately posterior to
the pectoralis minor muscle and receive lymph drainage both Figure 17-7. Axillary lymph node groups. Level I includes
from the axillary vein, external mammary, and scapular groups lymph nodes located lateral to the pectoralis minor muscle; level II
of lymph nodes, and directly from the breast; (e) the subcla- includes lymph nodes located deep to the pectoralis minor; and
vicular group (apical), which consists of six to twelve sets of level III includes lymph nodes located medial to the pectoralis
lymph nodes that lie posterior and superior to the upper bor- minor. The axillary vein with its major tributaries and the supracla-
der of the pectoralis minor muscle and receive lymph drainage vicular lymph node group are also illustrated. (Visual Art: © 2013.
from all of the other groups of axillary lymph nodes; and (f) the The University of Texas MD Anderson Cancer Center.)
through the interpectoral group of lymph nodes passes directly
into the central and subclavicular groups.
As indicated in Fig. 17-7, the lymph node groups are
assigned levels according to their anatomic relationship to the
pectoralis minor muscle. Lymph nodes located lateral to or below
the lower border of the pectoralis minor muscle are referred to as
level I lymph nodes, which include the axillary vein, external
mammary, and scapular groups. Lymph nodes located superficial
or deep to the pectoralis minor muscle are referred to as level II
lymph nodes, which include the central and interpectoral groups.
Lymph nodes located medial to or above the upper border of the
pectoralis minor muscle are referred to as level III lymph nodes,
which consist of the subclavicular group. The plexus of lymph
vessels in the breast arises in the interlobular connective tissue
and in the walls of the lactiferous ducts and communicates with
the subareolar plexus of lymph vessels. Efferent lymph vessels
from the breast pass around the lateral edge of the pectoralis
major muscle and pierce the clavipectoral fascia, ending in the
external mammary (anterior, pectoral) group of lymph nodes.
Some lymph vessels may travel directly to the subscapular (pos-
terior, scapular) group of lymph nodes. From the upper part of the
breast, a few lymph vessels pass directly to the subclavicular (api-
cal) group of lymph nodes. The axillary lymph nodes usually
2 receive >75% of the lymph drainage from the breast. The
rest is derived primarily from the medial aspect of the
breast, flows through the lymph vessels that accompany the per-
forating branches of the internal mammary artery, and enters the
parasternal (internal mammary) group of lymph nodes.
H
-R
F LH
H
DH
GR
ne
TR
mi
y/A
F
CR
pa
Ox
Do
PHYSIOLOGY OF THE BREAST 547
Breast Development and Function
Breast development and function are initiated by a variety of
hormonal stimuli, including estrogen, progesterone, prolactin,
oxytocin, thyroid hormone, cortisol, and growth hormone.17,18
Estrogen, progesterone, and prolactin especially have profound
3 trophic effects that are essential to normal breast develop-
ment and function. Estrogen initiates ductal development,
whereas progesterone is responsible for differentiation of epithe-
lium and for lobular development. Prolactin is the primary hor-
CHAPTER 17 THE BREAST
monal stimulus for lactogenesis in late pregnancy and the
postpartum period. It upregulates hormone receptors and stimu-
lates epithelial development. Fig. 17-8 depicts the secretion of
neurotrophic hormones from the hypothalamus, which is respon-
sible for regulation of the secretion of the hormones that affect
the breast tissues. The gonadotropins luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) regulate the release of
estrogen and progesterone from the ovaries. In turn, the release
of LH and FSH from the basophilic cells of the anterior pituitary
is regulated by the secretion of gonadotropin-releasing hormone
(GnRH) from the hypothalamus. Positive and negative feedback
effects of circulating estrogen and progesterone regulate the
secretion of LH, FSH, and GnRH. These hormones are respon-
sible for the development, function, and maintenance of breast
tissues (Fig. 17-9A). In the female neonate, circulating estrogen
and progesterone levels decrease after birth and remain low
throughout childhood because of the sensitivity of
Figure 17-8. Overview of the neuroendocrine con-
trol of breast development and function. ADH =
antidiuretic hormone; CRF = corticotropin-releasing
factor; GRF = growth hormone releasing factor;
LH-RH = luteinizing hormone–releasing hormone;
Oxy = oxytocin; TRH = thyrotropin-releasing hor-
mone. (Reproduced with permission from Bland KI,
Copeland EMI: The Breast: Comprehensive Man-
agement of Benign and Malignant Diseases, 4th ed.
Philadelphia, PA: Elsevier/Saunders; 2009.)
548
A
PART II
SPECIFIC CONSIDERATIONS
D C. Lactation. D. Senescence.
the hypothalamic-pituitary axis to negative feedback from these
hormones. With the onset of puberty, there is a decrease in the
sensitivity of the hypothalamic-pituitary axis to negative feed-
back and an increase in its sensitivity to positive feedback from
estrogen. These physiologic events initiate an increase in GnRH,
FSH, and LH secretion and ultimately an increase in estrogen
and progesterone secretion by the ovaries, leading to establish-
ment of the menstrual cycle. At the beginning of the menstrual
cycle, there is an increase in the size and density of the breasts,
which is followed by engorgement of the breast tissues and epi-
thelial proliferation. With the onset of menstruation, the breast
engorgement subsides and epithelial proliferation decreases.
Pregnancy, Lactation, and Senescence
A dramatic increase in circulating ovarian and placental estro-
gens and progestins is evident during pregnancy, which initiates
striking alterations in the form and substance of the breast (see
Fig. 17-9B).17-19 The breast enlarges as the ductal and lobular
epithelium proliferates, the areolar skin darkens, and the acces-
sory areolar glands (Montgomery’s glands) become prominent.
Figure 17-9. The breast at different physi-
ologic stages. The central column contains
three-dimensional depictions of microscopic
structures. A. Adolescence. B. Pregnancy.
In the first and second trimesters, the minor ducts branch and
develop. During the third trimester, fat droplets accumulate in
the alveolar epithelium, and colostrum fills the alveolar and duc-
tal spaces. In late pregnancy, prolactin stimulates the synthesis
of milk fats and proteins.
After delivery of the placenta, circulating progesterone
and estrogen levels decrease, permitting full expression of the
lactogenic action of prolactin. Milk production and release are
controlled by neural reflex arcs that originate in nerve endings
of the nipple-areola complex. Maintenance of lactation requires
regular stimulation of these neural reflexes, which results in
prolactin secretion and milk letdown. Oxytocin release results
from the auditory, visual, and olfactory stimuli associated with
nursing. Oxytocin initiates contraction of the myoepithelial
cells, which results in compression of alveoli and expulsion of
milk into the lactiferous sinuses. After weaning of the infant,
prolactin and oxytocin release decreases. Dormant milk causes
increased pressure within the ducts and alveoli, which results in
atrophy of the epithelium (Fig. 17-9C). With menopause, there
is a decrease in the secretion of estrogen and progesterone by
the ovaries and involution of the ducts and alveoli of the breast.
Table 17-1 549
The surrounding fibrous connective tissue increases in density,
and breast tissues are replaced by adipose tissues (Fig. 17-9D). Pathophysiologic mechanisms of gynecomastia
I. Estrogen excess states
Gynecomastia A. Gonadal origin
Gynecomastia refers to an enlarged breast in the male.20 Physi- 1. True hermaphroditism
ologic gynecomastia usually occurs during three phases of life: 2. Gonadal stromal (nongerminal) neoplasms of
the neonatal period, adolescence, and senescence. Common to the testis
each of these phases is an excess of circulating estrogens in a. Leydig cell (interstitial)
relation to circulating testosterone. Neonatal gynecomastia is b. Sertoli cell
caused by the action of placental estrogens on neonatal breast

CHAPTER 17 THE BREAST

c. Granulosa-theca cell
tissues, whereas in adolescence, there is an excess of estradiol 3. Germ cell tumors
relative to testosterone, and with senescence, the circulating a. Choriocarcinoma
testosterone level falls, which results in relative hyperestrin- b. Seminoma, teratoma
ism. In gynecomastia, the ductal structures of the male breast c. Embryonal carcinoma
enlarge, elongate, and branch with a concomitant increase in B. Nontesticular tumors
epithelium. During puberty, the condition often is unilateral 1. Adrenal cortical neoplasms
and typically occurs between ages 12 and 15 years. In contrast, 2. Lung carcinoma
senescent gynecomastia is usually bilateral. In the nonobese 3. Hepatocellular carcinoma
male, breast tissue measuring at least 2 cm in diameter must C. Endocrine disorders
be present before a diagnosis of gynecomastia may be made. D. Diseases of the liver—nonalcoholic and alcoholic
Mammography and ultrasonography are used to differentiate cirrhosis
breast tissues. Dominant masses or areas of firmness, irregular- E. Nutrition alteration states
ity, and asymmetry suggest the possibility of a breast cancer, II. Androgen deficiency states
particularly in the older male. Gynecomastia generally does not A. Senescence
predispose the male breast to cancer. However, the hypoandro- B. Hypoandrogenic states (hypogonadism)
genic state of Klinefelter’s syndrome (XXY), in which gyneco- 1. Primary testicular failure
mastia is usually evident, is associated with an increased risk of a. Klinefelter’s syndrome (XXY)
breast cancer. Gynecomastia is graded based on the degree of b. Reifenstein’s syndrome
breast enlargement, the position of the nipple with reference to c. Rosewater-Gwinup-Hamwi familial
the inframammary fold, and the degree of breast ptosis and skin gynecomastia
redundancy: Grade I—mild breast enlargement without skin d. Kallmann syndrome
redundancy; Grade IIa—moderate breast enlargement without e. Kennedy’s disease with associated
skin redundancy; Grade IIb—moderate breast enlargement with gynecomastia
skin redundancy; and Grade III—marked breast enlargement f. Eunuchoidal state (congenital anorchia)
with skin redundancy and ptosis. g. Hereditary defects of androgen biosynthesis
Table 17-1 identifies the pathophysiologic mechanisms h. Adrenocorticotropic hormone deficiency
that may initiate gynecomastia: estrogen excess states; andro- 2. Secondary testicular failure
gen deficiency states; pharmacologic causes; and idiopathic a. Trauma
causes. Estrogen excess results from an increase in the secretion b. Orchitis
of estradiol by the testicles or by nontesticular tumors, nutri- c. Cryptorchidism
tional alterations such as protein and fat deprivation, endocrine d. Irradiation
disorders (hyperthyroidism, hypothyroidism), and hepatic dis- C. Renal failure
ease (nonalcoholic and alcoholic cirrhosis). Refeeding gyne- III. Pharmacologic causes
comastia is related to the resumption of pituitary gonadotropin IV. Systemic diseases with idiopathic mechanisms
secretion after pituitary shutdown. Androgen deficiency may
initiate gynecomastia. Concurrently occurring with decreased
circulating testosterone levels is an elevated level of circulating
testosterone-binding globulin, which results in a reduction of spironolactone, antineoplastic agents, diazepam) also have been
free testosterone. This senescent gynecomastia usually occurs implicated. Drugs such as reserpine, theophylline, verapamil,
in men age 50 to 70 years. Hypoandrogenic states can be from tricyclic antidepressants, and furosemide induce gynecomastia
primary testicular failure or secondary testicular failure. Kline- through idiopathic mechanisms.
felter’s syndrome (XXY) is an example of primary testicular When gynecomastia is caused by androgen deficiency,
failure that is manifested by gynecomastia, hypergonadotropic then testosterone administration may cause regression. When it
hypogonadism, and azoospermia. Secondary testicular failure is caused by medications, then these are discontinued if possi-
may result from trauma, orchitis, and cryptorchidism. Renal ble. When endocrine defects are responsible, then these receive
failure, regardless of cause, also may initiate gynecomastia. specific therapy. As soon as gynecomastia is progressive and
Pharmacologic causes of gynecomastia include drugs does not respond to other treatments, surgical therapy is con-
with estrogenic activity (digitalis, estrogens, anabolic steroids, sidered. Techniques include local excision, liposuction or sub-
marijuana) or drugs that enhance estrogen synthesis (human cutaneous mastectomy. Attempts to reverse gynecomastia with
chorionic gonadotropin). Drugs that inhibit the action or syn- danazol have been successful, but the androgenic side effects of
thesis of testosterone (cimetidine, ketoconazole, phenytoin, the drug are considerable.
550 INFECTIOUS AND INFLAMMATORY DISORDERS
OF THE BREAST
Infections in the postpartum period remain proportionately the
most common time for breast infections to occur. Infections of
the breast unrelated to lactation are proportionately less com-
mon, however, are still a relatively common presentation to
breast specialists. The latter are classified as intrinsic (second-
ary to abnormalities in the breast) or extrinsic (secondary to an
infection in an adjacent structure, e.g., skin, thoracic cavity) the
most common being probably periductal mastitis and infected
sebaceous cysts, respectively.
PART II
Bacterial Infection
Staphylococcus aureus and Streptococcus species are the
organisms most frequently recovered from nipple discharge
from an infected breast.17 Typically breast abscesses are seen
SPECIFIC CONSIDERATIONS
in staphylococcal infections and present with point tenderness,
erythema, and hyperthermia. When these abscesses are related
to lactation they usually occur within the first few weeks of
breastfeeding. If there is progression of a staphylococcal infec-
tion, this may result in subcutaneous, subareolar, interlobular
(periductal), and retromammary abscesses (unicentric or multi-
centric). Previously almost all breast abscesses were treated by
operative incision and drainage, but now the initial approach is
antibiotics and repeated aspiration of the abscess, usually ultra-
sound-guided aspiration.21 Operative drainage is now reserved
for those cases that do not resolve with repeated aspiration and
antibiotic therapy or cases in which there is some other indica-
tion for incision and drainage (e.g., thinning or necrosis of the
overlying skin). Preoperative ultrasonography is effective in
delineating the required extent of the drainage procedure. While
staphylococcal infections tend to be more localized and may
be situated deep in the breast tissues, streptococcal infections
usually present with diffuse superficial involvement. They are
treated with local wound care, including application of warm
compresses, and the administration of IV antibiotics (penicillins
or cephalosporins). Breast infections may be chronic, possibly
with recurrent abscess formation. In this situation, cultures are
performed to identify acid-fast bacilli, anaerobic and aerobic
bacteria, and fungi. Uncommon organisms may be encountered,
and long-term antibiotic therapy may be required.
Biopsy of the abscess cavity wall should be considered at
the time of incision and drainage to rule out underlying breast
cancer in patients where antibiotics and drainage have been
ineffective.
Nowadays hospital-acquired puerperal infections of the
breast are much less common, but nursing women who pres-
ent with milk stasis or noninfectious inflammation may still
develop this problem. Epidemic puerperal mastitis is initiated
by highly virulent strains of methicillin-resistant S aureus that
are transmitted via the suckling neonate and may result in sub-
stantial morbidity and occasional mortality. Purulent fluid may
be expressed from the nipple. In this circumstance, breastfeed-
ing is stopped, antibiotics are started, and surgical therapy is
initiated. Nonepidemic (sporadic) puerperal mastitis refers to
involvement of the interlobular connective tissue of the breast
by an infectious process. The patient develops nipple fissuring
and milk stasis, which initiates a retrograde bacterial infection.
Emptying of the breast using breast suction pumps shortens the
duration of symptoms and reduces the incidence of recurrences.
The addition of antibiotic therapy results in a satisfactory out-
come in >95% of cases.
Zuska’s disease, also called recurrent periductal
mastitis, is a condition of recurrent retroareolar infections and
abscesses.22,23 Smoking has been implicated as a risk factor for
this condition.24,25 This syndrome is managed symptomatically
by antibiotics coupled with incision and drainage as necessary.
Attempts to obtain durable long-term control by wide debride-
ment of chronically infected tissue and/or terminal duct resec-
tion have been reported and can be curative, but they can also
be frustrated by postoperative infections.26
Mycotic Infections
Fungal infections of the breast are rare and usually involve blas-
tomycosis or sporotrichosis.27 Intraoral fungi that are inoculated
into the breast tissue by the suckling infant initiate these infec-
tions, which present as mammary abscesses in close proxim-
ity to the nipple-areola complex. Pus mixed with blood may be
expressed from sinus tracts. Antifungal agents can be adminis-
tered for the treatment of systemic (noncutaneous) infections.
This therapy generally eliminates the necessity of surgical inter-
vention, but occasionally drainage of an abscess, or even partial
mastectomy, may be necessary to eradicate a persistent fungal
infection. Candida albicans affecting the skin of the breast
presents as erythematous, scaly lesions of the inframammary
or axillary folds. Scrapings from the lesions demonstrate fungal
elements (filaments and binding cells). Therapy involves the
removal of predisposing factors such as maceration and the topi-
cal application of nystatin.
Hidradenitis Suppurativa
Hidradenitis suppurativa of the nipple-areola complex or axilla
is a chronic inflammatory condition that originates within the
accessory areolar glands of Montgomery or within the axillary
sebaceous glands.27 Women with chronic acne are predisposed
to developing hidradenitis. When located in and about the
nipple-areola complex, this disease may mimic other chronic
inflammatory states, Paget’s disease of the nipple, or invasive
breast cancer. Involvement of the axillary skin is often multifo-
cal and contiguous. Antibiotic therapy with incision and drain-
age of fluctuant areas is appropriate treatment. Excision of the
involved areas may be required. Large areas of skin loss may
necessitate coverage with advancement flaps or split-thickness
skin grafts.
Mondor’s Disease
Mondor’s disease is a variant of thrombophlebitis that involves
the superficial veins of the anterior chest wall and breast.28 In
1939, Mondor described the condition as “string phlebitis,” a
thrombosed vein presenting as a tender, cord-like structure.29
Frequently involved veins include the lateral thoracic vein, the
thoracoepigastric vein, and, less commonly, the superficial epi-
gastric vein. Typically, a woman presents with acute pain in
the lateral aspect of the breast or the anterior chest wall. A ten-
der, firm cord is found to follow the distribution of one of the
major superficial veins. Rarely, the presentation is bilateral, and
most women have no evidence of thrombophlebitis in other ana-
tomic sites. This benign, self-limited disorder is not indicative
of a cancer. When the diagnosis is uncertain, or when a mass is
present near the tender cord, biopsy is indicated. Therapy for
Mondor’s disease includes the liberal use of anti-inflammatory
medications and application of warm compresses along the
symptomatic vein. The process usually resolves within 4 to
6 weeks. When symptoms persist or are refractory to therapy,
excision of the involved vein segment may be considered.
COMMON BENIGN DISORDERS AND 551
DISEASES OF THE BREAST
Benign breast disorders and diseases encompass a wide range
of clinical and pathologic entities. Surgeons require an in-depth
understanding of benign breast disorders and diseases so that clear
explanations may be given to affected women, appropriate treat-
ment is instituted, and unnecessary long-term follow up is avoided.

Aberrations of Normal Development and

Involution

CHAPTER 17 THE BREAST

The basic principles underlying the aberrations of normal devel-
opment and involution (ANDI) classification of benign breast
conditions are the following: (a) benign breast disorders and
diseases are related to the normal processes of reproductive life
and to involution; (b) there is a spectrum of breast conditions
that ranges from normal to disorder to disease; and (c) the ANDI
classification encompasses all aspects of the breast condition,
4 including pathogenesis and the degree of abnormality.30
The horizontal component of Table 17-2 defines ANDI
along a spectrum from normal, to mild abnormality (disorder),
to severe abnormality (disease). The vertical component indi-
cates the period during which the condition develops.
Early Reproductive Years. Fibroadenomas are seen and pres-
ent symptomatically predominantly in younger women age 15
to 25 years (Fig. 17-10).31 Fibroadenomas usually grow to 1 or
2 cm in diameter and then are stable but may grow to a larger
size. Small fibroadenomas (≤1 cm in size) are considered nor-
mal, whereas larger fibroadenomas (≤3 cm) are disorders, and
giant fibroadenomas (>3 cm) are disease. Similarly, multiple
fibroadenomas (more than five lesions in one breast) are very
uncommon and are considered disease. It is noted that with
the introduction of mammographic screening, asymptomatic
Figure 17-10. Fibroadenoma (40x). These benign tumors are typi-
cally well circumscribed and are comprised of both stromal and
glandular elements. (Used with permission from Dr. Sindhu Menon,
Consultant Histopathologist and Dr. Rahul Deb, Consultant
Histopathologist and Lead Breast Pathologist, Royal Derby Hospital,
Derby, UK.)
fibroadenomas are sometimes found in an older screened popu-
lation. The precise etiology of adolescent breast hypertrophy is
unknown. A spectrum of changes from limited to massive stro-
mal hyperplasia (gigantomastia) is seen. Nipple inversion is a
disorder of development of the major ducts, which prevents nor-
mal protrusion of the nipple. Mammary duct fistulas arise when
nipple inversion predisposes to major duct obstruction, leading
to recurrent subareolar abscess and mammary duct fistula.

Table 17-2
ANDI classification of benign breast disorders
  NORMAL DISORDER DISEASE
Early reproductive years Lobular development Fibroadenoma Giant fibroadenoma
(age 15–25 y)  Stromal development Adolescent hypertrophy Gigantomastia
  Nipple eversion Nipple inversion Subareolar abscess
      Mammary duct fistula
Later reproductive years Cyclical changes of Cyclical mastalgia Incapacitating mastalgia
(age 25–40 y) menstruation
    Nodularity  
  Epithelial hyperplasia of Bloody nipple discharge  
pregnancy
Involution (age 35–55 y) Lobular involution Macrocysts —
    Sclerosing lesions  
  Duct involution    
  Dilatation Duct ectasia Periductal mastitis
  Sclerosis Nipple retraction —
  Epithelial turnover Epithelial hyperplasia Epithelial hyperplasia with atypia
ANDI = aberrations of normal development and involution.
Reproduced with permission from Mansel RE, Webster D, Sweetland H: Hughes, Mansel & Webster’s Benign Disorders and Diseases of the Breast, 3rd ed.
London: Elsevier/Saunders; 2009.
552 Later Reproductive Years. Cyclical mastalgia and nodular- Table 17-3
ity usually are associated with premenstrual enlargement of the
breast and are regarded as normal. Cyclical pronounced mastal- Cancer risk associated with benign breast disorders and
gia and severe painful nodularity are viewed differently than are in situ carcinoma of the breast
physiologic discomfort and lumpiness. Painful nodularity that
persists for >1 week of the menstrual cycle is considered a disor- ABNORMALITY RELATIVE RISK
der. In epithelial hyperplasia of pregnancy, papillary projections Nonproliferative lesions of the breast No increased risk
sometimes give rise to bilateral bloody nipple discharge. Sclerosing adenosis No increased risk
Involution. Involution of lobular epithelium is dependent on Intraductal papilloma No increased risk
the specialized stroma around it. However, an integrated invo-
Florid hyperplasia 1.5 to 2-fold
lution of breast stroma and epithelium is not always seen, and
PART II

disorders of the process are common. When the stroma invo- Atypical lobular hyperplasia 4-fold
lutes too quickly, alveoli remain and form microcysts, which are Atypical ductal hyperplasia 4-fold
precursors of macrocysts. The macrocysts are common, often Ductal involvement by cells of 7-fold
subclinical, and do not require specific treatment. Sclerosing atypical ductal hyperplasia
adenosis is considered a disorder of both the proliferative and
Lobular carcinoma in situ 10-fold
SPECIFIC CONSIDERATIONS

the involutional phases of the breast cycle. Duct ectasia (dilated

ducts) and periductal mastitis are other important components Ductal carcinoma in situ 10-fold
of the ANDI classification. Periductal fibrosis is a sequela of Data from Dupont WD, Page DL. Risk factors for breast cancer in
periductal mastitis and may result in nipple retraction. About women with proliferative breast disease, N Engl J Med. 1985 Jan 17;
60% of women ≥70 years of age exhibit some degree of epi- 312(3):146-151.
thelial hyperplasia (Fig. 17-11). Atypical proliferative diseases

include ductal and lobular hyperplasia, both of which display

some features of carcinoma in situ. Women with atypical ductal
or lobular hyperplasia have a fourfold increase in breast cancer
risk (Table 17-3).
Pathology of Nonproliferative Disorders
Of paramount importance for the optimal management of
benign breast disorders and diseases is the histologic differentia-
tion of benign, atypical, and malignant changes.32,33 Determin-
ing the clinical significance of these changes is a problem that
is compounded by inconsistent nomenclature. The classifica-
tion system originally developed by Page separates the various
types of benign breast disorders and diseases into three clini-
cally relevant groups: nonproliferative disorders, proliferative
disorders without atypia, and proliferative disorders with atypia
(Table 17-4). Nonproliferative disorders of the breast account
A
for 70% of benign breast conditions and carry no increased risk

Table 17-4
Classification of benign breast disorders
Nonproliferative disorders of the breast
Cysts and apocrine metaplasia
Duct ectasia
Mild ductal epithelial hyperplasia
Calcifications
Fibroadenoma and related lesions
Proliferative breast disorders without atypia
Sclerosing adenosis
Radial and complex sclerosing lesions
Ductal epithelial hyperplasia
B Intraductal papillomas
Atypical proliferative lesions
Figure 17-11. A. Ductal epithelial hyperplasia. The irregular intra-
Atypical lobular hyperplasia
cellular spaces and variable cell nuclei distinguish this process from
carcinoma in situ. B. Lobular hyperplasia. The presence of alveo- Atypical ductal hyperplasia
lar lumina and incomplete distention distinguish this process from Data from Godfrey SE: Is fibrocystic disease of the breast precancerous?
carcinoma in situ. (Used with permission from Dr. R.L. Hackett.) Arch Pathol Lab Med. 1986 Nov;110(11):991.
for the development of breast cancer. This category includes
cysts, duct ectasia, periductal mastitis, calcifications, fibroad-
enomas, and related disorders.
Breast macrocysts are an involutional disorder, have a
high frequency of occurrence, and are often multiple. Duct ecta-
sia is a clinical syndrome characterized by dilated subareolar
ducts that are palpable and often associated with thick nipple
discharge. Haagensen regarded duct ectasia as a primary event
that led to stagnation of secretions, epithelial ulceration, and
leakage of duct secretions (containing chemically irritating fatty
acids) into periductal tissue.34 This sequence was thought to pro-
duce a local inflammatory process with periductal fibrosis and
subsequent nipple retraction. An alternative theory considers
periductal mastitis to be the primary process, which leads to
weakening of the ducts and secondary dilatation. It is possible
that both processes occur and together explain the wide spec-
trum of problems seen, which include nipple discharge, nipple
retraction, inflammatory masses, and abscesses.
Calcium deposits are frequently encountered in the breast.
Most are benign and are caused by cellular secretions and
debris or by trauma and inflammation. Calcifications that are
associated with cancer include microcalcifications, which vary
in shape and density and are <0.5 mm in size, and fine, linear
calcifications, which may show branching. Fibroadenomas have
abundant stroma with histologically normal cellular elements.
They show hormonal dependence similar to that of normal
breast lobules in that they lactate during pregnancy and invo-
lute in the postmenopausal period. Adenomas of the breast are
well circumscribed and are composed of benign epithelium with
sparse stroma, which is the histologic feature that differentiates
them from fibroadenomas. They may be divided into tubular
adenomas and lactating adenomas. Tubular adenomas are seen
in young nonpregnant women, whereas lactating adenomas are
seen during pregnancy or during the postpartum period. Ham-
artomas are discrete breast tumors that are usually 2 to 4 cm in
diameter, firm, and sharply circumscribed. Adenolipomas con-
sist of sharply circumscribed nodules of fatty tissue that contain
normal breast lobules and ducts.
Fibrocystic Disease. The term fibrocystic disease is nonspe-
cific. Too frequently, it is used as a diagnostic term to describe
symptoms, to rationalize the need for breast biopsy, and to
explain biopsy results. Synonyms include fibrocystic changes,
cystic mastopathy, chronic cystic disease, chronic cystic mas-
titis, Schimmelbusch’s disease, mazoplasia, Cooper’s disease,
Reclus’ disease, and fibroadenomatosis. Fibrocystic disease
refers to a spectrum of histopathologic changes that are best
diagnosed and treated specifically.
Pathology of Proliferative Disorders
Without Atypia
Proliferative breast disorders without atypia include sclerosing
adenosis, radial scars, complex sclerosing lesions, ductal epithe-
lial hyperplasia, and intraductal papillomas.32,33 Sclerosing ade-
nosis is prevalent during the childbearing and perimenopausal
years and has no malignant potential. Histologic changes are
both proliferative (ductal proliferation) and involutional (stro-
mal fibrosis, epithelial regression). Sclerosing adenosis is char-
acterized by distorted breast lobules and usually occurs in the
context of multiple microcysts, but occasionally presents as a
palpable mass. Benign calcifications are often associated with
this disorder. Sclerosing adenosis can be managed by observa-
tion as long as the imaging features and pathologic findings are
concordant. Central sclerosis and various degrees of epithelial 553
proliferation, apocrine metaplasia, and papilloma formation
characterize radial scars and complex sclerosing lesions of the
breast. Lesions up to 1 cm in diameter are called radial scars,
whereas larger lesions are called complex sclerosing lesions.
Radial scars originate at sites of terminal duct branching where
the characteristic histologic changes radiate from a central area
of fibrosis. All of the histologic features of a radial scar are seen
in the larger complex sclerosing lesions, but there is a greater
disturbance of structure with papilloma formation, apocrine
CHAPTER 17 THE BREAST
metaplasia, and occasionally sclerosing adenosis. Distinguish-
ing between a radial scar and invasive breast carcinoma can be
challenging based on core-needle biopsy sampling. Often the
imaging features of a radial scar (which can be quite similar to
an invasive cancer) will dictate the need for either a vacuum-
assisted biopsy or surgical excision in order to exclude the pos-
sibility of carcinoma.
Mild ductal hyperplasia is characterized by the presence of
three or four cell layers above the basement membrane. Moder-
ate ductal hyperplasia is characterized by the presence of five
or more cell layers above the basement membrane. Florid duc-
tal epithelial hyperplasia occupies at least 70% of a minor duct
lumen. It is found in >20% of breast tissue specimens, is either
solid or papillary, and is associated with an increased cancer
risk (see Table 17-3). Intraductal papillomas arise in the major
ducts, usually in premenopausal women. They generally are
<0.5 cm in diameter but may be as large as 5 cm. A common
presenting symptom is nipple discharge, which may be serous
or bloody. Grossly, intraductal papillomas are pinkish tan, fri-
able, and usually attached to the wall of the involved duct by a
stalk. They rarely undergo malignant transformation, and their
presence does not increase a woman’s risk of developing breast
cancer (unless accompanied by atypia). However, multiple
intraductal papillomas, which occur in younger women and are
less frequently associated with nipple discharge, are susceptible
to malignant transformation.
Pathology of Atypical Proliferative Diseases
The atypical proliferative diseases have some of the features of
carcinoma in situ but either lack a major defining feature of car-
cinoma in situ or have the features in less than fully developed
form.34 Atypical ductal hyperplasia (ADH) appears similar to
low grade ductal carcinoma in situ (DCIS) histologically and is
composed of monotonous round, cuboidal, or polygonal cells
enclosed by basement membrane with rare mitoses. A lesion
will be considered to be ADH if it is up to 2 or 3 mm in size but
would be called DCIS if it is larger than 3 mm. The diagnosis
can be difficult to establish with core-needle biopsy specimen
alone and many cases will require excisional biopsy specimen
for classification. Individuals with a diagnosis of ADH are at
increased risk for development of breast cancer and should be
counseled appropriately regarding risk reduction strategies.
In 1978, Haagensen et al described lobular neoplasia, a
spectrum of disorders ranging from atypical lobular hyperplasia
to lobular carcinoma in situ (LCIS).35 Atypical lobular hyper-
plasia (ALH) results in minimal distention of lobular units with
cells that are similar to those seen in LCIS. The diagnosis of
LCIS is made when small monomorphic cells that distend the
terminal ductal lobular unit are noted. In cases of LCIS, the
acini are full and distended while the overall lobular architec-
ture is maintained (Fig. 17-12). Classic LCIS is not associated
with a specific mammographic or palpable abnormality but is
554
PART II
SPECIFIC CONSIDERATIONS
Figure 17-12. Lobular carcinoma in situ (100x). There are small
monomorphic cells that distend the terminal duct lobular unit, with-
out necrosis or mitoses. (Used with permission from Dr. Sindhu
Menon, Consultant Histopathologist and Dr. Rahul Deb, Consul-
tant Histopathologist and Lead Breast Pathologist, Royal Derby
Hospital, Derby, UK.)
an incidental finding noted on breast biopsy. There is a variant
of LCIS that has been termed pleomorphic LCIS. In the case of
pleomorphic LCIS, there can be calcifications or other suspi-
cious mammographic changes that dictate the need for biopsy.
Classic LCIS is not treated with excision as the patient is at
risk for developing invasive breast cancer in either breast and
therefore the patient is counseled regarding appropriate risk
reduction strategies. Pleomorphic LCIS can be difficult to dis-
tinguish from high-grade DCIS and there are some proponents
who have suggested that patients with pleomorphic LCIS be
managed similar to those with DCIS with attention to margins
and consideration for radiation therapy in the setting of breast
conserving treatment. The use of immunohistochemical stain-
ing for E-cadherin can help to discriminate between LCIS and
DCIS. In lobular neoplasias, such as ALH and LCIS, there is a
lack of E-cadherin expression, whereas the majority of ductal
lesions will demonstrate E-cadherin reactivity.
Treatment of Selected Benign Breast Disorders
and Diseases
Cysts. Because needle biopsy of breast masses may produce
artifacts that make mammography assessment more difficult,
many multidisciplinary teams prefer to image breast masses
before performing either fine-needle aspiration or core-needle
biopsy.36,37 In practice, however, the first investigation of pal-
pable breast masses may be a needle biopsy, which allows for
the early diagnosis of cysts. A 21-gauge needle attached to a
10-mL syringe is placed directly into the mass, which is fixed
by fingers of the nondominant hand. The volume of a typical
cyst is 5 to 10 mL, but it may be 75 mL or more. If the fluid
that is aspirated is not bloodstained, then the cyst is aspirated
to dryness, the needle is removed, and the fluid is discarded
because cytologic examination of such fluid is not cost effec-
tive. After aspiration, the breast is carefully palpated to exclude
a residual mass. In most cases, however, imaging has been per-
formed prior to a needle being introduced into the breast, and
indeed the majority of cysts are now aspirated under ultrasound
guidance. If a mass was noted on initial ultrasound or there is a
residual mass post aspiration, then a tissue specimen is obtained,
usually by core biopsy. When cystic fluid is bloodstained, fluid
can be sent for cytologic examination. A simple cyst is rarely of
concern, but a complex cyst may be the result of an underlying
malignancy. A pneumocystogram can be obtained by injecting
air into the cyst and then obtaining a repeat mammogram. When
this technique is used, the wall of the cyst cavity can be more
carefully assessed for any irregularities.
Fibroadenomas. Most fibroadenomas are self-limiting and
many go undiagnosed, so a more conservative approach is
reasonable. Careful ultrasound examination with core-needle
biopsy will provide for an accurate diagnosis. Ultrasonogra-
phy may reveal specific features that are pathognomonic for
fibroadenoma, and in a young woman (e.g., under 25 years)
where the risk of breast cancer is already very low a core-
needle biopsy may not be necessary. In patients where biopsy
is performed, the patient is counseled concerning the ultra-
sound and biopsy results, and surgical excision of the fibroad-
enoma may be avoided. Cryoablation and ultrasound-guided
vacuum-assisted biopsy are approved treatments for fibroad-
enomas of the breast, especially lesions <3 cm. Larger lesions
are often still best treated by excision. With short-term follow-
up, a significant percentage of fibroadenomas will decrease
in size and will no longer be palpable.38 However, many will
remain palpable, especially those larger than 2 cm. 39 There-
fore, women should be counseled that the options for treat-
ment include surgical removal, cryoablation, vacuum assisted
biopsy, or observation.
Sclerosing Disorders. The clinical significance of scleros-
ing adenosis lies in its imitation of cancer. On physical exami-
nation, it may be confused with cancer, by mammography,
and at gross pathologic examination. Excisional biopsy and
histologic examination are frequently necessary to exclude the
diagnosis of cancer. The diagnostic work-up for radial scars
and complex sclerosing lesions frequently involves stereo-
tactic biopsy. It usually is not possible to differentiate these
lesions with certainty from cancer by mammographic features,
so a larger tissue biopsy is recommended either by way of
vacuum-assisted biopsy or an open surgical excisional biopsy.
The mammographic appearance of a radial scar or sclerosing
adenosis (mass density with spiculated margins) will usually
lead to an assessment that the results of a core-needle biopsy
specimen showing benign disease are discordant with the
radiographic findings.
Periductal Mastitis. Painful and tender masses behind the
nipple-areola complex are aspirated with a 21-gauge needle
attached to a 10-mL syringe. Any fluid obtained is submitted
for culture using a transport medium appropriate for the detec-
tion of anaerobic organisms. In the absence of pus, women are
started on a combination of antibiotics to cover polymicrobial
infections while awaiting the results of culture. Antibiotics are
then continued based on sensitivity tests. Many cases respond
satisfactorily to antibiotics alone, but when considerable puru-
lent material is present, repeated ultrasound guided aspiration
is performed, and ultimately in a proportion of cases surgical
treatment is required. Unlike puerperal abscesses, a subareo-
lar abscess is usually unilocular and often is associated with
a single duct system. Ultrasound will accurately delineate its
extent. In those cases that come to surgery, the surgeon may
either undertake simple drainage with a view toward formal
Table 17-5
Treatment of recurrent subareolar sepsis
SUITABLE FOR SUITABLE FOR TOTAL
FISTULECTOMY DUCT EXCISION
Small abscess localized to Large abscess affecting >50%
one segment of the areolar circumference
Recurrence involving the Recurrence involving a
same segment different segment
Mild or no nipple inversion Marked nipple inversion
Patient unconcerned about Patient requests correction of
nipple inversion nipple inversion
Younger patient Older patient
No discharge from other Purulent discharge from other
ducts ducts
No prior fistulectomy Recurrence after fistulectomy
Modified with permission from Mansel RE, Webster DJT: Benign
Disorders and Diseases of the Breast: Concepts and Clinical
Management, 2nd ed. London: Elsevier/Saunders; 2000.
surgery, should the problem recur, or proceed with definitive
surgery. In a woman of childbearing age, simple drainage
is preferred, but if there is an anaerobic infection, recurrent
infection frequently develops. Recurrent abscess with fistula
is a difficult problem. Treatment of periductal fistula was ini-
tially recommended to be opening up of the fistulous track
and allowing it to granulate.40 This approach may still be used,
especially if the fistula is recurrent after previous attempts at
fistulectomy. However, nowadays the preferred initial surgical
treatment is by fistulectomy and primary closure with anti-
biotic coverage.41 Excision of all the major ducts is an alter-
native option depending on the circumstances (Table 17-5).
When a localized periareolar abscess recurs at the previous
site and a fistula is present, the preferred operation is fistulec-
tomy, which has minimal complications and a high degree of
success. However, when subareolar sepsis is diffused rather
than localized to one segment or when more than one fistula is
present, total duct excision is the most expeditious approach.
The first circumstance is seen in young women with squamous
metaplasia of a single duct, whereas the latter circumstance is
seen in older women with multiple ectatic ducts. Age is not
always a reliable guide, however, and fistula excision is the
preferred initial procedure for localized sepsis irrespective of
age. Antibiotic therapy is useful for recurrent infection after
fistula excision, and a 2- to 4-week course is recommended
before total duct excision.
Nipple Inversion. More women request correction of con-
genital nipple inversion than request correction for the nipple
inversion that occurs secondary to duct ectasia. Although the
results are usually satisfactory, women seeking correction for
cosmetic reasons should always be made aware of the surgi-
cal complications of altered nipple sensation, nipple necrosis,
and postoperative fibrosis with nipple retraction. Because nipple
inversion is a result of shortening of the subareolar ducts, a com-
plete division of these ducts is necessary for permanent correc-
tion of the disorder.
RISK FACTORS FOR BREAST CANCER 555
Hormonal and Nonhormonal Risk Factors
Increased exposure to estrogen is associated with an increased
risk for developing breast cancer, whereas reducing exposure
is thought to be protective.42-48 Correspondingly, factors that
increase the number of menstrual cycles, such as early men-
arche, nulliparity, and late menopause, are associated with
increased risk. Moderate levels of exercise and a longer lacta-
tion period, factors that decrease the total number of menstrual
cycles, are protective. The terminal differentiation of breast epi-
CHAPTER 17 THE BREAST
thelium associated with a full-term pregnancy is also protective,
so older age at first live birth is associated with an increased risk
of breast cancer. Finally, there is an association between obesity
and increased breast cancer risk. Because the major source of
estrogen in postmenopausal women is the conversion of andro-
stenedione to estrone by adipose tissue, obesity is associated
with a long-term increase in estrogen exposure.
Nonhormonal risk factors include radiation exposure.
Young women who receive mantle radiation therapy for Hodg-
kin’s lymphoma have a breast cancer risk that is 75 times greater
than that of age-matched control subjects. Survivors of the
atomic bomb blasts in Japan during World War II have a very
high incidence of breast cancer, likely because of somatic muta-
tions induced by the radiation exposure. In both circumstances,
radiation exposure during adolescence, a period of active breast
development, magnifies the deleterious effect. Studies also sug-
gest that the risk of breast cancer increases as the amount of
alcohol a woman consumes increases.49 Alcohol consumption
is known to increase serum levels of estradiol. Finally, evidence
suggests that long-term consumption of foods with a high fat
content contributes to an increased risk of breast cancer by
increasing serum estrogen levels.
Risk Assessment Models
The average lifetime risk of breast cancer for newborn U.S.
women is 12%.50,51 The longer a woman lives without cancer, the
lower her risk of developing breast cancer. Thus, a woman age
50 years has an 11% lifetime risk of developing breast cancer,
and a woman age 70 years has a 7% lifetime risk of developing
breast cancer. Because risk factors for breast cancer interact,
evaluating the risk conferred by combinations of risk factors is
difficult. There are several risk assessment models available to
predict the risk of breast cancer. From the Breast Cancer Detec-
tion Demonstration Project, a mammography screening program
conducted in the 1970s, Gail et al developed the model most
frequently used in the United States, which incorporates age, age
at menarche, age at first live birth, the number of breast biopsy
specimens, any history of atypical hyperplasia, and number of
first-degree relatives with breast cancer.52 It predicts the cumula-
tive risk of breast cancer according to decade of life. To calculate
breast cancer risk using the Gail model, a woman’s risk factors
are translated into an overall risk score by multiplying her rela-
tive risks from several categories (Table 17-6). This risk
5 score is then compared to an adjusted population risk of
breast cancer to determine a woman’s individual or absolute risk.
The output is a 5-year risk and a lifetime risk of developing
breast cancer. A software program incorporating the Gail model
is available from the National Cancer Institute at http://bcra.nci.
nih.gov/brc. This model was recently modified to more accu-
rately assess risk in African American women.52,53 There have
also been modifications that project individualized absolute
556 Table 17-6
breast cancer and their age at diagnosis. Risk factors that are
less consistently associated with breast cancer (diet, use of oral
Relative risk estimates for the Gail model contraceptives, lactation) or are rare in the general population
(radiation exposure) are not included in either the Gail or Claus
VARIABLE RELATIVE RISK risk assessment model. Other models have been proposed that
Age at menarche (years) account for mammographic breast density in assessing breast
≥14 1.00 cancer risk.54,56
12–13 1.10 Neither the Gail model nor the Claus model accounts for
<12 1.21 the risk associated with mutations in the breast cancer suscepti-
Number of biopsy specimens/history of bility genes BRCA1 and BRCA2 (described in detail in the fol-
benign breast disease, age <50 y lowing section). The BRCAPRO model is a Mendelian model
that calculates the probability that an individual is a carrier of a
PART II

0 1.00
1 1.70
≥2 2.88
Number of biopsy specimens/history of
benign breast disease, age ≥50 y
0 1.02
SPECIFIC CONSIDERATIONS
mutation in one of the breast cancer susceptibility genes based
on their family history of breast and ovarian cancer.57 The prob-
ability that an individual will develop breast or ovarian cancer
is derived from this mutation probability based on age-specific
incidence curves for both mutation carriers and noncarriers.58

1 1.27 Use of the BRCAPRO model in the clinic is challenging since it

≥2 1.62
Age at first live birth (years)
<20 y
Number of first-degree relatives with
history of breast cancer
0 1.00
1 2.61
≥2 6.80
20–24 y
Number of first-degree relatives with
history of breast cancer
0 1.24
1 2.68
≥2 5.78
25–29 y
Number of first-degree relatives with
history of breast cancer
0 1.55
1 2.76
≥2 4.91
≥30 y
Number of first-degree relatives with
history of breast cancer
0 1.93
1 2.83
≥2 4.17
Reproduced with permission from Armstrong K, Eisen A, Weber B:
Assessing the risk of breast cancer, N Engl J Med. 2000
Feb 24;342(8):564-571.
invasive breast cancer risk for Asian and Pacific Island American
women. The Gail model is the most widely used model in the
United States. Gail and colleagues have also described a revised
model that includes body weight and mammographic density but
excludes age at menarche.54
Claus et al, using data from the Cancer and Steroid Hor-
mone Study, a case-control study of breast cancer, developed
the other frequently used risk assessment model, which is based
on assumptions about the prevalence of high-penetrance breast
cancer susceptibility genes.55 Compared with the Gail model, the
Claus model incorporates more information about family his-
tory but excludes other risk factors. The Claus model provides
individual estimates of breast cancer risk according to decade of
life based on presence of first- and second-degree relatives with
requires input of all family history information regarding breast
and ovarian cancer. The Tyrer-Cuzick model attempts to utilize
both family history information and individual risk information.
It uses the family history to calculate the probability that an
individual carries a mutation in one of the breast cancer suscep-
tibility genes, and then the risk is adjusted based on personal
risk factors, including age at menarche, parity, age at first live
birth, age at menopause, history of atypical hyperplasia or LCIS,
height, and body mass index.59 Once a risk model has been uti-
lized to assess breast cancer risk, this must be communicated
to the individual and put into context with competing risk and
medical comorbidities. This information can then be used to
discuss options that are available to the individual for manag-
ing risk.
Risk Management
Several important medical decisions may be affected by a wom-
an’s underlying risk of developing breast cancer.60-68 These deci-
sions include when to use postmenopausal hormone replacement
therapy, at what age to begin mammography screening or incor-
porate magnetic resonance imaging (MRI) screening, when to
use tamoxifen to prevent breast cancer, and when to perform
prophylactic mastectomy to prevent breast cancer. Postmeno-
pausal hormone replacement therapy was widely prescribed in
the 1980s and 1990s because of its effectiveness in controlling
the symptoms of estrogen deficiency, namely vasomotor symp-
toms such as hot flashes, night sweats and their associated sleep
deprivation, osteoporosis, and cognitive changes. Furthermore,
these hormone supplements were thought to reduce coronary
artery disease as well. Use of combined estrogen and progester-
one became standard for women who had not undergone hyster-
ectomy because unopposed estrogen increases the risk of uterine
cancer. Concerns of prolonging a woman’s lifetime exposure to
estrogen, coupled with conflicting data regarding the impact of
these hormones on cardiovascular health, motivated the imple-
mentation of large-scale phase 3 clinical trials to definitively
evaluate the risks vs. benefits of postmenopausal hormone
replacement therapy. The Women’s Health Initiative (WHI)
was therefore designed by the National Institutes of Health as
a series of clinical trials to study the effects of diet, nutritional
supplements, and hormones on the risk of cancer, cardiovascular
disease, and bone health in postmenopausal women. Findings
from primary studies of postmenopausal hormone replacement
therapy were released in 2002, demonstrating conclusively that
breast cancer risk is threefold to fourfold higher after >4 years
of use and there is no significant reduction in coronary artery or
cerebrovascular risks. The Collaborative Group on Hormonal
Factors in Breast Cancer combined and reanalyzed data from a
number of studies totaling 52,705 women with breast cancer and
108,411 women without breast cancer. They found an increased
risk of breast cancer with every use of estrogen replacement
therapy. They also reported increased risk among current users
but not past users and risk increased with increasing duration
of use of hormone replacement therapy.69 Cheblowski et al
also reported from the WHI study that estrogen + progesterone
increased the incidence of breast cancer.70 This was con-
firmed by the Million Women study, which also showed that
the increased risk was substantially greater for the combined
estrogen + progesterone replacement therapy than other types
of hormone replacement therapy.71
Breast Cancer Screening. Routine use of screening mam-
mography in women ≥50 years of age has been reported to
reduce mortality from breast cancer by 25%.72 This reduc-
6 tion comes at an acceptable economic cost. More recently,
there has been debate over the potential harms associated with
breast screening.73 Controversy over the age to initiate screening
mammography is evident in the current recommendations. The
U.S. Preventive Services Task Force (USPSTF), the American
Cancer Society (ACS), and the National Comprehensive Cancer
Network (NCCN) are three organizations with differing recom-
mendations for screening mammography in average risk
women. The guidelines, however, similarly define high-risk
women as those with personal history of breast cancer, history
of chest radiation at young age, and confirmed or suspected
genetic mutation known to increase risk for developing breast
cancer. The USPSTF recommends biennial screening mammog-
raphy for women age 50 to 74 years. The USPSTF applies these
guidelines to asymptomatic women age >40 years who do not
have a preexisting breast cancer or who were not previously
diagnosed with a high-risk breast lesion, and who are not at high
risk for breast cancer because of a known underlying genetic
mutation or history of chest radiation at a young age.74-76 In
October 2015, the ACS released updated guidelines stating
average-risk women should start annual screening mammogra-
phy at 45 years of age. Women age 45 to 54 years should be
screened annually, and those 55 years and older should transi-
tion to biennial screening or have the opportunity to continue
annual screening. Women should have the opportunity to begin
annual screening between the ages of 40 and 44 years and
should continue screening as long as their overall health is good
and have a life expectancy of 10 years or longer. The ACS does
not recommend clinical breast examination for breast cancer
screening among average-risk women at any age.77 The NCCN
recommends that average-risk women begin annual screening
mammograms at ≥40 years of age, along with annual clinical
breast exams and breast awareness.78
The United Kingdom recently established an independent
expert panel to review the published literature and estimate
the benefits and harms associated with screening women
>50 years of age in its national screening program.79 The expert
panel estimated that an invitation to breast screening delivers
about a 20% reduction in breast cancer mortality. At the same
time, however, the panel estimated that in women invited to the
screening, about 11% of the cancers diagnosed in their lifetime
constitute overdiagnosis. Despite the overdiagnosis, the panel
concluded that breast screening confers significant benefit and
should continue. The use of screening mammography in women 557
<50 years of age is more controversial for several reasons: (a)
breast density is greater, and screening mammography is less
likely to detect early breast cancer (i.e., reduced sensitivity);
(b) screening mammography results in more false-positive test
findings (i.e., reduced specificity), which results in unneces-
sary biopsy specimens; and (c) younger women are less likely
to have breast cancer (i.e., lower incidence), so fewer young
women will benefit from screening.80,81 In the United States,
on a population basis, however, the benefits of screening mam-
CHAPTER 17 THE BREAST
mography in women between the ages of 40 and 49 years is still
felt to outweigh the risks; although targeting mammography to
women at higher risk of breast cancer improves the balance of
risks and benefits and is the approach some health care sys-
tems have taken. In one study of women age 40 to 49 years, an
abnormal mammography finding was three times more likely
to be cancer in a woman with a family history of breast cancer
than in a woman without such a history. Furthermore, as noted
previously in the section Risk Assessment Models, mounting
data regarding mammographic breast density demonstrate an
independent correlation with breast cancer risk. Incorporation
of breast density measurements into breast cancer risk assess-
ment models appears to be a promising strategy for increasing
the accuracy of these tools. Unfortunately, widespread applica-
tion of these modified models is hampered by inconsistencies
in the reporting of mammographic density. Ultrasonography can
also be used for breast cancer screening in women with dense
breasts, but there is no data available that the additional cancers
detected with this modality reduce mortality from breast cancer.
Current recommendations by the United States Preventive
Services Task Force are that women undergo biennial mammo-
graphic screening between the ages of 50 and 74 years.77 The
use of MRI for breast cancer screening is recommended by the
ACS for women with a 20% to 25% or greater lifetime risk using
risk assessment tools based mainly on family history, BRCA
mutation carriers, those individuals who have a family member
with a BRCA mutation who have not been tested themselves,
individuals who received radiation to the chest between the
ages of 10 and 30 years, and those individuals with a history of
Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-
Ruvalcaba syndrome or those who have a first-degree relative
with one of these syndromes. MRI is an extremely sensitive
screening tool that is not limited by the density of the breast
tissue as mammography is; however, its specificity is moderate,
leading to more false-positive events and the increased need for
biopsy.
Chemoprevention. Tamoxifen, a selective estrogen receptor
modulator, was the first drug shown to reduce the incidence
of breast cancer in healthy women. There have been four pro-
spective studies published evaluating tamoxifen vs. placebo for
reducing the incidence of invasive breast cancer for women at
increased risk. The largest trial was the Breast Cancer Preven-
tion Trial (NSABP P-01), which randomly assigned >13,000
women with a 5-year Gail relative risk of breast cancer of 1.66%
or higher or LCIS to receive tamoxifen or placebo. After a mean
follow-up period of 4 years, the incidence of breast cancer
was reduced by 49% in the group receiving tamoxifen.60 The
decrease was evident only in ER-positive breast cancers with no
significant change in ER-negative tumors. The Royal Marsden
Hospital Tamoxifen Chemoprevention Trial,78 the Italian Tamox-
ifen Prevention Trial,82 and the International Breast Cancer
Intervention Study I (IBIS-I) trial all83 showed a reduction in
558 ER-positive breast cancers with the use of tamoxifen compared
with placebo. There was no effect on mortality; however, the
trials were not powered to assess either breast cancer mortality
or all-cause mortality events. The adverse events were similar in
all four randomized trials, including an increased risk of endo-
metrial cancer, thromboembolic events, cataract formation, and
vasomotor disturbances in individuals receiving tamoxifen.
Tamoxifen therapy currently is recommended only for
women who have a Gail relative risk of 1.66% or higher, who
are age 35 to 59, women over the age of 60, or women with
a diagnosis of LCIS or atypical ductal or lobular hyperplasia.
In addition, deep vein thrombosis occurs 1.6 times as often,
PART II
pulmonary emboli 3.0 times as often, and endometrial cancer
2.5 times as often in women taking tamoxifen. The increased
risk for endometrial cancer is restricted to early stage cancers
in postmenopausal women. Cataract surgery is required almost
twice as often among women taking tamoxifen. Gail et al sub-
SPECIFIC CONSIDERATIONS
sequently developed a model that accounts for underlying risk
of breast cancer as well as comorbidities to determine the net
risk-benefit ratio of tamoxifen use for chemoprevention.84
The NSABP completed a second chemoprevention trial,
designed to compare tamoxifen and raloxifene for breast cancer
risk reduction in high-risk postmenopausal women. Raloxifene,
another selective estrogen receptor modulator, was selected for
the experimental arm in this follow-up prevention trial because
its use in managing postmenopausal osteoporosis suggested
that it might be even more effective at breast cancer risk reduc-
tion, but without the adverse effects of tamoxifen on the uterus.
The P-2 trial, the Study of Tamoxifen and Raloxifene (known
as the STAR trial), randomly assigned 19,747 postmenopausal
women at high-risk for breast cancer to receive either tamoxi-
fen or raloxifene. The initial report of the P-2 trial showed the
two agents were nearly identical in their ability to reduce breast
cancer risk, but raloxifene was associated with a more favor-
able adverse event profile.85 An updated analysis revealed that
raloxifene maintained 76% of the efficacy of tamoxifen in pre-
vention of invasive breast cancer with a more favorable side
effect profile. The risk of developing endometrial cancer was
significantly higher with tamoxifen use at longer follow-up.86
Although tamoxifen has been shown to reduce the incidence
of LCIS and DCIS, raloxifene did not have an effect on the
frequency of these diagnoses.
Aromatase inhibitors (AIs) have been shown to be more
effective than tamoxifen in reducing the incidence of contra-
lateral breast cancers in postmenopausal women receiving AIs
for adjuvant treatment of invasive breast cancer. The MAP.3
trial was the first study to evaluate an AI as a chemopreventive
agent in postmenopausal women at high risk for breast cancer.
The trial randomized 4560 women to exemestane 25 mg daily
vs. placebo for 5 years. After a median follow-up of 35 months,
exemestane was shown to reduce invasive breast cancer inci-
dence by 65%. Side effect profiles demonstrated more grade II
or higher arthritis and hot flashes in patients taking exemestane.87
The IBIS II trial on the other hand, randomized 3864 postmeno-
pausal women to either anastrozole, a nonsteroidal aromatase
inhibitor, vs. placebo with a further randomization to bisphospho-
nate or not based on bone density.88,89 After a median follow-up
of 5 years, anastrozole reduced the incidence of invasive breast
cancer by about 50%. The trial also had an initial sub-study
that looked at the effect of the aromatase inhibitor on cogni-
tive function and reported no adverse effects.90 The American
Society of Clinical Oncology recommends tamoxifen for
chemoprevention in premenopausal or postmenopausal women
and consideration for raloxifene or exemestane in postmeno-
pausal women who are noted to be at increased risk of breast
cancer.91,92 The discussion with an individual patient should
include risk assessment and potential risks and benefits with
each agent.
Risk-Reducing Surgery. A retrospective study of women at
high risk for breast cancer found that prophylactic mastectomy
reduced their risk by >90%.62 However, the effects of prophylac-
tic mastectomy on the long-term quality of life are poorly quan-
tified. A study involving women who were carriers of a breast
cancer susceptibility gene (BRCA) mutation found that the ben-
efit of prophylactic mastectomy differed substantially according
to the breast cancer risk conferred by the mutations. For women
with an estimated lifetime risk of 40%, prophylactic mastec-
tomy added almost 3 years of life, whereas for women with an
estimated lifetime risk of 85%, prophylactic mastectomy added
>5 years of life.66 Domchek et al evaluated a cohort of BRCA1
and 2 mutation carriers who were followed prospectively
and reported on outcomes with risk-reducing surgery.93 They
found that risk-reducing mastectomy was highly effective at
preventing breast cancer in both BRCA1 and 2 mutation carriers.
Risk-reducing salpingo-oophorectomy was highly effective at
reducing the incidence of ovarian cancer and breast cancer in
BRCA mutation carriers and was associated with a reduction in
breast cancer-specific mortality, ovarian cancer-specific mor-
tality, and all-cause mortality. While studies of bilateral pro-
phylactic or risk-reducing mastectomy have reported dramatic
reductions in breast cancer incidence among those without
known BRCA mutations, there is little data to support a survival
benefit. Another consideration is that while most patients are
satisfied with their decision to pursue risk-reducing surgery,
some are dissatisfied with the cosmetic outcomes mostly due to
reconstructive issues.
BRCA Mutations
BRCA1. Up to 5% of breast cancers are caused by inheritance
of germline mutations such as BRCA1 and BRCA2, which
are inherited in an autosomal dominant fashion with varying
degrees of penetrance (Table 17-7).94-100 BRCA1 is located on
chromosome arm 17q, spans a genomic region of approximately
100 kilobases (kb) of DNA, and contains 22 coding exons for
1863 amino acids. Both BRCA1 and BRCA2 function as tumor-
suppressor genes, and for each gene, loss of both alleles is
required for the initiation of cancer. Data accumulated since
the isolation of the BRCA1 gene suggest a role in transcription,
cell-cycle control, and DNA damage repair pathways. More
than 500 sequence variations in BRCA1 have been identified.
It now is known that germline mutations in BRCA1 represent
a predisposing genetic factor in as many as 45% of hereditary
breast cancers and in at least 80% of hereditary ovarian cancers.
Female mutation carriers have been reported to have up to an
85% lifetime risk (for some families) for developing breast
cancer and up to a 40% lifetime risk for developing ovarian
cancer. The initial families reported had high penetrance and
subsequently the average lifetime risk has been reported to lie
between 60% and 70%. Breast cancer susceptibility in these
families appears as an autosomal dominant trait with high pen-
etrance. Approximately 50% of children of carriers inherit the
trait. In general, BRCA1-associated breast cancers are invasive
ductal carcinomas, are poorly differentiated, are in the majority
Table 17-7
Incidence of sporadic, familial, and hereditary breast
cancer
Sporadic breast cancer 65%–75%
Familial breast cancer 20%–30%
Hereditary breast cancer 5%–10%
BRCA1 a
45%
BRCA2 35%
p53a (Li-Fraumeni syndrome) 1%
STK11/LKB1 (Peutz-Jeghers syndrome)
a
<1%
PTEN (Cowden disease)
a
<1%
MSH2/MLH1a (Muir-Torre syndrome) <1%
ATM (Ataxia-telangiectasia)
a
<1%
Unknown 20%
a
Affected gene.
Data from Martin AM, Weber BL: Genetic and hormonal risk factors in
breast cancer, J Natl Cancer Inst. 2000 Jul 19;92(14):1126-1135.
hormone receptor negative, and have a triple receptor negative
(immunohistochemical profile: ER-negative, PR-negative, and
HER2-negative) or basal phenotype (based on gene expression
profiling). BRCA1-associated breast cancers have a number of
distinguishing clinical features, such as an early age of onset
compared with sporadic cases; a higher prevalence of bilateral
breast cancer; and the presence of associated cancers in some
affected individuals, specifically ovarian cancer and possibly
colon and prostate cancers.
Several founder mutations have been identified in BRCA1.
The two most common mutations are 185delAG and 5382insC,
which account for 10% of all the mutations seen in BRCA1.
These two mutations occur at a 10-fold higher frequency
in the Ashkenazi Jewish population than in non-Jewish
Caucasians. The carrier frequency of the 185delAG mutation
in the Ashkenazi Jewish population is 1% and, along with the
5382insC mutation, accounts for almost all BRCA1 mutations in
this population. Analysis of germline mutations in Jewish and
non-Jewish women with early-onset breast cancer indicates that
20% of Jewish women who develop breast cancer before age
40 years carry the 185delAG mutation. There are founder
BRCA1 mutations in other populations including, among others,
Dutch, Polish, Finnish, and Russian populations.101-105
BRCA2. BRCA2 is located on chromosome arm 13q and spans
a genomic region of approximately 70 kb of DNA. The 11.2-kb
coding region contains 26 coding exons.94-100 It encodes a pro-
tein of 3418 amino acids. The BRCA2 gene bears no homology
to any previously described gene, and the protein contains no
previously defined functional domains. The biologic function
of BRCA2 is not well defined, but like BRCA1, it is postulated
to play a role in DNA damage response pathways. BRCA2 mes-
senger RNA also is expressed at high levels in the late G1 and
S phases of the cell cycle. The kinetics of BRCA2 protein regu-
lation in the cell cycle is similar to that of BRCA1 protein, which
suggests that these genes are coregulated. The mutational spec-
trum of BRCA2 is not as well established as that of BRCA1.
To date, >250 mutations have been found. The breast cancer
risk for BRCA2 mutation carriers is close to 85%, and the life-
time ovarian cancer risk, while lower than for BRCA1, is still
estimated to be close to 20%. Breast cancer susceptibility in 559
BRCA2 families is an autosomal dominant trait and has a high
penetrance. Approximately 50% of children of carriers inherit
the trait. Unlike male carriers of BRCA1 mutations, men with
germline mutations in BRCA2 have an estimated breast cancer
risk of 6%, which represents a 100-fold increase over the risk in
the general male population. BRCA2-associated breast cancers
are invasive ductal carcinomas, which are more likely to be
well differentiated and to express hormone receptors than are
BRCA1-associated breast cancers. BRCA2-associated breast
CHAPTER 17 THE BREAST
cancer has a number of distinguishing clinical features, such
as an early age of onset compared with sporadic cases, a higher
prevalence of bilateral breast cancer, and the presence of associ-
ated cancers in some affected individuals, specifically ovarian,
colon, prostate, pancreatic, gallbladder, bile duct, and stomach
cancers, as well as melanoma. A number of founder mutations
have been identified in BRCA2. The 6174delT mutation is found
in Ashkenazi Jews with a prevalence of 1.2% and accounts for
60% of ovarian cancer and 30% of early-onset breast cancer
patients among Ashkenazi women.106 Another BRCA2 founder
mutation, 999del5, is observed in Icelandic and Finnish popula-
tions, while more recently 3036delACAA has been observed in
a number of Spanish families.107-109
Identification of BRCA Mutation Carriers. Identifying
hereditary risk for breast cancer is a four-step process that
includes: (a) obtaining a complete, multigenerational family
history, (b) assessing the appropriateness of genetic testing for
a particular patient, (c) counseling the patient, and (d) interpret-
ing the results of testing.110 Genetic testing should not be offered
in isolation, but only in conjunction with patient education and
counseling, including referral to a genetic counselor. Initial
determinations include whether the individual is an appropriate
candidate for genetic testing and whether genetic testing will be
informative for personal and clinical decision-making. A thor-
ough and accurate family history is essential to this process, and
the maternal and paternal sides of the family are both assessed
because 50% of the women with a BRCA mutation have inher-
ited the mutation from their fathers. To help clinicians advise
women about genetic testing, statistically based models that
determine the probability that an individual carries a BRCA
mutation have been developed. A method for calculating carrier
probability that has been demonstrated to have acceptable per-
formance (i.e., both in terms of calibration and discrimination)
such as the Manchester scoring system and BODICEA should
be used to offer referral to a specialist genetic clinic. A heredi-
tary risk of breast cancer is considered if a family includes Ash-
kenazi Jewish heritage; a first-degree relative with breast cancer
before age 50; a history of ovarian cancer at any age in the
patient or first- or second-degree relative with ovarian cancer;
breast and ovarian cancer in the same individual; two or more
first- or second-degree relatives with breast cancer at any age;
patient or relative with bilateral breast cancer; and male breast
cancer in a relative at any age.111 The threshold for genetic test-
ing is lower in individuals who are members of ethnic groups in
whom the mutation prevalence is increased.
BRCA Mutation Testing. Appropriate counseling for the
individual being tested for a BRCA mutation is strongly rec-
ommended, and documentation of informed consent is
required.110,112 The test that is clinically available for analyzing
BRCA mutations is gene sequence analysis. In a family with a
history suggestive of hereditary breast cancer and no previously
560 tested member, the most informative strategy is first to test
an affected family member. This person undergoes complete
sequence analysis of both the BRCA1 and BRCA2 genes. If a
mutation is identified, relatives are usually tested only for that
specific mutation. An individual of Ashkenazi Jewish ancestry
is tested initially for the three specific mutations that account
for hereditary breast and ovarian cancer in that population. If
results of that test are negative, it may then be appropriate to
fully analyze the BRCA1 and BRCA2 genes.
A positive test result is one that discloses the presence of a
BRCA mutation that interferes with translation or function of the
BRCA protein. A woman who carries a deleterious mutation has
PART II
a breast cancer risk of up to 85% (in some families) as well as
a greatly increased risk of ovarian cancer. A negative test result
is interpreted according to the individual’s personal and family
history, especially whether a mutation has been previously iden-
tified in the family, in which case the woman is generally tested
SPECIFIC CONSIDERATIONS
only for that specific mutation. If the mutation is not present,
the woman’s risk of breast or ovarian cancer may be no greater
than that of the general population. In addition, no BRCA muta-
tion can be passed on to the woman’s children. In the absence
of a previously identified mutation, a negative test result in an
affected individual generally indicates that a BRCA mutation is
not responsible for the familial cancer. However, the possibil-
ity remains of an unusual abnormality in one of these genes
that cannot yet be identified through clinical testing. It also is
possible that the familial cancer is indeed caused by an identifi-
able BRCA mutation but that the individual tested had sporadic
cancer, a situation known as phenocopy. This is especially pos-
sible if the individual tested developed breast cancer close to the
age of onset of the general population (age 60 years or older)
rather than before age 50 years, as is characteristic of BRCA
mutation carriers. Overall, the false-negative rate for BRCA
mutation testing is <5%. Some test results, especially when a
single base-pair change (missense mutation) is identified, may
be difficult to interpret. This is because single base-pair changes
do not always result in a nonfunctional protein. Thus, missense
mutations not located within critical functional domains, or
those that cause only minimal changes in protein structure, may
not be disease associated and are usually reported as indetermi-
nate results. In communicating indeterminate results to women,
care must be taken to relay the uncertain cancer risk associ-
ated with this type of mutation and to emphasize that ongoing
research might clarify its meaning. In addition, testing other
family members with breast cancer to determine if a genetic
variant tracks with their breast cancer may provide clarification
as to its significance. Indeterminate genetic variance currently
accounts for 12% of the test results.
Concern has been expressed that the identification of
hereditary risk for breast cancer may interfere with access to
affordable health insurance. This concern refers to discrimina-
tion directed against an individual or family based solely on an
apparent or perceived genetic variation from the normal human
genotype. The Health Insurance Portability and Accountability
Act of 1996 (HIPAA) made it illegal in the United States for
group health plans to consider genetic information as a preexist-
ing condition or to use it to deny or limit coverage. Most states
also have passed laws that prevent genetic discrimination in the
provision of health insurance. In addition, individuals applying
for health insurance are not required to report whether relatives
have undergone genetic testing for cancer risk, only whether
those relatives have actually been diagnosed with cancer.
Currently, there is little documented evidence of genetic dis-
crimination resulting from findings of available genetic tests.
Cancer Prevention for BRCA Mutation Carriers. Risk man-
agement strategies for BRCA1 and BRCA2 mutation carriers
include the following:
1. Risk-reducing mastectomy and reconstruction
2. Risk-reducing salpingo-oophorectomy
3. Intensive surveillance for breast and ovarian cancer
4. Chemoprevention
Although removal of breast tissue reduces the likeli-
hood that BRCA1 and BRCA2 mutation carriers will develop
breast cancer, mastectomy does not remove all breast tissue,
and women continue to be at risk because a germline muta-
tion is present in any remaining breast tissue. For postmeno-
pausal BRCA1 and BRCA2 mutation carriers who have not had
a mastectomy, it may be advisable to avoid hormone replace-
ment therapy because no data exist regarding the effect of the
therapy on the penetrance of breast cancer susceptibility genes.
Because breast cancers in BRCA mutation carriers have the
same mammographic appearance as breast cancers in noncarri-
ers, a screening mammogram is likely to be effective in BRCA
mutation carriers, provided it is performed and interpreted by
an experienced radiologist with a high level of suspicion. Pres-
ent screening recommendations for BRCA mutation carriers
who do not undergo risk-reducing mastectomy include clinical
breast examination every 6 months and mammography every
12 months beginning at age 25 years because the risk of breast
cancer in BRCA mutation carriers increases after age 30 years.
Recent attention has been focused on the use of MRI for breast
cancer screening in high-risk individuals and known BRCA
mutation carriers. MRI appears to be more sensitive at detect-
ing breast cancer in younger women with dense breasts.113 How-
ever, as noted previously, MRI does lead to the detection of
benign breast lesions that cannot easily be distinguished from
malignancy, and these false-positive events can result in more
interventions, including biopsy specimens. The current recom-
mendations from the American Cancer Society are for annual
MRI in women with a 20% to 25% or greater lifetime risk of
developing breast cancer (mainly based on family history),
women with a known BRCA1 or BRCA2 mutation, those who
have a first-degree relative with a BRCA1 or BRCA2 mutation
and have not had genetic testing themselves, women who were
treated with radiation therapy to the chest between the ages of
10 and 30 years, and those who have Li-Fraumeni syndrome,
Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or
a first-degree relative with one of these syndromes.75,114 Despite
a 49% reduction in the overall incidence of breast cancer and
a 69% reduction in the incidence of estrogen receptor positive
tumors in high-risk women taking tamoxifen reported in the
NSABP P1 trial, there is insufficient evidence to recommend
the use of tamoxifen uniformly for BRCA1 mutation carriers.60
Cancers arising in BRCA1 mutation carriers are usually high
grade and are most often hormone receptor negative. Approxi-
mately 66% of BRCA1-associated DCIS lesions are estrogen
receptor negative, which suggests early acquisition of the hor-
mone-independent phenotype. In the NSABP P1 trial there was
a 62% reduction in the incidence of breast cancer in BRCA2
carriers, similar to the overall reduction seen in the P1 trial. In
contrast, there was no reduction seen in breast cancer incidence
in BRCA1 carriers who started tamoxifen in P1 age 35 years or
older.115 Tamoxifen appears to be more effective at preventing
estrogen receptor-positive breast cancers.
The risk of ovarian cancer in BRCA1 and BRCA2 muta-
tion carriers ranges from 20% to 40%, which is 10 times higher
than that in the general population. Risk-reducing salpingo-
oophorectomy is a reasonable prevention option in mutation
carriers. In women with a documented BRCA1 or BRCA2
mutation, consideration for bilateral risk-reducing salpingo-
oophorectomy should be between the ages of 35 and 40 years
at the completion of childbearing. Removing the ovaries
reduces the risk of ovarian cancer and breast cancer when per-
formed in premenopausal BRCA mutation carriers. Hormone
replacement therapy is discussed with the patient at the time
of oophorectomy. The Cancer Genetics Studies Consortium
recommends yearly transvaginal ultrasound timed to avoid
ovulation and annual measurement of serum cancer antigen
125 levels beginning at age 25 years as the best screening
modalities for ovarian carcinoma in BRCA mutation carriers
who have opted to defer risk-reducing surgery.
PALB2 (partner and localizer of BRCA2) has recently been
characterized as a potential high-risk gene for breast cancer.
PALB2 allows nuclear localization of BRCA2 and provides a
scaffold for the BRCA1–PALB2–BRCA2 complex. Analysis by
Antoniou et al has suggested that the risk of breast cancer for
PALB2 mutation carriers is as high as that of BRCA2 mutation
carriers.116 The absolute risk of breast cancer for PALB2 female
mutation carriers by 70 years of age ranged from 33% (95%
CI, 25–44) for those with no family history of breast cancer to
58% (95% CI, 50–66) for those with two or more first-degree
relatives with breast cancer at 50 years of age. The risk of breast
cancer for female PALB2 mutation carriers, depending on the
age, was about five to nine times as high compared with the gen-
eral population. While screening with mammogram along with
MRI has been suggested for PALB2 mutation carriers starting
at age 30 with consideration of risk-reducing mastectomy, there
is currently insufficient evidence regarding the risk of ovarian
cancer and its management.
Other hereditary syndromes associated with an increased
risk of breast cancer include Cowden disease (PTEN mutations,
in which cancers of the thyroid, GI tract, and benign skin and
subcutaneous nodules are also seen), Li-Fraumeni syndrome
(TP53 mutations, also associated with sarcomas, lymphomas,
and adrenocortical tumors), hereditary diffuse gastric cancer
syndrome (CDH1 mutations, associated with diffuse gastric
cancer and lobular breast cancers), and syndromes of breast
and melanoma. With the discovery of additional genes related
to breast cancer susceptibility, panel testing is available for a
number of genes in addition to BRCA1 and BRCA2. The inter-
pretation of results is complex and is best done with a genetic
counselor.
EPIDEMIOLOGY AND NATURAL HISTORY OF
BREAST CANCER
Epidemiology
Breast cancer is the most common site-specific cancer in women
and is the leading cause of death from cancer for women age
20 to 59 years. Based on Surveillance, Epidemiology, and End
Results registries (SEER) data, 266,120 new cases were esti-
mated in 2018 with 40,920 estimated deaths attributed to breast
cancers.117 It accounts for 30% of all newly diagnosed cancers in
women and is responsible for 14% of the cancer-related deaths 561
in women.
Breast cancer was the leading cause of cancer-related
mortality in women until 1987, when it was surpassed by
lung cancer. In the 1970s, the probability that a woman in the
United States would develop breast cancer at some point in her
lifetime was estimated at 1 in 13; in 1980 it was 1 in 11; and in
2004 it was 1 in 8. Cancer registries in Connecticut and upper
New York State document that the age-adjusted incidence of
new breast cancer cases had steadily increased since the mid-
CHAPTER 17 THE BREAST
1940s. The incidence in the United States, based on data from
nine SEER registries, has been decreasing by 23% per year
since 2000. The increase had been approximately 1% per year
from 1973 to 1980, and there was an additional increase in inci-
dence of 4% between 1980 and 1987, which was characterized
by frequent detection of small primary cancers. The increase
in breast cancer incidence occurred primarily in women age
≥55 years and paralleled a marked increase in the percentage of
older women who had mammograms taken. At the same time,
incidence rates for regional metastatic disease dropped and
breast cancer mortality declined. From 1960 to 1963, 5-year
overall survival rates for breast cancer were 63% and 46% in
white and African American women, respectively, whereas the
rates for 1981 to 1983 were 78% and 64%, respectively. For
2002 to 2008 rates were 92% and 78%, respectively.
There is a 10-fold variation in breast cancer incidence
among different countries worldwide. Cyprus and Malta have
the highest age-adjusted mortality for breast cancer (29.6 per
100,000 population), whereas Haiti has the lowest (2.0 deaths
per 100,000 population). The United States has an age-adjusted
mortality for breast cancer of 19.0 cases per 100,000 population.
Women living in less industrialized nations tend to have a lower
incidence of breast cancer than women living in industrialized
countries, although Japan is an exception. In the United States,
Mormons, Seventh Day Adventists, American Indians, Alaska
natives, Hispanic/Latina Americans, and Japanese and Filipino
women living in Hawaii have a below-average incidence of
breast cancer, whereas nuns (due to nulliparity) and Ashkenazi
Jewish women have an above-average incidence.
The incidence rates of breast cancer increased in most
countries through the 1990s. Since the estimates for 1990, there
was an overall increase in incidence rates of approximately
0.5% annually. It was predicted that there would be approxi-
mately 1.4 million new cases in 2010. The cancer registries in
China have noted annual increases in incidence of up to 3% to
4%, and in eastern Asia, increases are similar.
Data from the SEER program reveal declines in breast
cancer incidence over the past decade, and this is widely attrib-
uted to decreased use of hormone replacement therapy as a con-
sequence of the Women’s Health Initiative reports.118
Breast cancer burden has well-defined variations by geog-
raphy, regional lifestyle, and racial or ethnic background.119 In
general, both breast cancer incidence and mortality are rela-
tively lower among the female populations of Asia and Africa,
relatively underdeveloped nations, and nations that have not
adopted Westernized reproductive and dietary patterns. In
contrast, European and North American women and women
from heavily industrialized or Westernized countries have a
substantially higher breast cancer burden. These international
patterns are mirrored in breast cancer incidence and mortality
rates observed for the racially, ethnically, and culturally diverse
population of the United States.120
562 Although often related, the factors that influence breast
cancer incidence may differ from those that affect mortality.
Incidence rates are lower among populations that are heavily
weighted with women who begin childbearing at young ages
and who have multiple full-term pregnancies followed by pro-
longed lactation. These are features that characterize many
underdeveloped nations and also many eastern nations. Breast
cancer mortality rates should be lower in populations that have a
lower incidence, but the mortality burden will simultaneously be
adversely affected by the absence of effective mammographic
screening programs for early detection and diminished access
to multidisciplinary cancer treatment programs. These features
PART II
are likely to account for much of the disproportionate mortal-
ity risks that are seen in underdeveloped nations. Similar fac-
tors probably account for differences in breast cancer burden
observed among the various racial and ethnic groups within
the United States. Interestingly, breast cancer incidence and
SPECIFIC CONSIDERATIONS
mortality rates rise among second- and third-generation Asian
Americans as they adopt Western lifestyles.
Disparities in breast cancer survival among subsets of the
American population are generating increased publicity because
they are closely linked to disparities in socioeconomic status.
Poverty rates and proportions of the population that lack health
care insurance are two to three times higher among minority
racial and ethnic groups such as African Americans and His-
panic/Latino Americans. These socioeconomic disadvantages
create barriers to effective breast cancer screening and result
in delayed breast cancer diagnosis, advanced stage distribu-
tion, inadequacies in comprehensive treatment, and, ultimately,
increased mortality rates. Furthermore, the rapid growth in the
Hispanic population is accompanied by increasing problems in
health education because of linguistic barriers between physi-
cians and recently immigrated, non–English-speaking patients.
Recent studies also are documenting inequities in the treatments
delivered to minority breast cancer patients, such as increased
rates of failure to provide systemic therapy, use of sentinel
lymph node dissection, and breast reconstruction. Some of the
treatment delivery disparities are related to inadequately con-
trolled comorbidities (such as hypertension and diabetes), which
are more prevalent in minority populations. However, some
studies that adjust for these factors report persistent and unex-
plained unevenness in treatment recommendations. It is clear
that breast cancer disparities associated with racial or ethnic
background have a multifactorial cause, and improvements in
outcome will require correction of many public health problems
at both the patient and provider levels.
Advances in the ability to characterize breast cancer sub-
types and the genetics of the disease are now provoking specula-
tion regarding possible hereditary influences on breast cancer
risk that are related to racial or ethnic ancestry.121 These questions
become particularly compelling when one looks at disparities
in breast cancer burden between African Americans and Cau-
casians. Lifetime risk of breast cancer is lower for African
Americans, yet a paradoxically increased breast cancer mortal-
ity risk also is seen. African Americans also have a younger age
distribution for breast cancer; among women <45 years of age,
breast cancer incidence is highest among African Americans
compared to other subsets of the American population. Lastly
and most provocatively, African American women of all ages
have notably higher incidence rates for estrogen receptor-
negative tumors. These same patterns of disease are seen in con-
temporary female populations of western, sub-Saharan Africa,
Middlesex Hospital 1805-1933 (250 cases)
100
90
86%
80
83%
70
68%
66%
60
% Survival
54%
50
40 44% 41%
30
Natural survival
20 28%
Survival untreated
10
18% cases
9%
3.6% 2% 0.8%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Median
survival
2.7 years
Duration of life from onset of symptoms (years)
Figure 17-13. Survival of women with untreated breast cancer
compared with natural survival. (Reproduced with permission
from Bloom HJG, Richardson WW, Harries EJ: Natural history
of untreated breast cancer (1805-1933). Comparison of untreated
and treated cases according to histological grade of malignancy,
Br Med J. 1962 Jul 28;2(5299):213-221.)
who are likely to share ancestry with African American women
as a consequence of the Colonial-era slave trade. Interestingly,
male breast cancer also is seen with increased frequency among
both African Americans and Africans.
Natural History
Bloom and colleagues described the natural history of breast
cancer based on the records of 250 women with untreated breast
cancers who were cared for on charity wards in the Middlesex
Hospital, London, between 1805 and 1933. The median
survival of this population was 2.7 years after initial diagnosis
(Fig.  17-13).122 The 5- and 10-year survival rates for these
women were 18.0% and 3.6%, respectively. Only 0.8% survived
for 15 years or longer. Autopsy data confirmed that 95% of these
women died of breast cancer, whereas the remaining 5% died
of other causes. Almost 75% of the women developed ulcer-
ation of the breast during the course of the disease. The longest
surviving patient died in the 19th year after diagnosis.
Primary Breast Cancer. More than 80% of breast cancers
show productive fibrosis that involves the epithelial and stro-
mal tissues. With growth of the cancer and invasion of the
surrounding breast tissues, the accompanying desmoplastic
response entraps and shortens Cooper’s suspensory ligaments to
produce a characteristic skin retraction. Localized edema (peau
d’orange) develops when drainage of lymph fluid from the skin
is disrupted. With continued growth, cancer cells invade the
skin, and eventually ulceration occurs. As new areas of skin
are invaded, small satellite nodules appear near the primary
ulceration. The size of the primary breast cancer correlates with
disease-free and overall survival, but there is a close associa-
tion between cancer size and axillary lymph node involvement
(Fig. 17-14). In general, up to 20% of breast cancer recurrences
are local-regional, >60% are distant, and 20% are both local-
regional and distant.
 nodes adhere to each other and form a conglomerate mass. 563
100
315
Cancer cells may grow through the lymph node capsule and fix
90 * 297 to contiguous structures in the axilla, including the chest wall.
636 173
80 * N - (335)
Typically, axillary lymph nodes are involved sequentially from
177
the low (level I) to the central (level II) to the apical (level III)
Percent survivors

531
70 *
321
142
lymph node groups. Approximately 95% of the women who die
60 * 263
144 Whole series (716) of breast cancer have distant metastases, and traditionally the
50 *
234 N + 1 (198) most important prognostic correlate of disease-free and over-
65
*
40 *
*
all survival was axillary lymph node status (see Fig. 17-14A).
* * N + (381)
30
92 90 Women with node-negative disease had less than a 30% risk of

CHAPTER 17 THE BREAST

recurrence, compared with as much as a 75% risk for women
20 N + >3 (183)
25
with node-positive disease.
10
Distant Metastases. At approximately the 20th cell dou-
bling, breast cancers acquire their own blood supply (neovas-
2 4 6 8 10
cularization). Thereafter, cancer cells may be shed directly into
A Years after mastectomy
the systemic venous blood to seed the pulmonary circulation
via the axillary and intercostal veins or the vertebral column
via Batson’s plexus of veins, which courses the length of the
0.98 vertebral column. These cells are scavenged by natural killer
lymphocytes and macrophages. Successful implantation of
0.95
Proportion of patients with metastases

metastatic foci from breast cancer predictably occurs after the

0.90
0.80
0.70
0.60
0.50
0.40
xx
0.30
xx
0.20
10
Volume (ml)
2 3
B Diameter (cm)
Figure 17-14. A. Overall survival for women with breast cancer
according to axillary lymph node status. The time periods are years
after radical mastectomy. (Reproduced with permission from Vala-
gussa P, Bonadonna G, Veronesi U, et al: Patterns of relapse and
survival following radical mastectomy. Analysis of 716 consecutive
patients, Cancer. 1978 Mar;41(3):1170-1178.) B. Risk of metasta-
ses according to breast cancer volume and diameter. (Reproduced
with permission from Koscielny S, Tubiana M, Lê MG, et al: Breast
cancer: Relationship between the size of the primary tumour and
the probability of metastatic dissemination, Br J Cancer. 1984
Jun;49(6):709-715.)
Axillary Lymph Node Metastases. As the size of the pri-
mary breast cancer increases, some cancer cells are shed into
cellular spaces and transported via the lymphatic network of
the breast to the regional lymph nodes, especially the axillary
lymph nodes. Lymph nodes that contain metastatic cancer are
at first ill-defined and soft but become firm or hard with con-
tinued growth of the metastatic cancer. Eventually the lymph
x
primary cancer exceeds 0.5 cm in diameter, which corresponds
to the 27th cell doubling. For 10 years after initial treatment,
distant metastases are the most common cause of death in breast
x x cancer patients. For this reason, conclusive results cannot be
derived from breast cancer trials until at least 5 to 10 years
x
have elapsed. Although 60% of the women who develop distant
metastases will do so within 60 months of treatment, metastases
x may become evident as late as 20 to 30 years after treatment
x of the primary cancer.123 Patients with estrogen receptor nega-
tive breast cancers are proportionately more likely to develop
recurrence in the first 3 to 5 years, whereas those with estrogen
receptor positive tumors have a risk of developing recurrence,
which drops off more slowly beyond 5 years than is seen with
ER-negative tumors.124 Recently, a report showed that tumor
100
size and nodal status remain powerful predictors of late recur-
rences compared to more recently developed tools such as the
immunohistochemical score (IHC4) and two gene expression
4 5 6 7 8 9 10 11
profile tests (Recurrence Score and PAM50).125 Common sites
of involvement, in order of frequency, are bone, lung, pleura,
soft tissues, and liver. Brain metastases are less frequent over-
all, although with the advent of adjuvant systemic therapies it
has been reported that CNS disease may be seen earlier.126,127
There are also reports of factors that are associated with the
risk of developing brain metastases.128 For example, they are
more likely to be seen in patients with triple receptor negative
breast cancer (ER-negative, PR-negative, and HER2-negative)
or patients with HER2-positive breast cancer who have received
chemotherapy and HER2-directed therapies.
HISTOPATHOLOGY OF BREAST CANCER
Carcinoma In Situ
Cancer cells are in situ or invasive depending on whether or not
they invade through the basement membrane.129,130 Broders’s
original description of in situ breast cancer stressed the absence
of invasion of cells into the surrounding stroma and their confine-
ment within natural ductal and alveolar boundaries.129 Because
areas of invasion may be minute, the accurate diagnosis of in
situ cancer necessitates the analysis of multiple microscopic sec-
tions to exclude invasion. In 1941, Foote and Stewart published
564 a landmark description of LCIS, which distinguished it from
DCIS.130 In the late 1960s, Gallagher and Martin published their
study of whole-breast sections and described a stepwise progres-
sion from benign breast tissue to in situ cancer and subsequently
to invasive cancer. Before the widespread use of mammography,
diagnosis of breast cancer was by physical examination. At that
time, in situ cancers constituted <6% of all breast cancers, and
LCIS was more frequently diagnosed than DCIS by a ratio of
>2:1. However, when screening mammography became popular,
a 14-fold increase in the incidence of in situ cancer (45%) was
demonstrated, and DCIS was more frequently diagnosed than
LCIS by a ratio of >2:1. Table 17-8 lists the clinical and patho-
PART II
and contributes to its diagnosis. The frequency of LCIS in the
general population cannot be reliably determined because it usu-
ally presents as an incidental finding. The average age at diag-
nosis is 45 years, which is approximately 15 to 25 years younger
than the age at diagnosis for invasive breast cancer. LCIS has a
distinct racial predilection, occurring 12 times more frequently
in white women than in African-American women. Invasive
breast cancer develops in 25% to 35% of women with LCIS.
Invasive cancer may develop in either breast, regardless of
which breast harbored the initial focus of LCIS, and is detected
synchronously with LCIS in 5% of cases. In women with a his-
tory of LCIS, up to 65% of subsequent invasive cancers are duc-

logic characteristics of DCIS and LCIS. Multicentricity refers
to the occurrence of a second breast cancer outside the breast
quadrant of the primary cancer (or at least 4 cm away), whereas
multifocality refers to the occurrence of a second cancer within
the same breast quadrant as the primary cancer (or within 4 cm of
SPECIFIC CONSIDERATIONS
tal, not lobular, in origin. For these reasons, LCIS is regarded
as a marker of increased risk for invasive breast cancer rather
than as an anatomic precursor. Individuals should be counseled
regarding their risk of developing breast cancer and appropriate
risk reduction strategies, including observation with screening,

it). Multicentricity occurs in 60% to 90% of women with LCIS, chemoprevention, and risk-reducing bilateral mastectomy.
whereas the rate of multicentricity for DCIS is reported to be Ductal Carcinoma In Situ. Although DCIS is predominantly
40% to 80%. LCIS occurs bilaterally in 50% to 70% of cases, seen in the female breast, it accounts for 5% of male breast
whereas DCIS occurs bilaterally in 10% to 20% of cases. cancers. Published series suggest a detection frequency of 7% in
Lobular Carcinoma In Situ. LCIS originates from the termi- all biopsy tissue specimens. The term intraductal carcinoma is
nal duct lobular units and develops only in the female breast. frequently applied to DCIS, which carries a high risk for progres-
It is characterized by distention and distortion of the terminal sion to an invasive cancer. Histologically, DCIS is characterized
duct lobular units by cells that are large but maintain a normal by a proliferation of the epithelium that lines the minor ducts,
nuclear to cytoplasmic ratio. Cytoplasmic mucoid globules are resulting in papillary growths within the duct lumina. Early in
a distinctive cellular feature. LCIS may be observed in breast their development, the cancer cells do not show pleomorphism,
tissues that contain microcalcifications, but the calcifications mitoses, or atypia, which leads to difficulty in distinguishing
associated with LCIS typically occur in adjacent tissues. This early DCIS from benign hyperplasia. The papillary growths
neighborhood calcification is a feature that is unique to LCIS (papillary growth pattern) eventually coalesce and fill the duct
lumina so that only scattered, rounded spaces remain between
the clumps of atypical cancer cells, which show hyperchroma-
sia and loss of polarity (cribriform growth pattern). Eventually
Table 17-8
pleomorphic cancer cells with frequent mitotic figures obliterate
Salient characteristics of in situ ductal (DCIS) and the lumina and distend the ducts (solid growth pattern). With
lobular (LCIS) carcinoma of the breast continued growth, these cells outstrip their blood supply and
become necrotic (comedo growth pattern). Calcium deposition
  LCIS DCIS occurs in the areas of necrosis and is a common feature seen
Age (years) 44–47 54–58 on mammography. DCIS is now frequently classified based on
Incidencea 2%–5% 5%–10% nuclear grade and the presence of necrosis (Table 17-9). Based
Clinical signs None Mass, pain, nipple
discharge
Mammographic signs None Microcalcifications Table 17-9
Premenopausal 2/3 1/3 Classification of breast ductal carcinoma in situ (DCIS)
Incidence of synchronous 5% 2%–46% DETERMINING
invasive carcinoma
CHARACTERISTICS
Multicentricity 60%–90% 40%–80%
Bilaterality 50%–70% 10%–20% HISTOLOGIC NUCLEAR
Axillary metastasis 1% 1%–2% SUBTYPE  GRADE NECROSIS DCIS GRADE 
Subsequent carcinomas:     Comedo High Extensive High
Incidence 25%–35% 25%–70% Intermediatea Intermediate Focal or absent Intermediate
Laterality Bilateral Ipsilateral Noncomedo b
Low Absent Low
Interval to diagnosis 15–20 y 5–10 y a
Often a mixture of noncomedo patterns.
b
Solid, cribriform, papillary, or focal micropapillary.
Histologic type Ductal Ductal
Adapted with permission from Koo JS, Kim MJ, Kim EK, et al:
In biopsy specimens of mammographically detected breast lesions.
a
Comparison of immunohistochemical staining in breast papillary
Reproduced with permission from Bland KI, Copeland ED: The Breast: neoplasms of cytokeratin 5/6 and p63 in core needle biopsies and
Comprehensive Management of Benign and Malignant Diseases, 2nd ed. surgical excisions, Appl Immunohistochem Mol Morphol. 2012
Philadelphia, PA: Elsesvier/Saunders; 1998. Mar;20(2):108-115.
on multiple consensus meetings, grading of DCIS has been rec-
ommended. Although there is no universal agreement on clas-
sification, most systems endorse the use of cytologic grade and
presence or absence of necrosis.131
The risk for invasive breast cancer is increased nearly
fivefold in women with DCIS.132 The invasive cancers are
observed in the ipsilateral breast, usually in the same quadrant
as the DCIS that was originally detected, which suggests that
DCIS is an anatomic precursor of invasive ductal carcinoma
(Fig. 17-15A and B).
Invasive Breast Carcinoma
Invasive breast cancers have been described as lobular or duc-
tal in origin.128-131 Early classifications used the term lobular
to describe invasive cancers that were associated with LCIS,
whereas all other invasive cancers were referred to as ductal.
A Surgical therapy for Paget’s disease may involve lumpectomy
B Medullary carcinoma is a special-type breast cancer;
Figure 17-15. Ductal carcinoma in situ (DCIS). A. Craniocau-
dal mammographic view shows a poorly defined mass containing
microcalcifications. (Used with permission from Dr. Anne Turnbull,
Consultant Radiologist/Director of Breast Screening, Royal Derby
Hospital, Derby, UK.) B. Histopathologic preparation of the sur-
gical specimen confirms DCIS with necrosis (100x). (Used with
permission from Dr. Sindhu Menon, Consultant Histopathologist
and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast
Pathologist, Royal Derby Hospital, Derby, UK.)
Current histologic classifications recognize special types of 565
breast cancers (10% of total cases), which are defined by spe-
cific histologic features. To qualify as a special-type cancer, at
least 90% of the cancer must contain the defining histologic
features. About 80% of invasive breast cancers are described as
invasive ductal carcinoma of no special type (NST). These can-
cers generally have a worse prognosis than special-type cancers.
Foote and Stewart originally proposed the following classifica-
tion for invasive breast cancer130:
CHAPTER 17 THE BREAST
1. Paget’s disease of the nipple
2. Invasive ductal carcinoma—Adenocarcinoma with produc-
tive fibrosis (scirrhous, simplex, NST), 80%
3. Medullary carcinoma, 4%
4. Mucinous (colloid) carcinoma, 2%
5. Papillary carcinoma, 2%
6. Tubular carcinoma, 2%
7. Invasive lobular carcinoma, 10%
8. Rare cancers (adenoid cystic, squamous cell, apocrine)
Paget’s disease of the nipple was described in 1874. It fre-
quently presents as a chronic, eczematous eruption of the nipple,
which may be subtle but may progress to an ulcerated, weeping
lesion. Paget’s disease usually is associated with extensive DCIS
and may be associated with an invasive cancer. A palpable mass
may or may not be present. A nipple biopsy specimen will show
a population of cells that are identical to the underlying DCIS
cells (pagetoid features or pagetoid change). Pathognomonic
of this cancer is the presence of large, pale, vacuolated cells
(Paget cells) in the rete pegs of the epithelium. Paget’s disease
may be confused with superficial spreading melanoma. Differ-
entiation from pagetoid intraepithelial melanoma is based on the
presence of S-100 antigen immunostaining in melanoma and
carcinoembryonic antigen immunostaining in Paget’s disease.
or mastectomy, depending on the extent of involvement of the
nipple-areolar complex and the presence of DCIS or invasive
cancer in the underlying breast parenchyma.
Invasive ductal carcinoma of the breast with productive
fibrosis (scirrhous, simplex, NST) accounts for 80% of breast
cancers and presents with macroscopic or microscopic axillary
lymph node metastases in up to 25% of screen-detected cases
and up to 60% of symptomatic cases. This cancer occurs most
frequently in perimenopausal or postmenopausal women in the
fifth to sixth decades of life as a solitary, firm mass. It has poorly
defined margins, and its cut surfaces show a central stellate con-
figuration with chalky white or yellow streaks extending into
surrounding breast tissues. The cancer cells often are arranged
in small clusters, and there is a broad spectrum of histologic
types with variable cellular and nuclear grades (Fig. 17-16A
and B). In a large patient series from the SEER database, 75%
of ductal cancers showed estrogen receptor expression.133
it accounts for 4% of all invasive breast cancers and is a fre-
quent phenotype of BRCA1 hereditary breast cancer. Grossly,
the cancer is soft and hemorrhagic. A rapid increase in size
may occur secondary to necrosis and hemorrhage. On physi-
cal examination, it is bulky and often positioned deep within
the breast. Bilaterality is reported in 20% of cases. Medullary
carcinoma is characterized microscopically by: (a) a dense lym-
phoreticular infiltrate composed predominantly of lymphocytes
and plasma cells; (b) large pleomorphic nuclei that are poorly
566
PART II
SPECIFIC CONSIDERATIONS

A B

Figure 17-16. Invasive ductal carcinoma with productive fibrosis (scirrhous, simplex, no special type) A. 100x. B. 200x. (Used with permis-
sion from Dr. Sindhu Menon, Consultant Histopathologist and Dr. Rahul Deb, Consultant Histopathologist and Lead Breast Pathologist,
Royal Derby Hospital, Derby, UK.)

differentiated and show active mitosis; and (c) a sheet-like by mammographic screening and usually is diagnosed in the
growth pattern with minimal or absent ductal or alveolar dif- perimenopausal or early menopausal periods. Under low-power
ferentiation. Approximately 50% of these cancers are associated magnification, a haphazard array of small, randomly arranged
with DCIS, which characteristically is present at the periphery tubular elements is seen. In a large SEER database 94% of
of the cancer, and <10% demonstrate hormone receptors. In rare tubular cancers were reported to express estrogen receptor.133
circumstances, mesenchymal metaplasia or anaplasia is noted. Approximately 10% of women with tubular carcinoma or with
Because of the intense lymphocyte response associated with invasive cribriform carcinoma, a special-type cancer closely
the cancer, benign or hyperplastic enlargement of the lymph related to tubular carcinoma, will develop axillary lymph node
nodes of the axilla may contribute to erroneous clinical staging. metastases. However, the presence of metastatic disease in one
Women with this cancer have a better 5-year survival rate than or two axillary lymph nodes does not adversely affect survival.
those with NST or invasive lobular carcinoma. Distant metastases are rare in tubular carcinoma and invasive
Mucinous carcinoma (colloid carcinoma), another spe- cribriform carcinoma. Long-term survival approaches 100%.
cial-type breast cancer, accounts for 2% of all invasive breast Invasive lobular carcinoma accounts for 10% of breast
cancers and typically presents in the older population as a bulky cancers. The histopathologic features of this cancer include
tumor. This cancer is defined by extracellular pools of mucin, small cells with rounded nuclei, inconspicuous nucleoli, and
which surround aggregates of low-grade cancer cells. The cut scant cytoplasm (Fig. 17-17). Special stains may confirm the
surface of this cancer is glistening and gelatinous in quality.
Fibrosis is variable, and when abundant it imparts a firm consis-
tency to the cancer. Over 90% of mucinous carcinomas display
hormone receptors.133 Lymph node metastases occur in 33%
of cases, and 5- and 10-year survival rates are 73% and 59%,
respectively. Because of the mucinous component, cancer cells
may not be evident in all microscopic sections, and analysis
of multiple sections is essential to confirm the diagnosis of a
mucinous carcinoma.
Papillary carcinoma is a special-type cancer of the breast
that accounts for 2% of all invasive breast cancers. It generally
presents in the seventh decade of life and occurs in a dispropor-
tionate number of nonwhite women. Typically, papillary car-
cinomas are small and rarely attain a size of 3 cm in diameter.
These cancers are defined by papillae with fibrovascular stalks
and multilayered epithelium. In a large series from the SEER
database 87% of papillary cancers have been reported to express
estrogen receptor.133 McDivitt and colleagues noted that these
tumors showed a low frequency of axillary lymph node metas- Figure 17-17. Lobular carcinoma (100×). Uniform, relatively
tases and had 5- and 10-year survival rates similar to those for small lobular carcinoma cells are seen arranged in a single-file
mucinous and tubular carcinoma.134 orientation (“Indian file”). (Used with permission from Dr. Sindhu
Tubular carcinoma is another special-type breast cancer Menon, Consultant Histopathologist and Dr. Rahul Deb, Consul-
and accounts for 2% of all invasive breast cancers. It is reported tant Histopathologist and Lead Breast Pathologist, Royal Derby
in as many as 20% of women whose cancers are diagnosed Hospital, Derby, UK.)
presence of intracytoplasmic mucin, which may displace the
nucleus (signet-ring cell carcinoma). At presentation, invasive
lobular carcinoma varies from clinically inapparent carcinomas
to those that replace the entire breast with a poorly defined mass.
It is frequently multifocal, multicentric, and bilateral. Because
of its insidious growth pattern and subtle mammographic fea-
tures, invasive lobular carcinoma may be difficult to detect.
Over 90% of lobular cancers express estrogen receptor.133
DIAGNOSIS OF BREAST CANCER
In ∼30% of cases, the woman discovers a lump in her breast.
Other less frequent presenting signs and symptoms of breast
cancer include: (a) breast enlargement or asymmetry; (b) nipple
changes, retraction, or discharge; (c) ulceration or erythema of
the skin of the breast; (d) an axillary mass; and (e) musculoskel-
etal discomfort. However, up to 50% of women presenting with
breast complaints have no physical signs of breast pathology.
Breast pain usually is associated with benign disease.
Misdiagnosed breast cancer accounts for the greatest num-
ber of malpractice claims for errors in diagnosis and for the
largest number of paid claims. Litigation often involves younger
women, whose physical examination and mammogram may
be misleading. If a young woman (≤45 years) presents with a
palpable breast mass and equivocal mammographic findings,
ultrasound examination and biopsy are used to avoid a delay
in diagnosis.
Examination
Inspection. The clinician inspects the woman’s breast with
her arms by her side (Fig. 17-18A), with her arms straight up
in the air (Fig. 17-18B), and with her hands on her hips (with
and without pectoral muscle contraction).135,136 Symmetry, size,
and shape of the breast are recorded, as well as any evidence of
edema (peau d’orange), nipple or skin retraction, or erythema.
With the arms extended forward and in a sitting position, the
woman leans forward to accentuate any skin retraction.
Figure 17-18. Examination of the breast. A. Inspection of the
breast with arms at sides. B. Inspection of the breast with arms
raised. C. Palpation of the breast with the patient supine. D. Palpa-
tion of the axilla.
567
CHAPTER 17 THE BREAST
Figure 17-19. A breast examination record.
Palpation. As part of the physical examination, the breast is
carefully palpated. With the patient in the supine position (see
Fig. 17-18C) the clinician gently palpates the breasts, making
certain to examine all quadrants of the breast from the sternum
laterally to the latissimus dorsi muscle and from the clavicle
inferiorly to the upper rectus sheath. The examination is per-
formed with the palmar aspects of the fingers, avoiding a grasp-
ing or pinching motion. The breast may be cupped or molded
in the examiner’s hands to check for retraction. A systematic
search for lymphadenopathy then is performed. Figure 17-18D
shows the position of the patient for examination of the axilla.
By supporting the upper arm and elbow, the examiner stabi-
lizes the shoulder girdle. Using gentle palpation, the clinician
assesses all three levels of possible axillary lymphadenopathy.
Careful palpation of supraclavicular and parasternal sites also is
performed. A diagram of the chest and contiguous lymph node
sites is useful for recording location, size, consistency, shape,
mobility, fixation, and other characteristics of any palpable
breast mass or lymphadenopathy (Fig. 17-19).
Imaging Techniques
Mammography. Mammography has been used in North Amer-
ica since the 1960s, and the techniques used continue to be mod-
ified and improved to enhance image quality.137-140 Conventional
mammography delivers a radiation dose of 0.1 cGy per study.
By comparison, chest radiography delivers 25% of this dose.
However, there is no increased breast cancer risk associated
with the radiation dose delivered with screening mammography.
Screening mammography is used to detect unexpected breast
cancer in asymptomatic women. In this regard, it supplements
history taking and physical examination. With screening mam-
mography, two views of the breast are obtained: the craniocau-
dal (CC) view (Fig. 17-20A,B) and the mediolateral oblique
(MLO) view (Fig. 17-20C,D). The MLO view images the great-
est volume of breast tissue, including the upper outer quadrant
and the axillary tail of Spence. Compared with the MLO view,
the CC view provides better visualization of the medial aspect
of the breast and permits greater breast compression. Diagnos-
tic mammography is used to evaluate women with abnormal
568
PART II
SPECIFIC CONSIDERATIONS

A B

C D

Figure 17-20. A-D. Mammogram of a premenopausal breast with a dense fibroglandular pattern. E-H. Mammogram of a postmenopausal
breast with a sparse fibroglandular pattern. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening,
Royal Derby Hospital, Derby, UK.)

E F
G H
Figure 17-20. (Continued)
findings such as a breast mass or nipple discharge. In addition
to the MLO and CC views, a diagnostic examination may use
views that better define the nature of any abnormalities, such as
the 90° lateral and spot compression views. The 90° lateral view
is used along with the CC view to triangulate the exact location
of an abnormality. Spot compression may be done in any pro-
jection by using a small compression device, which is placed
directly over a mammographic abnormality that is obscured by
569
CHAPTER 17 THE BREAST
overlying tissues (Fig. 17-21C). The compression device mini-
mizes motion artifact, improves definition, separates overlying
tissues, and decreases the radiation dose needed to penetrate
the breast. Magnification techniques (×1.5) often are combined
with spot compression to better resolve calcifications and the
margins of masses. Mammography also is used to guide inter-
ventional procedures, including needle localization and needle
biopsy.
570
PART II
SPECIFIC CONSIDERATIONS
A B
Figure 17-21. Mammogram revealing a small, spiculated mass in the right breast A. A small, spiculated mass is seen in the right breast with
skin tethering (CC view). B. Mass seen on oblique view of the right breast. C. Spot compression mammography view of the cancer seen in
A and B. The spiculated margins of the cancer are accentuated by compression. (Used with permission from Dr. Anne Turnbull, Consultant
Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)
Specific mammographic features that suggest a diagnosis
of breast cancer include a solid mass with or without stellate
features, asymmetric thickening of breast tissues, and clustered
microcalcifications. The presence of fine, stippled calcium in
and around a suspicious lesion is suggestive of breast cancer
and occurs in as many as 50% of nonpalpable cancers. These
microcalcifications are an especially important sign of cancer
in younger women, in whom it may be the only mammographic
abnormality. The clinical impetus for screening mammogra-
phy came from the Health Insurance Plan study and the Breast
Cancer Detection Demonstration Project, which demonstrated
a 33% reduction in mortality for women after72 screening mam-
mography. Mammography was more accurate than clinical
examination for the detection of early breast cancers, providing
a true-positive rate of 90%. Only 20% of women with nonpal-
pable cancers had axillary lymph node metastases, compared
with 50% of women with palpable cancers.141 Current guide-
lines of the National Comprehensive Cancer Network suggest
that normal-risk women ≥20 years of age should have a breast
examination at least every 3 years. Starting at age 40 years,
breast examinations should be performed yearly, and a yearly
mammogram should be taken.142 Screening mammography in
women ≥50 years of age has been noted to reduce breast cancer
mortality by 20% to 25%.72,79 With the increased discussion
about the potential harms associated with breast screening, the
United Kingdom recently established an independent expert
panel to review the published literature and estimate the ben-
efits and harms associated with its national screening program
for women age >50 years. The panel estimated that in women
invited to screening, about 11% of the cancers diagnosed in
their lifetime constitute overdiagnosis. Despite this overdiagno-
sis, the panel concluded that breast screening programs confer
significant benefit and should continue. The use of screening
C
mammography in women <50 years of age is more controversial
for previously noted reasons: (a) reduced sensitivity, (b) reduced
specificity, and (c) lower incidence of breast cancer. Because of
the combination of these three reasons, targeting mammography
screening to women <50 years of age, who are at higher risk of
breast cancer, improves the balance of risks and benefits and is
the approach some health care systems have taken. There are
now a number of risk assessment models—as described earlier
in this chapter—that can be used to estimate a younger woman’s
risk of developing breast cancer and that help assess the risks
and benefits of regular screening.
Screen film mammography has replaced xeromam-
mography because it requires a lower dose of radiation and
provides similar image quality. Digital mammography was
developed to allow the observer to manipulate the degree
of contrast in the image. This is especially useful in women
with dense breasts and women <50 years of age. Recently,
investigators directly compared digital vs. screen film mam-
mography in a prospective (DMIST) trial that enrolled over
42,000 women.143 The investigators found that digital and
screen film mammography had similar accuracy; however,
digital mammography was more accurate in women <50 years
of age, women with mammographically dense breasts, and
premenopausal or perimenopausal women. The use of digital
breast tomosynthesis with 3D images has been introduced as
an alternative to standard 2D mammography imaging that is
limited by superimposition of breast parenchyma and breast
density.144,145 The STORM trial reported that in 7,292 women
screened, 3D mammography had a higher cancer detection
rate and fewer false-positive recalls than the standard 2D
imaging.146,147 Randomized controlled trials are planned to fur-
ther study tomosynthesis and its role in breast cancer screen-
ing. Standard two-dimensional mammography has limitations,
such as the parenchymal density or superimposition of breast 571
tissue, which obscures cancers or causes normal structures to
appear suspicious reducing the sensitivity of mammography
and increasing the false-positive rates. Digital breast tomo-
synthesis is a technology developed to assist with overcom-
ing these limitations. In digital breast tomosynthesis, multiple
projection images are reconstructed to allow visual review of
thin breast sections, each reconstructed slice as thin as 0.5 mm,
which provides better characterization of noncalcified lesions.
These multiple projection exposures are obtained by a digi-

CHAPTER 17 THE BREAST

tal detector from a mammography X-ray source that moves
through a limited arc angle while the breast is compressed.
Then these projection image data sets are reconstructed using
specific algorithms, which provide the clinical reader a series
of images through the entire breast.148
In 2011, tomosynthesis was approved by the U.S. Food
and Drug Administration (FDA) to be used in combination with
standard digital mammography for breast cancer screening. The
total radiation dose when tomosynthesis is added is about twice
the current dose of digital mammography alone but remains
below the limits set by the FDA.149
The STORM-2 trial reported that synthetic 2D-3D
A
mammography yields similar breast cancer detection as dual-
acquisition 2D-3D mammography with the advantage of reduc-
ing radiation exposure.150
Contrast-enhanced digital mammography (CEDM) was
also approved by the FDA in 2001, which utilizes an iodinated
contrast material and modified digital mammography units for
imaging.148 CEDM has been shown to be feasible and detects
breast cancers at a rate similar to MRI, which has potential to
offer an alternative to MRI.151 The advantages of CEDM over
MRI are that the use of compression limits motion, there is
decrease in cost, decrease in exam time, and there is an option
for patients who are unable to tolerate MRI or who due to vari-
ous reasons cannot have MRI due to incompatibility, such as the
presence of a pacemaker or tissue expanders.148,152
Ductography. The primary indication for ductography is
nipple discharge, particularly when the fluid contains blood.
Radiopaque contrast media is injected into one or more of the
major ducts, and mammography is performed. A duct is gen-
tly enlarged with a dilator, and then a small, blunt cannula is
inserted under sterile conditions into the nipple ampulla. With
the patient in a supine position, 0.1 to 0.2 mL of dilute con-
trast media is injected, and CC and MLO mammographic views
are obtained without compression. Intraductal papillomas are B
seen as small filling defects surrounded by contrast media
(Fig. 17-22). Cancers may appear as irregular masses or as mul- Figure 17-22. Ductogram. Craniocaudal (A) and mediolateral
tiple intraluminal filling defects. oblique (B) mammographic views demonstrate a mass (arrows)
posterior to the nipple and outlined by contrast, which also fills
Ultrasonography. Second only to mammography in fre- the proximal ductal structures. (Used with permission from B.
quency of use for breast imaging, ultrasonography is an impor- Steinbach.)
tant method of resolving equivocal mammographic findings,
defining cystic masses, and demonstrating the echogenic qual-
ities of specific solid abnormalities. On ultrasound examina- of breast lesions. Its findings are highly reproducible, and
tion, breast cysts are well circumscribed, with smooth margins it has a high patient acceptance rate, but it does not reliably
and an echo-free center (Fig. 17-23). Benign breast masses detect lesions that are ≤1 cm in diameter. Ultrasonography can
usually show smooth contours, round or oval shapes, weak also be utilized to image the regional lymph nodes in patients
internal echoes, and well-defined anterior and posterior mar- with breast cancer (Fig. 17-26). The sensitivity of examination
gins (Fig. 17-24). Breast cancer characteristically has irregular for the status of axillary nodes ranges from 35% to 82% and
walls (Fig. 17-25) but may have smooth margins with acous- specificity ranges from 73% to 97%. The features of a lymph
tic enhancement. Ultrasonography is used to guide fine-needle node involved with cancer include cortical thickening, change
aspiration biopsy, core-needle biopsy, and needle localization in shape of the node to more circular appearance, size larger
572
PART II
SPECIFIC CONSIDERATIONS
B echoes.153
C a known breast cancer has shown a contralateral breast cancer
Figure 17-23. Breast cyst. A. Simple cyst. Ultrasound image
of the mass shows it to be anechoic with a well-defined back
wall, characteristic of a cyst. B. Complex solid and cystic mass.
C. Complex solid and cystic mass characteristic of intracystic
papillary tumor. (Used with permission from Dr. Anne Turnbull,
Consultant Radiologist/Director of Breast Screening, Royal Derby
Hospital, Derby, UK.)
A
Figure 17-24. Ultrasonography images of benign breast tumors.
A. Fibroadenoma. B. Intraductal papilloma (see arrow). (Used with
permission from Dr. Anne Turnbull, Consultant Radiologist/Director
of Breast Screening, Royal Derby Hospital, Derby, UK.)
than 10 mm, absence of a fatty hilum and hypoechoic internal
Magnetic Resonance Imaging. In the process of evaluating
magnetic resonance imaging (MRI) as a means of character-
izing mammographic abnormalities, additional breast lesions
have been detected. However, in the circumstance of negative
findings on both mammography and physical examination,
the probability of a breast cancer being diagnosed by MRI
is extremely low. There is current interest in the use of MRI
to screen the breasts of high-risk women and of women with
a newly diagnosed breast cancer. In the first case, women
who have a strong family history of breast cancer or who
carry known genetic mutations require screening at an early
age because mammographic evaluation is limited due to the
increased breast density in younger women. In the second
case, an MRI study of the contralateral breast in women with
in 5.7% of these women (Fig. 17-27). MRI can also detect
additional tumors in the index breast (multifocal or multicen-
tric disease) that may be missed on routine breast imaging and
this may alter surgical decision making (Fig. 17-28). In fact,
MRI has been advocated by some for routine use in surgical
treatment planning based on the fact that additional disease
can be identified with this advanced imaging modality and the
 573

CHAPTER 17 THE BREAST

B
A

C D

Figure 17-25. Ultrasonography images of malignant breast lesions. A. 25 mm irregular mass. B. Ultrasound 30 mm mass anterior to an
implant. C. Ultrasound breast cancer with calcification. D. Ultrasound shows a 9 mm spiculated mass (see arrow) with attenuation. (Used with
permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)

extent of disease may be more accurately assessed. A random-
ized trial performed in the United Kingdom (COMICE trial)
that enrolled 1623 women did not show a decrease in rates of
reoperation in those women randomized to undergo MRI in
addition to mammography and ultrasonography (19%) com-
pared to those undergoing standard breast imaging without
MRI (19%).154 Houssami and colleagues performed a meta-
analysis including two randomized trials and seven compara-
tive cohort studies to examine the effect of preoperative MRI
compared to standard preoperative evaluation on surgical out-
comes.155 They reported that the use of MRI was associated
with increased mastectomy rates. This is problematic because
there is no evidence that the additional disease detected by
MRI is of clinical or biologic significance, particularly in
light of the low local-regional failure rates currently reported
in patients undergoing breast conserving surgery who receive
whole breast irradiation and systemic therapies. There is an
ongoing trial in the Alliance for Clinical Trials in Oncology
that is randomizing patients to preoperative MRI vs. standard
imaging to assess the impact of MRI on local regional recur-
rence rates in patients with triple receptor negative and HER2
positive breast cancers.
The use of dedicated breast coils is mandatory in the MRI
imaging of the breast. A BIRADS lexicon is assigned to each
examination and an abnormality noted on MRI that is not seen
on mammography requires a focused ultrasound examination
for further assessment. If the abnormality is not seen on corre-
sponding mammogram or ultrasound, then MRI-guided biopsy
is necessary. Some clinical scenarios where MRI may be use-
ful include the evaluation of a patient who presents with nodal
metastasis from breast cancer without an identifiable primary
tumor; to assess response to therapy in the setting of neoadjuvant
574
PART II
SPECIFIC CONSIDERATIONS
B Director of Breast Screening, Royal Derby Hospital, Derby, UK.)
systemic treatment; to select patients for partial breast irradia-
tion techniques; and evaluation of the treated breast for tumor
recurrence.
Breast Biopsy
Nonpalpable Lesions. Image-guided breast biopsy specimens
are frequently required to diagnose nonpalpable lesions.156
Ultrasound localization techniques are used when a mass is
present, whereas stereotactic techniques are used when no mass
is present (microcalcifications or architectural distortion only).
The combination of diagnostic mammography, ultrasound or
stereotactic localization, and fine-needle aspiration (FNA)
biopsy achieves almost 100% accuracy in the preoperative diag-
nosis of breast cancer. However, although FNA biopsy permits
Figure 17-26. Ultrasonography images of lymph nodes. A. Nor-
mal axillary lymph node (see arrows). B. Indeterminate axillary
lymph node. C. Malignant appearing axillary lymph node. (Used
with permission from Dr. Anne Turnbull, Consultant Radiologist/
cytologic evaluation, core-needle permits the analysis of breast
tissue architecture and allows the pathologist to determine
whether invasive cancer is present. This permits the surgeon and
patient to discuss the specific management of a breast cancer
before therapy begins. Core-needle biopsy is preferred over
open biopsy for nonpalpable breast lesions because a single sur-
gical procedure can be planned based on the results of the core
biopsy. The advantages of core-needle biopsy include a
7 low complication rate, minimal scarring, and a lower cost
compared with excisional breast biopsy.
Palpable Lesions. FNA or core biopsy of a palpable breast mass
can usually be performed in an outpatient setting.157 A 1.5-in,
22-gauge needle attached to a 10-mL syringe or a 14-gauge
core biopsy needle is used. For FNA, use of a syringe holder
Figure 17-27. MRI examination revealing contral-
ateral breast cancer (see arrows) in a patient diag-
nosed with unilateral breast cancer on mammography
(two arrows). (Used with permission from Dr. Anne
Turnbull, Consultant Radiologist/Director of Breast
Screening, Royal Derby Hospital, Derby, UK.)

enables the surgeon performing the FNA biopsy to control the
syringe and needle with one hand while positioning the breast
mass with the opposite hand. After the needle is placed in the
mass, suction is applied while the needle is moved back and
forth within the mass. Once cellular material is seen at the hub
of the needle, the suction is released and the needle is with-
drawn. The cellular material is then expressed onto microscope
slides. Both air-dried and 95% ethanol–fixed microscopic sec-
tions are prepared for analysis. When a breast mass is clinically
and mammographically suspicious, the sensitivity and specific-
ity of FNA biopsy approaches 100%. Core-needle biopsy of
palpable breast masses is performed using a 14-gauge needle,
such as the Tru-Cut needle. Automated devices also are avail-
able. Vacuum-assisted core biopsy devices (with 8–10 gauge
needles) are commonly utilized with image guidance where
between 4 and 12 samples can be acquired at different posi-
tions within a mass, area of architectural distortion or micro-
calcifications. If the target lesion was microcalcifications, the
specimen should be radiographed to confirm appropriate sam-
pling. A radiopaque marker should be placed at the site of the
biopsy to mark the area for future intervention. In some cases
the entire lesion is removed with the biopsy technique and clip
placement allows for accurate targeting of the site for surgi-
cal resection. Tissue specimens are placed in formalin and then
processed to paraffin blocks. Although the false-negative rate
for core-needle biopsy specimens is very low, a tissue speci-
men that does not show breast cancer cannot conclusively rule
out that diagnosis because a sampling error may have occurred.
The clinical, radiographic, and pathologic findings should be
in concordance. If the biopsy findings do not concur with the
clinical and radiographic findings, the multidisciplinary team
(including clinician, radiologist, and pathologist) should review
the findings and decide whether or not to recommend an image-
guided or open biopsy to be certain that the target lesion has
been adequately sampled for diagnosis.
BREAST CANCER STAGING AND BIOMARKERS
Breast Cancer Staging
The clinical stage of breast cancer is determined primarily
through physical examination of the skin, breast tissue, and
regional lymph nodes (axillary, supraclavicular, and internal
mammary).158 However, clinical determination of axillary lymph
node metastases has an accuracy of only 33%. Ultrasound (US)
is more sensitive than physical examination alone in determining
axillary lymph node involvement during preliminary staging of
breast carcinoma. FNA or core biopsy of sonographically inde-
terminate or suspicious lymph nodes can provide a more defini-
tive diagnosis than US alone.153,159 Pathologic stage combines
575
Figure 17-28. MRI imaging of the breast reveal-
ing multifocal tumors not detected with standard
breast imaging. (Used with permission from Dr. Anne
Turnbull, Consultant Radiologist/Director of Breast
Screening, Royal Derby Hospital, Derby, UK.)
CHAPTER 17 THE BREAST
the findings from pathologic examination of the resected pri-
mary breast cancer and axillary or other regional lymph nodes.
Fisher and colleagues found that accurate predictions regarding
the occurrence of distant metastases were possible after resec-
tion and pathologic analysis of 10 or more levels I and II axillary
lymph nodes.160 A frequently used staging system is the TNM
(tumor, nodes, and metastasis) system. The American Joint
Committee on Cancer (AJCC) has recently modified the TNM
system for breast cancer to include both anatomic and biologic
factors161 (Tables 17-10 and 17-11). Koscielny and colleagues
demonstrated that tumor size correlates with the presence of
axillary lymph node metastases (see Fig. 17-14B). Others have
shown an association between tumor size, axillary lymph node
metastases, and disease-free survival. One of the most important
predictors of 10- and 20-year survival rates in breast cancer is
the number of axillary lymph nodes involved with metastatic
disease. Routine biopsy of internal mammary lymph nodes is
not generally performed; however, it has been reported that in
the context of a “triple node” biopsy approach either the internal
mammary node or a low axillary node when positive alone
carried the same prognostic weight. When both nodes were
positive, the prognosis declined to the level associated with
apical node positivity. A double node biopsy of the low axil-
lary node and either the apical or the internal mammary node
gave the same maximum prognostic information as a triple node
biopsy.162 With the advent of sentinel lymph node dissection
and the use of preoperative lymphoscintigraphy for localization
of the sentinel nodes, surgeons have again begun to biopsy the
internal mammary nodes but in a more targeted manner. The
8th edition of the AJCC staging system does allow for staging
based on findings from the internal mammary sentinel nodes.163
Drainage to the internal mammary nodes is more frequent with
central and medial quadrant cancers. Clinical or pathologic evi-
dence of metastatic spread to supraclavicular lymph nodes is
no longer considered stage IV disease, but routine scalene or
supraclavicular lymph node biopsy is not indicated.
Biomarkers
Breast cancer biomarkers are of several types. Risk factor
biomarkers are those associated with increased cancer risk.164-
168
These include familial clustering and inherited germline
abnormalities, proliferative breast disease with atypia, and
mammographic density. Exposure biomarkers are a subset of
risk factors that include measures of carcinogen exposure such
as DNA adducts. Surrogate endpoint biomarkers are biologic
alterations in tissue that occur between cancer initiation and
development. These biomarkers are used as endpoints in short-
term chemoprevention trials and include histologic changes,
indices of proliferation, and genetic alterations leading to
cancer. Prognostic biomarkers provide information regarding
576 Table 17-10
TNM staging system for breast cancer
Primary tumor (T)
The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size
should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification,
it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of
1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p”
modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic
measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size.
TX Primary tumor cannot be assessed
PART II

T0 No evidence of primary tumor

Tis (DCIS)* Ductal carcinoma in situ
Tis (Paget) Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the
underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are
categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget
SPECIFIC CONSIDERATIONS

disease should still be noted.

T1 Tumor ≤20 mm in greatest dimension
T1mi Tumor ≤1 mm in greatest dimension
T1a Tumor >1 mm but ≤5 mm in greatest dimension (round any measurement >l.0–1.9 mm to 2 mm).
T1b Tumor >5 mim but ≤10 mm in greatest dimension
T1c Tumor >10 mm but ≤20 mm in greatest dimension
T2 Tumor >20 mm but ≤50 mm in greatest dimension
T3 Tumor >50 mm in greatest dimension
T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules);
invasion of the dermis alone does not qualify as T4
T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall
structures does not qualify as T4
T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin
that does not meet the criteria for inflammatory carcinoma
T4c Both T4a and T4b are present
T4d Inflammatory carcinoma (see section “Rules for Classification”)
*Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th edition.
Regional lymph nodes—Clinical (N)
cNX* Regional lymph nodes cannot be assessed (e.g., previously removed)
cN0 No regional lymph node metastases (by imaging or clinical examination)
cN1 Metastases to movable ipsilateral Level I, II axillary lymph node(s)
cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)
cN2 Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;
or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases
cN2a Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures
cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases
cN3 Metastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary
lymph node involvement;
or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases;
or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph
cN3a node involvement
cN3b Metastases in ipsilateral infraclavicular lymph node(s)
cN3c Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
Metastases in ipsilateral supraclavicular lymph node(s)
Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core
needle biopsy respectively.
*the cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of
physical examination of the axilla.
**cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases
treated with neoadjuvant therapy.

(Continued)
Table 17-10 577

TNM staging system for breast cancer (Continued)

Regional lymph nodes—Pathologic (pN)
pNX Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)
pN0 No regional lymph node metastasis identified or ITCs only
pN0(i+) ITCs only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s)
pN0(mol+) Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected
pN1 Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes
with micrometastases or macrometastases by sentinel lymph node biopsy

CHAPTER 17 THE BREAST

pN1mi Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)
pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis larger than 2.0 mm
pN1b Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs
pN1c pN1a and pNlb combined
pN2 Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in
the absence of axillary lymph node metastases
pN2a Metastases in 4–9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)
pN2b Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation;
with pathologically negative axillary nodes
pN3 Metastases in 10 or more axillary lymph nodes;
or in infraclavicular (Level III axillary) lymph nodes;
or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive
Level I, II axillary lymph nodes;
or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node
biopsy in clinically negative ipsilateral internal mammary lymph nodes;
pN3a or in ipsilateral supraclavicular lymph nodes
Metastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm);
pN3b or metastases to the infraclavicular (Level III axillary lymph) nodes
pNla or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
pN3c or pN2a in the presence of pNlb
Metastases in ipsilateral supraclavicular lymph nodes
Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy
respectively, with NO further resection of nodes.
Distant metastasis (M)
M0 No clinical or radiographic evidence of distant metastases*
cM0(i+) No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger
than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other
nonregional nodal tissue in a patient without symptoms or signs of metastases
cM1 Distant metastases detected by clinical and radiographic means
pM1 Any histologically proven metastases in distant organs; or if in non-regional nodes, metastases greater than
0.2 mm
Used with the permission of the American College of Surgeons. Amin MB, Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed. Springer
New York, 2017.

cancer outcome irrespective of therapy, whereas predictive bio-
markers provide information regarding response to therapy.169
Candidate prognostic and predictive biomarkers and biologic
targets for breast cancer include (a) the steroid hormone recep-
tor pathway; (b) growth factors and growth factor receptors
such as human epidermal growth factor receptor 2 (HER2)/
neu, epidermal growth factor receptor (EGFR), transforming
growth factor, platelet-derived growth factor, and the insulin-
like growth factor family; (c) indices of proliferation such as
proliferating cell nuclear antigen (PCNA) and Ki-67; (d) indi-
ces of angiogenesis such as vascular endothelial growth factor
(VEGF) and the angiogenesis index; (e) the mammalian target
of rapamycin (mTOR) signaling pathway; (f) tumor-suppressor
genes such as p53; (g) the cell cycle, cyclins, and cyclin-depen-
dent kinases; (h) the proteasome; (i) the COX-2 enzyme; (j) the
peroxisome proliferator-activated receptors (PPARs); and (k)
indices of apoptosis and apoptosis modulators such as bcl-2
and the bax:bcl-2 ratio.
Steroid Hormone Receptor Pathway. Hormones play an
important role in the development and progression of breast
cancer. Estrogens, estrogen metabolites, and other steroid hor-
mones such as progesterone all have been shown to have an
effect. Breast cancer risk is related to estrogen exposure over
time. In postmenopausal women, hormone replacement therapy
consisting of estrogen plus progesterone increases the risk of
breast cancer by 26% compared to placebo.70 Patients with hor-
mone receptor-positive tumors survive two to three times longer
after a diagnosis of metastatic disease than do patients with hor-
mone receptor-negative tumors. Patients with tumors negative
for both estrogen receptors and progesterone receptors are not
considered candidates for hormonal therapy. Tumors positive
578 Table 17-11
cancer specimens. The tumor hormone receptor status should
be ascertained for both premenopausal and postmenopausal
TNM stage groupings patients to identify patients who are most likely to benefit from
endocrine therapy.
Then the stage
When T is... And N is... And M is... group is... Growth Factor Receptors and Growth Factors. Overexpres-
sion of EGFR in breast cancer correlates with estrogen recep-
Tis N0 M0 0 tor–negative status and with p53 overexpression.170-172 Similarly,
T1 N0 M0 IA increased immunohistochemical membrane staining for the
T0 N1mi M0 IB HER2 growth factor receptor in breast cancer is associated with
mutated TP53, Ki67 overexpression, and estrogen receptor–
T1 N1mi M0 IB
negative status. HER2 is a member of the ErbB family of
PART II

T0 N1 M0 IIA growth factor receptors in which ligand binding results in recep-

T1 N1 M0 IIA tor homodimerization and tyrosine phosphorylation by tyrosine
T2 N0 M0 IIA kinase domains within the receptor. Tyrosine phosphorylation
T2 N1 M0 IIB is followed by signal transduction, which results in changes in
cell behavior. An important property of this family of receptors
T3 N0 M0 IIB
SPECIFIC CONSIDERATIONS

is that ligand binding to one receptor type also may result in

T0 N2 M0 IIIA heterodimerization between two different receptor types that are
T1 N2 M0 IIIA coexpressed; this leads to transphosphorylation and transactiva-
T2 N2 M0 IIIA tion of both receptors in the complex (transmodulation). In this
context, the lack of a specific ligand for the HER2/neu receptor
T3 N1 M0 IIIA
suggests that HER2/neu may function solely as a co-receptor,
T3 N2 M0 IIIA modulating signaling by other EGFR family members. HER2/
T4 N0 M0 IIIB neu is both an important prognostic factor and a predictive fac-
T4 N1 M0 IIIB tor in breast cancer.173 When overexpressed in breast cancer,
T4 N2 M0 IIIB
HER2/neu promotes enhanced growth and proliferation, and
increases invasive and metastatic capabilities. Clinical studies
Any T N3 M0 IIIC have shown that patients with HER2/neu–overexpressing breast
Any T Any N M1 IV cancer have poorly differentiated tumors with high prolifera-
Notes: tion rates, positive lymph nodes, decreased hormone receptor
1. T1 includes Tl mi. expression, and an increased risk of recurrence and death due
2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as to breast cancer.173-177 Routine testing of the primary tumor
Stage IB.
specimen for HER2/neu expression should be performed on
3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged
using the N1 category. all invasive breast cancers. This can be done with immunohis-
4. M0 includes M0(i+). tochemical analysis to evaluate for overexpression of the cell-
5. The designation pM0 is not valid; any M0 is clinical. surface receptor at the protein level or by using fluorescence
6. If a patient presents with M1 disease prior to neoadjuvant systemic in situ hybridization to evaluate for gene amplification. While
therapy, the stage is Stage IV and remains Stage IV regardless of HER2/ERBB2 activation can also be assessed based on mRNA
response to neoadjuvant therapy. expression and reverse transcription polymerase chain reaction
7. Stage designation may be changed if postsurgical imaging studies
(RT-PCR) (Oncotype Dx, Genomic Health), this approach is not
reveal the presence of distant metastases, provided the studies are per-
formed within 4 months of diagnosis in the absence of disease progres- recommended for clinical decision-making because of the high
sion, and provided the patient has not received neoadjuvant therapy. false negative rate.178 Patients whose tumors show HER2 ampli-
8. Staging following neoadjuvant therapy is denoted with a “yc” or “yp” fication or HER2/neu protein overexpression are candidates for
prefix to the T and N classification. There is no anatomic stage group anti-HER2/neu therapy. Trastuzumab (Herceptin) is a recombi-
assigned if there is a complete pathological response (pCR) to neoad- nant humanized monoclonal antibody directed against HER2.
juvant therapy, for example, ypT0ypN0cM0.
Randomized clinical trials have demonstrated that single-agent
Used with the permission of the American College of Surgeons. Amin MB,
Edge SB, Greene FL, et al. (Eds.) AJCC Cancer Staging Manual, 8th Ed.
trastuzumab therapy is well tolerated and active in the treatment
Springer New York, 2017. of women with HER2/neu–overexpressing metastatic breast
cancer.179 Subsequent adjuvant trials demonstrated that trastu-
zumab also was highly effective in the treatment of women with
early-stage breast cancer when used in combination with che-
for estrogen or progesterone receptors have a higher response
motherapy.180-182 Patients who received trastuzumab in combina-
rate to endocrine therapy than tumors that do not express estro-
tion with chemotherapy had between a 40% and 50% reduction
gen or progesterone receptors. The determination of estrogen
in the risk of breast cancer recurrence and approximately a one-
and progesterone receptor status used to require biochemical
third reduction in breast cancer mortality compared with those
evaluation of fresh tumor tissue. Today, however, estrogen and
who received chemotherapy alone.181,183-185
progesterone receptor status can be measured in archived tis-
sue using immunohistochemical techniques. Hormone receptor Indices of Proliferation. PCNA is a nuclear protein asso-
status also can be measured in specimens obtained with fine- ciated with a DNA polymerase whose expression increases in
needle aspiration biopsy or core-needle biopsy, and this can help phase G1 of the cell cycle, reaches its maximum at the G1/S inter-
guide treatment planning. Testing for estrogen and progesterone face, and then decreases through G2.186-189 Immunohistochemical
receptors should be performed on all primary invasive breast staining for PCNA outlines the proliferating compartments in
breast tissue. Good correlation is noted between PCNA expres-
sion and (a) cell-cycle distributions seen on flow cytometry
based on DNA content, and (b) uptake of bromodeoxyuridine
and the proliferation-associated Ki67 antigen. Individual prolif-
eration markers are associated with slightly different phases of
the cell cycle and are not equivalent. PCNA and Ki67 expression
are positively correlated with p53 overexpression, high S-phase
fraction, aneuploidy, high mitotic index, and high histologic
grade in human breast cancer specimens, and are negatively cor-
related with estrogen receptor content. Ki67 was included with
three other widely measured breast cancer markers (ER, PR,
and HER2) into a panel of four immunohistochemical makers
(IHC4), which together provided similar prognostic informa-
tion to that in the 21 Gene Recurrence Score (Oncotype DX,
Genomic Health).190 While there has been significant interest in
using Ki67 as a biomarker, and while the IHC4 panel would be
much less expensive than the 21 Gene Recurrence Score, there
remain issues regarding reproducibility across laboratories.
Indices of Angiogenesis. Angiogenesis is necessary for the
growth and invasiveness of breast cancer and promotes cancer
progression through several different mechanisms, including
delivery of oxygen and nutrients and the secretion of growth-
promoting cytokines by endothelial cells.191,192 VEGF induces
its effect by binding to transmembrane tyrosine kinase recep-
tors. Overexpression of VEGF in invasive breast cancer is cor-
related with increased microvessel density and recurrence in
node-negative breast cancer. An angiogenesis index has been
developed in which microvessel density (CD31 expression)
is combined with expression of thrombospondin (a negative
modulator of angiogenesis) and p53 expression. Both VEGF
expression and the angiogenesis index may have prognostic
and predictive significance in breast cancer.193 Bevacizumab
(a monoclonal antibody to VEGF) was approved by the FDA
for use in metastatic breast cancer in combination with pacli-
taxel chemotherapy. This approval was based on results from a
phase 3 trial by the Eastern Cooperative Oncology Group. The
group’s E2100 trial showed that when bevacizumab was added
to paclitaxel chemotherapy, median progression-free survival
increased to 11.3 months from the 5.8 months seen in patients
who received paclitaxel alone.194 The results were not repro-
duced in other trials, and the indication for the drug was revoked
by the FDA in 2011.
Indices of Apoptosis. Alterations in programmed cell death
(apoptosis), which may be triggered by p53-dependent or
p53-independent factors, may be important prognostic and pre-
dictive biomarkers in breast cancer.195-197 Bcl-2 family proteins
appear to regulate a step in the evolutionarily conserved pathway
for apoptosis, with some members functioning as inhibitors of
apoptosis and others as promoters of apoptosis. Bcl-2 is the only
oncogene that acts by inhibiting apoptosis rather than by directly
increasing cellular proliferation. The death-signal protein bax
is induced by genotoxic stress and growth factor deprivation
in the presence of wild-type (normal) p53 and/or AP-1/fos.
The bax to bcl-2 ratio and the resulting formation of either bax-
baxhomodimers, which stimulate apoptosis, or bax–bcl-2 het-
erodimers, which inhibit apoptosis, represent an intracellular
regulatory mechanism with prognostic and predictive implica-
tions. In breast cancer, overexpression of bcl-2 and a decrease
in the bax to bcl-2 ratio correlate with high histologic grade,
the presence of axillary lymph node metastases, and reduced
disease-free and overall survival rates. Similarly, decreased bax
expression correlates with axillary lymph node metastases, a 579
poor response to chemotherapy, and decreased overall survival.
The remaining biomarkers and biologic targets listed ear-
lier are still in preclinical testing, and clinical trials are evaluat-
ing their importance in breast cancer for both prognostic and
predictive purposes.
Coexpression of Biomarkers. Selection of optimal therapy
for breast cancer requires both an accurate assessment of prog-
nosis and an accurate prediction of response to therapy. The
breast cancer markers that are most important in determining
CHAPTER 17 THE BREAST
therapy are estrogen receptor, progesterone receptor, and HER2/
neu. Clinicians evaluate clinical and pathologic staging and the
expression of estrogen receptor, progesterone receptor, and
HER2/neu in the primary tumor to assess prognosis and assign
therapy. Adjuvant! Online (http://www.adjuvantonline.com) is
one of a number of programs available to clinicians that incor-
porates clinical and pathologic factors for an individual patient
and calculates risk of recurrence and death due to breast cancer
and then provides an assessment of the reduction in risk of
recurrence that would be expected with the use of combination
chemotherapy, endocrine therapy, or both of these. Adjuvant!
Online was developed using information from the SEER data-
base, the EBCTCG overview analyses, and results from other
individual published trials.198 The website is updated and modi-
fied as new information becomes available. Clinicopathologic
factors are used to separate breast cancer patients into broad
prognostic groups, and treatment decisions are made on this
basis (Table 17-12). Other indices and programs that are vali-
dated and used include the Nottingham Prognostic Index, and
PREDICT.199-201 When an approach, which combines prognostic
factors is used, up to 70% of early breast cancer patients receive
adjuvant chemotherapy that is either unnecessary or ineffective.
As described earlier, a wide variety of biomarkers have been
shown to individually predict prognosis and response to therapy,
but they do not improve the accuracy of either the assessment of
prognosis or the prediction of response to therapy.
As knowledge regarding cellular, biochemical, and molec-
ular biomarkers for breast cancer have improved, prognostic
indices have been developed that combine the predictive power
Table 17-12
Traditional prognostic and predictive factors for
invasive breast cancer
TUMOR FACTORS HOST FACTORS
Nodal status Age
Tumor size Menopausal status
Histologic/nuclear grade Family history
Lymphatic/vascular invasion Previous breast cancer
Pathologic stage Immunosuppression
Hormone receptor status Nutrition
DNA content (ploidy, S-phase Prior chemotherapy
fraction)
Extent of intraductal component Prior radiation therapy
HER2/neu expression  
Modified with permission from Ellis N: Inherited Cancer Syndromes.
New York, NY: Springer-Verlag; 2004.
580 of several individual biomarkers with the relevant clinicopatho-
Table 17-13
logic factors.
Recent technological advances have enabled implemen- Diagnostic studies for breast cancer patients
tation of high throughput gene expression assays in clinical
practice.202 These assays enable detailed stratification of breast   CANCER STAGE
cancer patients for assessment of prognosis and for predic-
tion of response to therapy. The Oncotype DX is a 21-gene   0 I II III IV
RT-PCR–based assay that has been approved for use in newly History & physical X X X X X
diagnosed patients with node-negative, ER-positive breast Complete blood count, platelet     X X X
cancer.203 A recurrence score is generated, and those patients count
with high recurrence scores are likely to benefit from che-
Liver function tests and alkaline     X X X
motherapy, whereas those with low recurrence scores benefit
PART II

phosphatase level
most from endocrine therapy and may not require chemother-
apy. Results from the Trial Assessing Individualized Options Chest radiograph     X X X
for Treatment for breast cancer (TAILORx), designed to pro- Bilateral diagnostic mammograms, X X X X X
spectively validate the use of 21-gene expression assay, have ultrasound as indicated
shown that patients with low recurrence score (0 to 10) have a
SPECIFIC CONSIDERATIONS

Hormone receptor status X X X X X

low rate of local-regional and distant recurrence (98.7%) and
very good overall survival at 5 years (98%) with endocrine
therapy alone without chemotherapy.204 This study has ran-
domly assigned patients with an intermediate recurrence score
(11 to 25) to endocrine therapy alone or to chemotherapy fol-
lowed by endocrine therapy.
Additionally, retrospective analysis has shown that
the 21-gene recurrence score can be used in postmenopausal
patients with ER-positive tumors and 1 to 3 involved axillary
lymph nodes to predict the benefit of chemotherapy in addition
to endocrine therapy.205 Knowledge of the recurrence score has
been shown to alter treatment recommendations by oncologists,
and patients likewise change their decision to undergo treatment
based on the risk of recurrence.206 The MammaPrint assay uses
a 70-gene expression profile to assess the risk of distant metas-
tasis. Mammaprint is FDA approved for use in stage-1 or stage-
2, node negative, ER-positive or ER-negative breast cancers to
identify patients with high or low risk of recurrence. Although
fresh tissue was initially required to perform the assay, it has
since been adapted for use in paraffin-embedded tissue sam-
ples. The prospective RASTER study reported that patients
classified as low risk based on MammaPrint had a 97% distant
recurrence-free interval at five years.207 Results of the prospec-
tive MINDACT (MicroarrayInNode negative and 1–3 positive
lymph node Disease may Avoid ChemoTherapy) trial were
recently reported.208 The study was designed to assess whether
the 70-gene expression assay would help avoid chemotherapy in
patients who are considered clinically high risk but categorized
as low genomic risk based on the assay. A 5-year rate of distant
metastasis-free survival of more than 92% was identified as the
cutoff for the benefit of chemotherapy. At 5 years, the rate of
survival without distant metastasis in patients with high clinical
risk and low genomic risk was 94.7%, meeting the criteria for
noninferiority. However, the rate of disease-free survival and
overall survival was higher with chemotherapy in the intention
to treat population.
OVERVIEW OF BREAST CANCER THERAPY
Before diagnostic biopsy, the surgeon must consider the possi-
bility that a suspicious mass or mammographic finding may be
a breast cancer. Once a diagnosis of breast cancer is made, the
type of therapy offered to a breast cancer patient is determined
by the stage of the disease, the biologic subtype, and the general
health status of the individual. Laboratory tests and imaging
HER2/neu expression   X X X X
Bone scan       X X
Abdominal (without or without       X X
pelvis) computed tomographic
scan or ultrasound or magnetic
resonance imaging
Abdominal imaging and bone scanning are indicated for evaluation of
symptoms or abnormal laboratory test results at any presenting stage.
Data from NCCN Practice Guidelines in Oncology. Fort Washington,
PA: National Comprehensive Cancer Network, 2006.
studies are performed based on the initial stage as presented in
Table 17-13. Before therapy is initiated, the patient and the sur-
geon must share a clear perspective on the planned course of
treatment. Before initiating local therapy, the surgeon should
determine the clinical stage, histologic characteristics, and
8 appropriate biomarker levels.
In Situ Breast Cancer (Stage 0)
Both LCIS and DCIS may be difficult to distinguish from
atypical hyperplasia or from cancers with early invasion.60,209-214
Expert pathologic review is required in all cases. Bilateral
mammography is performed to determine the extent of the in
situ cancer and to exclude a second cancer. Because LCIS is
considered a marker for increased risk rather than an inevitable
precursor of invasive disease, the current treatment options for
LCIS include observation, chemoprevention, and bilateral total
mastectomy. The goal of treatment is to prevent or detect at
an early stage the invasive cancer that subsequently develops
in 25% to 35% of these women. There is no benefit to excis-
ing LCIS because the disease diffusely involves both breasts in
many cases and the risk of developing invasive cancer is equal
for both breasts. The use of tamoxifen as a risk-reduction strat-
egy should be considered in women with a diagnosis of LCIS.
Women with DCIS and evidence of extensive disease
(>4 cm of disease or disease in more than one quadrant) usu-
ally require mastectomy (Fig. 17-29). For women with lim-
ited disease, lumpectomy and radiation therapy are generally
recommended. For nonpalpable DCIS, needle localization or
other image-guided techniques are used to guide the surgical
resection. Specimen mammography is performed to ensure
that all visible evidence of cancer is excised. Adjuvant tamoxi-
fen therapy is considered for DCIS patients with ER-positive

A
B ated a prospective registry trial (ECOG 5194) to identify those
Figure 17-29. Extensive DCIS seen on mammography. A. Exten-
sive calcifications are seen throughout the breast on this cranial
caudal view. B. Magnification view of calcifications. Due to the
extent of the disease the patient is not a good candidate for breast
conserving surgery. (Used with permission from Dr. Anne Turnbull,
Consultant Radiologist/Director of Breast Screening, Royal Derby
Hospital, Derby, UK.)
disease. The gold standard against which breast conservation 581
therapy for DCIS is evaluated is mastectomy. Women treated
with mastectomy have local recurrence and mortality rates of
<2%. There is no randomized trial comparing mastectomy vs.
breast conserving surgery, and none of the randomized trials
of breast-conserving surgery with or without radiotherapy for
DCIS were powered to show a difference in mortality. Women
treated with lumpectomy and adjuvant radiation therapy in the
initial clinical trials were noted to have a local recurrence rate
that is increased compared to mastectomy. About 45% of these
CHAPTER 17 THE BREAST
recurrences will be invasive cancer when radiation therapy is
not used. The B-17 trial was conducted by the NSABP to assess
the need for radiation in patients treated with breast conserv-
ing surgery for DCIS.215 Patients were randomly assigned to
lumpectomy with radiation or lumpectomy alone, and after
a mean follow-up time of 90 months rates of both ipsilateral
noninvasive and invasive recurrences were significantly lower
in patients who received radiation. However, in the B-17 trial
the margins were not prospectively assessed, and it is estimated
that up to half of the patients may have had tumor at the mar-
gin of resection. The benefit of the addition of radiation over
breast-conserving surgery alone for DCIS has also been dem-
onstrated in several other randomized trials where margins were
prospectively assessed including the European Organization for
Research and Treatment of Cancer (EORTC) protocol 10853;
the United Kingdom, Australia, New Zealand DCIS Trial;
and the Swedish Trial.209,216-218 In 2016, the Society of Surgi-
cal Oncology (SSO), American Society for Radiation Oncol-
ogy (ASTRO), and the American Society of Clinical Oncology
(ASCO) established consensus guidelines on margins for
patients with DCIS undergoing breast-conserving surgery.219
Based on a multidisciplinary consensus panel using a meta-
analysis of margin width and ipsilateral breast tumor recur-
rence, a 2-mm margin was determined as adequate width for
DCIS for patients undergoing breast-conserving surgery with
whole-breast radiation therapy.219
Despite the data from randomized trials showing a benefit
in all patient subgroups with the addition of radiation in DCIS,
there has been an interest in trying to define a subset where
radiation could be avoided in order to minimize the cost and
inconvenience associated with radiation. In addition, there have
been several studies published where patients were treated with
excision alone and never developed invasive breast cancer even
at 25 years of follow-up. Silverstein and colleagues were pro-
ponents of avoiding radiation therapy in selected patients with
DCIS who have widely negative margins after surgery.213 They
reported that when greater than 10-mm margins were achieved,
there was no additional benefit from radiation therapy. When
margins were between 1 and 10 mm, there was a relative risk
of local recurrence of 1.49, compared to 2.54 for those with
margins less than 1 mm. These data suggested that appropri-
ately selected patients with DCIS might not require postopera-
tive radiation therapy.
The Eastern Cooperative Oncology Group (ECOG) initi-
patients who could safely undergo breast-conserving surgery
without radiation.222 Eligible patients were those with low or
intermediate grade DCIS measuring 2.5 cm or less who had
negative margins of at least 3 mm and those with high-grade
DCIS who had tumors measuring 1 cm or less with a negative
margin of at least 3 mm. At a median follow-up of 6.2 years,
patients with low or intermediate grade DCIS had an in-breast
582 recurrence rate of 6.1% while those with high-grade DCIS
had a recurrence rate of 15.3%. Approximately 4% of patients
developed a contralateral breast cancer during follow-up in both
the low/intermediate and high-grade groups. This study identi-
fied an acceptable recurrence rate for those patients with low
or intermediate grade DCIS treated with excision alone with a
margin of at least 3 mm. In contrast, patients with high-grade
DCIS had an unacceptably high local recurrence rate.
The Radiation Therapy Oncology Group (RTOG) initi-
ated the 9804 trial for patients with “good risk” DCIS and
randomized them to lumpectomy vs. lumpectomy with whole
breast irradiation. Eligible patients were those with unicentric,
PART II
low or intermediate grade DCIS measuring 2.5 cm or less with
a margin of 3 mm or greater. The trial was closed early due
to slow accrual; however, the results for 585 patients were
recently reported with a median follow-up of 6.46 years.223,224
The local recurrence rate at 5 years was 0.4% for patients ran-
SPECIFIC CONSIDERATIONS
domized to receive radiation and 3.2% for those who did not
receive radiation.
Solin et al utilized samples from the ECOG 5194 trial to
develop a quantitative multigene RT-PCR assay for predict-
ing recurrence risk in patients with DCIS treated with surgery
alone.201 They were able to define low, intermediate, and high
risk groups using a DCIS Score. The DCIS Score was able to
quantify the risk of recurrence in the breast for both DCIS and
invasive events. This tool has recently been evaluated in another
dataset and appears to be a promising tool for clinical use.225
When selecting therapy for patients with DCIS, one must con-
sider clinical and pathologic factors, including tumor size, grade,
mammographic appearance, and patient preference. There is no
single correct surgical treatment, and many patients will require
extensive counseling in order to make a decision regarding sur-
gical therapy. The role of axillary staging in patients with DCIS
is limited. One consideration is for patients undergoing mastec-
tomy. Since most lesions are currently diagnosed with needle
core biopsy, there is about a 20% incidence of invasive breast
cancer on final pathologic assessment of the primary tumor.
Since it is not feasible to perform sentinel node dissection after
mastectomy, most surgeons will recommend the use of sentinel
node dissection at the time of mastectomy for DCIS.
Results from the NSABP B-24 trial reported a signifi-
cant reduction in local recurrence after 5 years of tamoxifen in
women with ER-positive DCIS. Based on this finding, some
guidelines have advocated that all patients (women with ER-
positive DCIS without contraindications to tamoxifen therapy)
should be offered tamoxifen following surgery and radiation
therapy for a duration of 5 years. The B-24 trial revealed a sig-
nificant reduction in recurrence with adjuvant tamoxifen therapy
for patients with DCIS; however, the results were not initially
assessed based on ER status.226 There were 1804 women with
DCIS randomized to lumpectomy and radiation with or without
tamoxifen. The rate of breast cancer events was significantly
lower in those who received tamoxifen at a median follow-up of
74 months (8.2% vs. 13.4%, P = 0.0009). Subsequently, Allred
and colleagues evaluated 41% of patients with DCIS in the
NSABP B-24 trial to determine the effect of tamoxifen based
on ER status measured in the primary tumor.203 They found
that 76% of women had DCIS that was ER-positive and these
women had a greater reduction in ipsilateral breast tumor recur-
rence with tamoxifen than did patients with ER-negative DCIS
(11% vs. 5.2%, P <0.001). However, it should be noted that
15% of patients in B-24 had tumor at the resection margins. For
these patients, tamoxifen could be viewed as treating what, by
the current standard, would be viewed as inadequate local exci-
sion of the primary tumor.
Early Invasive Breast Cancer
(Stage I, IIA, or IIB)
There have been six prospective randomized trials comparing
breast-conserving surgery to mastectomy in early stage breast
cancer, and all have shown equivalent survival rates regardless
of the surgical treatment type. One caveat, however, is that the
majority of studies had a restriction of tumor size; most were
either 2 cm or 2.5 cm, while the NSABP B-06 trial was 4 cm, and
the NCI trial was up to 5 cm. NSABP B-06, which is the largest
of all the breast conservation trials, compared total mastectomy
to lumpectomy with or without radiation therapy in the treatment
of women with stages I and II breast cancer.227-233 After 5- and
8-year follow-up periods, the disease-free (DFS), distant dis-
ease-free, and overall survival (OS) rates for lumpectomy with
or without radiation therapy were similar to those observed after
total mastectomy. However, the incidence of ipsilateral breast
cancer recurrence was higher in the group not receiving radia-
tion therapy. These findings supported the use of lumpectomy
and radiation therapy in the treatment of stages I and II breast
cancer and this has since become the preferred method of treat-
ment for women with early stage breast cancer who have uni-
focal disease and who are not known BRCA mutation carriers.
Reanalysis of the B-06 study results was undertaken after
20 years of follow-up and confirmed that there was no differ-
ence in disease-free survival rates after total mastectomy or after
lumpectomy with or without adjuvant radiation therapy. The
in-breast recurrence rate was substantially higher in the lumpec-
tomy alone group (39.2%) compared with the lumpectomy
plus adjuvant radiation therapy group (14.3%), confirming the
importance of radiation therapy in the management of patients
with invasive disease. However, it should be noted that there
were several criteria in the B-06 study. There was a specific
lymphadenopathy exclusion criteria. Secondly, all patients ran-
domized to breast-conserving surgery had a frozen section, and
if the margins were involved, they were converted to mastec-
tomy but were included in the analysis as having had a breast-
conserving operation (on the basis of intention to treat). Finally,
in the breast-conserving group recurrences in the treated breast
were considered as a “nonevent.”
Data from all of the randomized trials where breast con-
servation was performed with or without radiation therapy have
been examined by the EBCTCG.12 At 15 years of follow-up, the
absolute reduction in mortality with the use of radiation therapy
after lumpectomy was 5.1% in node-negative patients and 7.1%
in node-positive patients. These data support the concept that
the addition of radiation not only improves local control but
also has an impact on survival. Similar to DCIS, clinicians have
sought to identify subgroups of patients who may not benefit
from the addition of radiation therapy, particularly older patients
who may have a shorter life expectancy due to medical comor-
bidities. Randomized trials have shown that in selected patients
with small, ER-positive, low-grade tumors, lumpectomy alone
without radiation therapy may be appropriate.211,212 The Cancer
and Leukemia Group B (CALGB) C9343 trial enrolled women
over the age of 70 with T1N0 breast cancer and randomized
them to lumpectomy with or without radiation therapy. All
patients received adjuvant tamoxifen.233a At 5 years, although
there were fewer local recurrences with radiation (1% vs. 4%,
P <0.001), there were no differences in DFS and OS. While
long-term follow-up at 10 years showed fewer local recurrences
with radiation (2% vs. 10%), there were no significant differ-
ences in time to distant metastasis, breast cancer–specific sur-
vival, or OS between the two groups. A trial similar to CALGB
C9343 was conducted in Canada where they enrolled women
age 50 years and older and randomized them to lumpectomy
with or without radiation. Mean age was 68 years, and 80% of
women had ER-positive tumors. Again, local recurrence rates
were lower in women who received radiation (0.6% vs. 7.7%,
P <0.001); however, at a median follow-up of 5.6 years, there
were no differences in DFS or OS. The PRIME-2 study enrolled
women age 65 years or older with ER-positive, node-negative,
up to 3 cm breast cancers, who had undergone breast-conserving
surgery and were candidates for adjuvant endocrine treatment.
They were assigned to receive whole-breast irradiation or no
treatment. After a median follow-up of 5 years, ipsilateral breast
tumor recurrence was 1.3% with radiation vs. 41% in those
assigned to no radiotherapy. However, no differences in distant
metastases, contralateral breast cancers, or overall survival were
noted between the groups.234 These studies suggest that radia-
tion can be avoided in select older patients with ER-positive,
early-stage breast cancer.
Accelerated partial breast irradiation (APBI) is also an
option for carefully selected patients with DCIS and early-stage
breast cancer. Since the majority of recurrences after breast
conservation occur in or adjacent to the tumor bed, there has
been interest in limiting the radiation to the area of the primary
tumor bed with a margin of normal tissue. APBI is delivered in
an abbreviated fashion (twice daily for 5 days) and at a lower
total dose compared with the standard course of 5 to 6 weeks of
radiation (50 Gy with or without a boost) in the case of whole
breast irradiation. Proponents have suggested that this shortened
course of treatment may increase the feasibility of breast con-
servation for some women and may improve radiation therapy
compliance. The RTOG 04-13/NSABP B-39 trial is a random-
ized comparison of whole breast irradiation to APBI in women
with early stage breast cancer. The trial has completed accrual,
and it will likely be several years before data are mature to
report outcomes between the two radiation treatment strategies.
TARGIT is another study that randomized 3451 patients in 33
centers in over 10 countries to intraoperative breast irradiation
(IORT) or external beam radiotherapy (EBRT). The prelimi-
nary results were reported in 2012: with a median follow-up of
2.4 years, use of IORT had a recurrence rate of 3.3% vs. 1.3%
with EBRT, a 2% increased recurrence risk.235,236 ASTRO
developed guidelines for the use of APBI outside of clinical
trials based on data reported from published studies.237,238 The
ASTRO guidelines describe patients “suitable” for APBI to
include women age 60 years or older with a unifocal, T1, ER-
positive tumor with no lymphovascular invasion and margins
of at least 2 mm. They describe a group where there is uncer-
tainty about the appropriateness of APBI (“cautionary” group)
to include patients with invasive lobular histology, a tumor size
of 2.1 cm to 3 cm, ER-negative disease, focal lymphovascular
invasion, or margins less than 2 mm. Finally, a group felt to be
“unsuitable” for APBI includes those with T3 or T4 disease,
ER-negative disease, multifocality, multicentricity, extensive
LVI, or positive margins.
Currently, mastectomy with axillary staging and breast
conserving surgery with axillary staging and radiation therapy
are considered equivalent treatments for patients with stages I 583
and II breast cancer. Breast conservation is considered for all
patients because of the important cosmetic advantages and
equivalent survival outcomes; however, this approach is not
advised in women who are known BRCA mutation carriers
due to the high lifetime risk for development of additional
breast cancers. Relative contraindications to breast conserva-
tion therapy include (a) prior radiation therapy to the breast or
chest wall, (b) persistently positive surgical margins after reex-
cision, (c) multicentric disease, and (d) scleroderma or lupus
CHAPTER 17 THE BREAST
erythematosus.
For most patients with early-stage disease, reconstruc-
tion can be performed immediately at the time of mastectomy.
Immediate reconstruction allows for skin-sparing, thus optimiz-
ing cosmetic outcomes. Skin-sparing mastectomy with immedi-
ate reconstruction has been popularized over the past decade as
reports of low local-regional failure rates have been reported
and reconstructive techniques have advanced. There is a grow-
ing interest in the use of nipple-areolar sparing mastectomy with
reports suggesting the oncologic safety of this approach in early
stage breast cancer. Patients who are planned for postmastec-
tomy radiation therapy may not be ideal candidates for nipple-
sparing mastectomy because of the effects of radiation on the
preserved nipple. In addition to providing optimal cosmesis
from preservation of the skin and/or the nipple-areolar complex,
immediate reconstruction allows patients to wake up with a
breast mound, which provides some psychological benefit for
the patient. Immediate reconstruction is also more economical
as both the extirpative and reconstructive surgery are combined
in one operation.
Immediate reconstruction can be performed using implants
or autologous tissue; tissue flaps commonly used include the
transverse rectus abdominis myocutaneous flap, deep inferior
epigastric perforator flap, and latissimus dorsi flap (with or
without an implant). If postmastectomy radiation therapy is
needed, a tissue expander can be placed at the time of mastec-
tomy to save the shape of the breast and reduce the amount of
skin replacement needed at the time of definitive reconstruc-
tion. The expander can be deflated at the initiation of radiation
therapy to allow for irradiation of the chest wall and regional
nodal basins. Removal of the tissue expander and definitive
reconstruction, usually with autologous tissue, can proceed
6 months to 1 year after completion of radiation therapy.
Axillary lymph node status has traditionally been an
important determinant in staging and prognosis for women with
early stage breast cancer. Historically, axillary lymph node dis-
section (ALND) was utilized for axillary staging and regional
control by removing involved lymph nodes. Randomized tri-
als evaluating immediate ALND over ALND performed in a
delayed fashion once clinically palpable axillary disease became
evident have not shown any detriment in survival.9,239 With
increased mammographic screening and detection of smaller,
node-negative breast cancers, it became clear that routine use
of ALND for axillary staging was not necessary in up to 75%
percent of women with operable breast cancer presenting with
a negative axilla at the time of screening. Lymphatic mapping
and sentinel lymph node (SLN) dissection were initially devel-
oped for assessment of patients with clinically node-negative
melanoma. Given the changing landscape of newly diagnosed
breast cancer patients with a clinically node-negative axilla, sur-
geons quickly began to explore the utility of SLN dissection as
a replacement for ALND in axillary staging.
584 In the early 1990s, David Krag at the University of
Vermont began performing SLN dissection with injection of a
radioisotope in the primary tumor site and localizing the SLN
node with a handheld gamma probe.240 He was able to identify
a SLN in 18 of 22 patients examined, and the SLN was posi-
tive in all 7 patients with positive lymph nodes. Giuliano and
colleagues initiated a pilot study in 1991 to examine the use of
SLN dissection using blue dye in patients with clinically nega-
tive nodes. They reported successful identification of a SLN
in 114 (65.5%) of 174 patients, and in 109 (95.6%), the SLN
accurately predicted the status of the axillary nodes.241,242 These
studies along with initial work by Doug Reintgen and Charles
PART II
Cox at the Moffitt Cancer Center and Umberto Veronesi and
his colleagues at the European Institute of Oncology in Milan
led the way toward validation of the technique in large single
institution and multicenter studies.
Following validation of the technique of SLN dissection
SPECIFIC CONSIDERATIONS
for staging of the axilla by multiple centers, randomized tri-
als were initiated in order to determine if SLN dissection could
replace ALND in the contemporary management of breast cancer
patients. The ALMANAC trial randomized 1031 patients with
primary operable breast cancer to SLN dissection vs. standard
axillary surgery. The incidence of lymphedema and sensory
loss for the SLN group was significantly lower than with the
standard axillary treatment. At 12 months, drain usage, length
of hospital stay, and time to resumption of normal day-to-day
activities after surgery were also statistically significantly lower
in the SLN group.221
The NSABP B-32 trial compared clinically node-negative
patients undergoing SLN dissection followed by ALND with
patients undergoing SLN dissection with ALND only if a SLN
was positive for metastatic disease.243 A total of 5611 patients
were randomized with a SLN identification rate of 97% and
a false-negative rate of 9.7%. A total of 26% of these clini-
cally node-negative patients had a positive SLN. Over 60% of
patients with positive SLNs had no additional positive lymph
nodes within the ALND specimen. The B-32 trial and other
randomized trials demonstrated no difference in DFS, OS, and
local-regional recurrence rates between patients with negative
SLNs who had SLN dissection alone compared with those who
underwent ALND.244,245 Most important, patients who had SLN
dissection alone were found to have decreased morbidity (arm
swelling and range of motion) and improved quality of life vs.
patients who underwent ALND.245,246
The American College of Surgeons Oncology Group
(ACOSOG) initiated the Z0010 and Z0011 trials in order to
evaluate the incidence and prognostic significance of occult
metastases identified in the bone marrow and SLNs (Z0010)
of early-stage clinically node-negative patients and to evaluate
the utility of ALND in patients with clinical T1-2, N0 breast
cancer with 1 or 2 positive SLNs for patients treated with
breast-conserving surgery and whole breast irradiation (WBI)
(Z0011).247,248
The Z0010 study enrolled 5539 patients with clinical T1-2
breast cancer planned for breast conserving surgery and WBI.247
Of these patients, 24% proved to have positive SLNs based on
standard pathologic assessment, and of the negative SLNs sub-
jected to immunohistochemical staining for cytokeratin, 10.5%
proved to have occult metastasis. Of the patients who had bone
marrow aspiration, 3.0% had immunohistochemically detected
tumor cells in the bone marrow. Although the presence of dis-
ease in the bone marrow identified a population at high risk for
recurrence, neither immunohistochemical detection of disease
in the SLNs or the bone marrow was statistically significant
on multivariable analysis with clinicopathologic and treatment
factors included. The investigators concluded that routine use
of immunohistochemistry to detect occult disease in SLNs is
not warranted.
The Z0011 trial was a companion study to Z0010 and was
designed to study the role of completion ALND on survival in
women with positive SLNs. Patients were not eligible if they
received neoadjuvant chemotherapy or neoadjuvant hormonal
therapy or if their treatment plan included mastectomy, lumpec-
tomy without radiation, or lumpectomy with APBI. WBI was to
be administered using standard tangential fields without specific
treatment of the axilla or additional fields targeting other nodal
basins. Patients with 1 or 2 positive SLNs were randomized to
completion ALND or no further surgery. Adjuvant systemic
therapy recommendations were left to the treating clinicians.
After median follow-up of 6.3 years, there was no difference
between patients randomized to ALND and those randomized
to no further surgery (SLN only) in terms of OS (91.9% and
92.5%, respectively; P = 0.25) or DFS (82.2% and 83.8%,
respectively; P = 0.14). The low local regional failure rates and
similar survival outcomes were recently reported with 10-year
follow-up.249,250
The morbidity of SLN dissection alone vs. SLN dissec-
tion with completion ALND has been reported by the ACOSOG
investigators.251,252 Immediate effects of SLN dissection in the
Z0010 trial included wound infection in 1%, axillary seroma in
7.1%, and axillary hematoma in 1.4%.251 At 6 months following
surgery, axillary paresthesias were noted in 8.6% of patients,
decreased range of motion in the upper extremity was reported
in 3.8%, and 6.9% of patients had a change in the arm circum-
ference of >2 cm on the ipsilateral side, which was reported
as lymphedema. Younger patients were more likely to report
paresthesias, whereas increasing age and body mass index were
more predictive of lymphedema. When adverse surgical effects
were examined in the Z0011 trial, patients undergoing SLN
dissection with ALND had more wound infections, seromas,
and paresthesias than those women undergoing SLN dissec-
tion alone. Lymphedema at 1 year after surgery was reported
by 13% in the SLN plus ALND group but only 2% in the SLN
dissection alone group. Arm circumference measurements were
greater at 1 year in patients undergoing SLN dissection plus
ALND, but the difference between study groups was not statisti-
cally significant.252 This supports the results published from the
ALMANAC trial.
Prior to the publication of ACOSOG Z0011, completion
ALND was standard of care for patients with positive SLNs.
Since the reporting of ACOSOG Z0011, the National Com-
prehensive Cancer Network (NCCN) guidelines now state that
there was no OS difference for patients with 1 or 2 positive
SLNs treated with breast-conserving surgery who underwent
completion ALND vs. those who had no further axillary sur-
gery. In addition, the American Society of Breast Surgeons
issued a consensus statement supporting omission of ALND for
patients who meet Z0011 criteria.253 The results of ACOSOG
Z0011 have revolutionized management of the axilla and
changed practice such that selected patients with axillary metas-
tasis can now avoid ALND if they have clinical and pathologic
features similar to those patients enrolled on Z0011. However,
there have been some concerns raised about the Z0011 study
that include the fact that the study only recruited about half of
the intended patients and that there was no standardization of
whether or not patients received irradiation to the low axilla
when the radiation oncologist irradiated the breast. These issues
have thus far limited the uptake of the results of Z0011 by some
centers.
The International Breast Cancer Study Group (IBCSG)
23-01 trial was similar in design to Z0011 but enrolled only
patients with micrometastases in the SLNs. Patients with SLN
micrometastases were randomized to ALND vs. no further sur-
gery. Unlike Z0011, the 23-01 trial did not exclude patients
treated with mastectomy. Approximately 9% of patients ran-
domized to each study arm underwent mastectomy. The inves-
tigators published the primary and secondary endpoints of the
trial showing no differences in OS or local-regional recurrence
between the study arms.254 However, as with the Z0011 trial,
some concerns have been raised regarding the 23-01 study. For
example, in the statistics on the primary endpoint, local recur-
rence included contralateral breast cancer and other tumor types
as events. No hypothesis was presented as to why the differ-
ence in axillary surgery should impact on either of these events.
Including these events therefore reduced the power of the study
to show a statistical difference between treatment arms. There
is also concern that the study appears underpowered to show a
meaningful difference in overall survival.
Most pathology laboratories perform a more detailed anal-
ysis of the SLN than is routinely done for axillary nodes recov-
ered from a levels I and II dissection. This can include examining
thin sections of the node with step sectioning at multiple levels
through the paraffin blocks or performing immunohistochemi-
cal staining of the SLN for cytokeratin or a combination of these
techniques. The results of ACOSOG Z0010 and NSABP B-32
showed no clinically meaningful difference in survival based
on detection of occult metastases in the SLNs using immu-
nohistochemical staining and do not support the routine use
in SLN processing. The type of intraoperative assessment of
SLNs also varies for different clinicians and pathology labo-
ratories. Some centers prefer to use touch preparation cyto-
logic analysis of the SLNs, whereas others use frozen-section
analysis, and the sensitivity and specificity of these assays vary
considerably. The GeneSearch Breast Lymph Node Assay is a
real-time reverse-transcriptase polymerase chain reaction assay
that detects breast tumor cell metastasis in lymph nodes through
the identification of the gene expression markers mammaglobin
and cytokeratin 19. These markers are present in higher lev-
els in breast tissue and not in nodal tissue (cell type-specific
messenger RNA). The GeneSearch breast lymph node assay
generates expression data for genes of interest, which are then
evaluated against predetermined criteria to provide a qualitative
(positive/negative) result. The assay is designed to detect foci
that correspond to metastases that are seen with examination by
standard hematoxylin and eosin staining and measure >0.2 mm.
The GeneSearch assay results have been compared with per-
manent-section histologic analysis and frozen-section analy-
sis of sentinel nodes in a prospective trial, and the assay was
approved by the FDA for the intraoperative assessment of senti-
nel nodes.255 When a positive node is identified intraoperatively
by touch preparation, frozen-section analysis, or GeneSearch
assay, the surgeon can proceed with immediate ALND. With
the findings of ACOSOG Z0011 that there is not a survival ben-
efit to the use of ALND in selected patients, many surgeons
have abandoned the intraoperative evaluation of SLNs. There
are a number of nomograms and predictive models designed to
determine which patients with a positive SLN are at risk for har- 585
boring additional positive non-SLNs in the axilla. These tools
can be helpful in determining the likelihood of additional disease
in the axilla and may be used clinically to counsel patients.256
In patients who present with axillary lymphadenopa-
thy that is confirmed to be metastatic disease on FNA or core
biopsy, SLN dissection is not necessary, and patients can pro-
ceed directly to ALND or be considered for preoperative sys-
temic therapy (see “Neoadjuvant [Preoperative] Chemotherapy”
under “Nonsurgical Breast Cancer Therapies”). Initially there
CHAPTER 17 THE BREAST
was controversy about the suitability of SLN dissection in
women with larger primary tumors (T3) and those treated with
neoadjuvant chemotherapy. The American Society of Clini-
cal Oncology has included SLN dissection is its guidelines as
appropriate for axillary staging in these patients.257,258 If an SLN
cannot be identified, then ALND is generally performed for
appropriate staging. However, this is not universally accepted,
and there are as yet no randomized studies that have assessed
how a patient with a locally advanced cancer at presentation
should be treated if SLN dissection reveals no metastases or
micrometastases after neoadjuvant therapy.
The ASCO guidelines suggest that adjuvant chemo-
therapy should be considered for patients with positive lymph
nodes, ER-negative disease, HER2-positive disease, Adju-
vant! Online mortality greater than 10%, grade 3 node-neg-
ative tumors >5 mm, triple-negative tumors, lymphovascular
invasion, or estimated distant relapse risk of greater than 15%
at 10 years based on the 21 gene recurrence score assay.259
Adjuvant endocrine therapy is considered for women with
hormone receptor-positive cancers, and an aromatase inhibi-
tor is recommended if the patient is postmenopausal. HER2/
neu status is determined for all patients with newly diagnosed
invasive breast cancer and when positive, should be used to
guide systemic therapy recommendations. The FDA approved
trastuzumab in November 2006 for use as part of a treatment
regimen containing doxorubicin, cyclophosphamide, and pacli-
taxel for treatment of HER2/neu-positive, node-positive breast
cancer.181,183 Subsequently, the BCIRG 006 study reported that
giving trastuzumab concurrently with docetaxel and carbopla-
tin appeared as effective as giving trastuzumab following an
anthracycline containing regimen.182,185 In addition to trastu-
zumab, pertuzumab has also recently been FDA approved for
adjuvant use in patients with HER2 amplified breast cancers
with high risk of recurrence.
Advanced Local-Regional Breast Cancer
(Stage IIIA or IIIB)
Women with stage IIIA and IIIB breast cancer have advanced
local-regional breast cancer but have no clinically detected
distant metastases (Fig. 17-30).260 In an effort to provide opti-
mal local-regional disease-free survival as well as distant dis-
ease-free survival for these women, surgery is integrated with
radiation therapy and chemotherapy (Fig. 17-31). However,
it should be noted that these patients have an increased risk
of distant metastasis that is often highlighted by radiological
evidence when staging PET or CT and bone scans are per-
formed. Thus, the paradigm for small screen detected cancers
where cure can be expected in >90% of patients, often by local
treatment alone, is not appropriate for patients with locally
advanced disease.
Preoperative (also known as neoadjuvant) chemotherapy
should be considered in the initial management of patients with
586
PART II
SPECIFIC CONSIDERATIONS

A B

Figure 17-30. Locally advanced breast cancer. A. Mammography of the right breast reveals a large tumor with enlarged axillary lymph
nodes. B. Imaging of the left breast is normal. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast
Screening, Royal Derby Hospital, Derby, UK.)

locally advanced stage III breast cancer, especially those with
estrogen receptor negative tumors. Chemotherapy is used to
maximize distant disease-free survival, whereas radiation ther-
apy is used to maximize local-regional control and disease-free
survival.
In selected patients with stage IIIA cancer, preoperative
chemotherapy can reduce the size of the primary cancer and
permit breast-conserving surgery. Investigators from the MD
Anderson Cancer Center reported that low local-regional fail-
ure rates could be achieved in selected patients with stage III
disease treated with preoperative chemotherapy followed by
breast-conserving surgery and radiation.261 The 5-year actuarial
ipsilateral breast tumor recurrence-free survival rates in this
study were 95%. They noted that the ipsilateral breast tumor
recurrence rates increased when patients had clinical N2 or N3
disease, >2 cm of residual disease in the breast at surgery, a
pattern of multifocal residual disease in the breast at surgery,
and lymphovascular space invasion in the primary tumor. This
study demonstrated that breast-conserving surgery can be used
for appropriately selected patients with locally advanced breast
cancer who achieve a good response with preoperative che-
motherapy. However, the Oxford overview of all randomized
studies of neoadjuvant therapy (vs. adjuvant therapy) reported a
hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates.

Figure 17-31. Treatment pathways for stage IIIA and stage IIIB breast cancer.
A meta-analysis reported a hazard ratio of 1.3.262 These stud-
ies included some patients treated with radiation therapy alone
without resection of the primary tumor bed, which results in
higher local failure rates. These findings are important in view
of the previous findings that the avoidance of recurrence in a
conserved breast avoids about one breast cancer death over the
next 15 years for every four such recurrences avoided.12 The
German Breast Cancer Group recently reported their local
recurrence rate in 5535 patients in seven studies. With a median
of 46 months (range 1–127) follow-up the local recurrence
rates ranged from 7.6% to 19.5% for T1-T4 tumors and from
6.4% to 17.9% for N0-N3 tumors treated with neoadjuvant
therapy.238 For patients with stage IIIA disease who experience
minimal response to chemotherapy and for patients with stage
IIIB breast cancer, preoperative chemotherapy can decrease
the local-regional cancer burden enough to permit subsequent
modified radical mastectomy to establish local-regional con-
trol. In both stages IIIA and IIIB disease, surgery is followed by
adjuvant radiation therapy. However there is a small percent-
age of patients who experience progression of disease during
neoadjuvant therapy, and therefore the surgeon should review
patients with the oncologist at regular points during the neoad-
juvant regimen.
For selected clinically indolent, ER-positive, locally
advanced tumors, primary endocrine therapy may be considered,
especially if the patient has other comorbid conditions. A series
of 195 patients with ER-positive, locally advanced breast cancer
treated by endocrine therapy—median age 69 years, median
tumor size 6 cm, median follow-up 61 months—reported a
5-year overall survival of 76%, a breast cancer–specific sur-
vival of 86%, and a metastasis-free survival of 77%. The median
time to an alternative treatment was 48 months.263 Given that
this was a 20-year series, the number of such patients is small
but should be considered when the clinician is discussing treat-
ment options. Results from the ACOSOG Z1031 trial suggest
that neoadjuvant endocrine therapy is a good option for tumor
downstaging in patients with strongly ER-positive tumors. The
preoperative endocrine prognostic index (PEPI score) can be
calculated based on pathologic findings from surgery following
neoadjuvant endocrine therapy. This can help guide decision-
making regarding the need for systemic chemotherapy in this
patient population.264,265
Internal Mammary Lymph Nodes
Metastatic disease to internal mammary lymph nodes may be
occult, may be evident on chest radiograph or CT scan, or may
present as a painless parasternal mass with or without skin
involvement. There is no consensus regarding the need for
internal mammary lymph node radiation therapy in women who
are at increased risk for occult involvement (cancers involving
the medial aspect of the breast, axillary lymph node involve-
ment) but who show no signs of internal mammary lymph node
involvement. Systemic chemotherapy and radiation therapy are
indicated in the treatment of grossly involved internal mammary
lymph nodes.
Distant Metastases (Stage IV)
Treatment for stage IV breast cancer is not curative but may
prolong survival and enhance a woman’s quality of life.266
Endocrine therapies that are associated with minimal toxicity
are preferred to cytotoxic chemotherapy in ER-positive disease.
Appropriate candidates for initial endocrine therapy include
women with hormone receptor-positive cancers who do not have
immediately life threatening disease (or “visceral crisis”). This 587
includes not only women with bone or soft tissue metastases
but also women with limited visceral metastases. Symptoms
per se (e.g., breathlessness) are not in themselves an indication
for chemotherapy. For example, breathlessness due to a pleural
effusion can be treated with percutaneous drainage, and if the
breathlessness is relieved, the patient should be commenced on
endocrine therapy; if the breathlessness is due to lymphangitic
spread, then chemotherapy would be the treatment of choice.
The same approach should be taken to other symptoms such
CHAPTER 17 THE BREAST
as pain. Systemic chemotherapy is indicated for women with
hormone receptor-negative cancers, “visceral crisis,” and
hormone-refractory metastases. Women with stage IV breast
cancer may develop anatomically localized problems that will
benefit from individualized surgical or radiation treatment,
such as brain metastases, pleural effusion, pericardial effusion,
biliary obstruction, ureteral obstruction, impending or existing
pathologic fracture of a long bone, spinal cord compression, and
painful bone or soft tissue metastases. Bisphosphonates or anti-
RANKL (receptor activator of nuclear factor kappa-B ligand)
agent, denosumab, which may be given in addition to chemo-
therapy or endocrine therapy, should be considered in women
with bone metastases. Whether to perform surgical resection
of the local-regional disease in women with stage IV breast
cancer has been debated after several reports have suggested
that women who undergo resection of the primary tumor have
improved survival over those who do not. Khan and associates
used the National Cancer Data Base to identify patterns of treat-
ment in women with metastatic breast cancer and found that
those who had surgical resection with negative margins had a
better prognosis than those women who did not have surgical
therapy.267 Gnerlich et al reported similar findings using the
SEER database, and there have been several reports subsequent
to this study from single institutions that have confirmed these
findings.268 Some have suggested that the finding of improved
survival is due to selection bias and that local therapy should be
reserved for palliation of symptoms. A randomized trial through
ECOG (E2108) was designed to address this question.269 The
surgical management of patients with stage IV disease should
be addressed by obtaining multidisciplinary input and by con-
sidering the treatment goals of each individual patient and the
patient’s treating physicians.
Local-Regional Recurrence
Women with local-regional recurrence of breast cancer may
be separated into two groups: those who have had mastec-
tomy and those who have had lumpectomy. Women treated
previously with mastectomy undergo surgical resection of
the local-regional recurrence and appropriate reconstruction.
Chemotherapy and antiestrogen therapy are considered, and
adjuvant radiation therapy is given if the chest wall has not pre-
viously received radiation therapy or if the radiation oncologist
feels that given the time from previous treatment there is scope
for further radiation therapy, particularly if this is palliative.
Women treated previously with a breast-conservation procedure
undergo a mastectomy and appropriate reconstruction. Chemo-
therapy and antiestrogen therapy are considered depending of
the hormone receptor status and HER2 status of the tumor.
Breast Cancer Prognosis
Survival rates for women diagnosed with breast cancer in the
United States can be obtained from the SEER Program of the
588 National Cancer Institute. Data have been collected since 1973
and are updated at regular intervals. The overall 5-year rela-
tive survival for breast cancer patients from the time period of
2003 to 2009 from 18 SEER geographic areas was 89.2%.270
The 5-year relative survival by race was reported to be 90.4%
for white women and 78.7% for black women. The 5-year sur-
vival rate for patients with localized disease (61% of patients)
is 98.6%; for patients with regional disease (32% of patients),
84.4%; and for patients with distant metastatic disease (5%
of patients), 24.3%. Breast cancer survival has significantly
increased over the past two decades due to improvements in
PART II
screening and local and systemic therapies. Data from the
American College of Surgeons National Cancer Data Base can
also be accessed; this data reports survival based on stage of
disease at presentation using the AJCC staging system.
SPECIFIC CONSIDERATIONS
SURGICAL TECHNIQUES IN
BREAST CANCER THERAPY
Excisional Biopsy With Needle Localization
Excisional biopsy implies complete removal of a breast lesion
with a margin of normal-appearing breast tissue. In the past,
surgeons would obtain prior consent from the patient, allow-
ing mastectomy if the initial biopsy results confirmed cancer.
Today it is important to consider the options for local therapy
(lumpectomy vs. mastectomy with or without reconstruction)
and the need for nodal assessment with SLN dissection. Needle-
core biopsy is the preferred diagnostic method, and excisional
biopsy should be reserved for those cases in which the needle
biopsy results are discordant with the imaging findings or clini-
cal examination (Fig. 17-32). In general, circumareolar incisions
can be used to access lesions that are subareolar or within a short
distance of the nipple-areolar complex. Elsewhere in the breast,
incisions can be placed along the lines of tension in the skin
that are generally concentric with the nipple-areola complex. In
the lower half of the breast, the use of radial incisions typically
A B
provides the best outcome. When the tumor is quite distant from
the central breast, the biopsy incision can be excised separately
from the primary mastectomy incision, should a mastectomy be
required. Radial incisions in the upper half of the breast are not
recommended because of possible scar contracture resulting in
displacement of the ipsilateral nipple-areola complex. Similarly,
curvilinear incisions in the lower half of the breast may displace
the nipple-areolar complex downward.
After excision of a suspicious breast lesion, the specimen
should be X-rayed to confirm that the lesion has been excised
with appropriate margins. The biopsy tissue specimen is ori-
entated for the pathologist using sutures, clips, or dyes. Addi-
tional margins (superior, inferior, medial, lateral, superficial,
and deep) may be taken from the surgical bed if the specimen
X-ray shows the lesion is close to one or more margins. Some
surgeons also take additional shavings from the margins as one
approach to confirm complete excision of the suspicious lesion.
Electrocautery or absorbable ligatures are used to achieve
wound hemostasis. Cosmesis may be facilitated by approxima-
tion of the surgical defect using 3-0 absorbable sutures. A run-
ning subcuticular closure of the skin using 4-0 or 5-0 absorbable
monofilament sutures is performed. Wound drainage is usually
not required.
Excisional biopsy with needle or seed localization requires
a preoperative visit to the mammography suite for placement of
a localization wire or a radioactive or magnetic seed that can be
detected intraoperatively with a handheld probe. The lesion can
also be targeted by sonography in the imaging suite or in the
operating room. The lesion to be excised is accurately localized
by mammography, and the tip of a thin wire hook or a seed is
positioned close to the lesion (Fig. 17-33). Using the wire hook
as a guide, or detection of the seed with a handheld probe, the
surgeon subsequently excises the suspicious breast lesion while
removing a margin of normal-appearing breast tissue. Before
the patient leaves the operating room, specimen radiography is
performed to confirm complete excision of the suspicious lesion
(Fig. 17-34).
Figure 17-32. Lesion to be targeted for excisional
biopsy. A. Craniocaudal view of the left breast
demonstrating 2 lesions (arrows) to be targeted
for needle localization and excision. B. Oblique
view demonstrating target lesions. (Used with
permission from Dr. Anne Turnbull, Consultant
Radiologist/Director of Breast Screening, Royal
Derby Hospital, Derby, UK.)
 589

CHAPTER 17 THE BREAST

A

B
Figure 17-33. Wire localization procedure. Mammographic
images of hookwire in place targeting lesions for excision in the left
breast (A) and the right breast (B). (Used with permission from Dr.
Anne Turnbull, Consultant Radiologist/Director of Breast Screen-
ing, Royal Derby Hospital, Derby, UK.)
C
Figure 17-34. Specimen mammography. Specimen mam-
mograms demonstrating excision of targeted (A) density,
(B) calcifications, and (C) spiculated mass seen on preoperative
imaging. (Used with permission from Dr. Anne Turnbull, Con-
sultant Radiologist/Director of Breast Screening, Royal Derby
Hospital, Derby, UK.)
590 Sentinel Lymph Node Dissection
Sentinel lymph node (SLN) dissection is primarily used to
assess the regional lymph nodes in women with early breast
cancers who are clinically node-negative by physical examina-
tion and imaging studies.271-279 This method also is accurate in
women with larger tumors (T3 N0), but nearly 75% of
9 these women will prove to have axillary lymph node
metastases on histologic examination, and wherever possible it
is better to identify them preoperatively as this will allow a
definitive procedure for known axillary disease. SLN dissection
has also been reported to be accurate for staging of the axilla
PART II
after chemotherapy in women with clinically node-negative dis-
ease at initial presentation.280,281 Tan et al in a review and meta-
analysis of 449 cases of SLN biopsy in clinically lymph
node-negative disease reported a sensitivity of 93%, giving a
false negative rate of 7% with a negative predictive value of
SPECIFIC CONSIDERATIONS
94% and an overall accuracy of 95%.282 Clinical situations
where SLN dissection is not recommended include patients with
inflammatory breast cancers, those with biopsy proven metasta-
sis, DCIS without mastectomy, or prior axillary surgery.
Although limited data are available, SLN dissection appears to
be safe in pregnancy when performed with radioisotope alone.
Evidence from large prospective studies suggests that
the combination of intraoperative gamma probe detection of
radioactive colloid and intraoperative visualization of blue dye
(isosulfan blue dye or methylene blue) is more accurate for
identification of SLNs than the use of either agent alone. Some
surgeons use preoperative lymphoscintigraphy, although it is
not required for identification of the SLNs. On the day before
surgery, or the day of surgery, the radioactive colloid is injected
either in the breast parenchyma around the primary tumor or
prior biopsy site, into the subareolar region, or subdermally in
proximity to the primary tumor site. With a 25-gauge needle,
0.5 mCi of 0.2-μm technetium 99m–labeled sulfur colloid is
injected for same-day surgery, or a higher dose of 2.5 mCi of
technetium-labeled sulfur colloid is administered when the
isotope is to be injected on the day before surgery. Subdermal
injections are given in proximity to the cancer site or in the
subareolar location. Later, in the operating room, 3 to 5 mL of
blue dye is injected either in the breast parenchyma or in the
subareolar location. It is not recommended that the blue dye be
used in a subdermal injection because this can result in tattoo-
ing of the skin (isosulfan blue dye) or skin necrosis (methylene
blue). For nonpalpable cancers, the injection of the technetium-
labeled sulfur colloid solution can be guided by ultrasound or
by mammographic guidance. In women who have undergone
previous excisional biopsy, the injections are made in the breast
parenchyma around the biopsy cavity but not into the cavity
itself. Women are told preoperatively that the isosulfan blue
dye injection will cause a change in the color of their urine and
that there is a very small risk of allergic reaction to the dye (1
in 10,000). Anaphylactic reactions have been documented, and
some groups administer a regimen of antihistamine, steroids,
and a histamine H-2 receptor antagonist preoperatively as a
prophylactic regimen to prevent allergic reactions. The use of
radioactive colloid is safe, and radiation exposure is very low.
Sentinel node dissection can be performed in pregnancy with
the radioactive colloid without the use of blue dye.
A hand-held gamma counter is used to transcutaneously
identify the location of the SLN. This can help to guide place-
ment of the incision. A 3- to 4-cm incision is made in line with
that used for an axillary dissection, which is a curved transverse
incision in the lower axilla just below the hairline. After dis-
secting through the subcutaneous tissue, the surgeon dissects
through the axillary fascia, being mindful to identify blue lym-
phatic channels. Following these channels can lead directly to
the SLN and limit the amount of dissection through the axillary
tissues. The gamma probe is used to facilitate the dissection and
to pinpoint the location of the SLN. As the dissection continues,
the signal from the probe increases in intensity as the SLN is
approached. The SLN also is identified by visualization of blue
dye in the afferent lymph vessel and in the lymph node itself.
Before the SLN is removed, a 10-second in vivo radioactivity
count is obtained. After removal of the SLN, a 10-second ex
vivo radioactive count is obtained, and the node is then sent to
the pathology laboratory for either permanent- or frozen-section
analysis. The lowest false-negative rates for SLN dissection
have been obtained when all blue lymph nodes and all lymph
nodes with counts >10% of the 10-second ex vivo count of the
SLN are harvested (“10% rule”). Based on this, the gamma
counter is used before closing the axillary wound to measure
residual radioactivity in the surgical bed. A search is made for
additional SLNs if the counts remain high. This procedure is
repeated until residual radioactivity in the surgical bed is less
than 10% of the 10-second ex vivo count of the most radioac-
tive SLN and all blue nodes have been removed. Studies have
demonstrated that 98% of all positive SLNs will be recovered
with the removal of four SLNs; therefore, it is not necessary to
remove greater than four SLNs for accurate staging of the axilla.
Results from the NSABP B-32 trial showed that the false-
negative rate for SLN dissection is influenced by tumor loca-
tion, type of diagnostic biopsy, and number of SLNs removed
at surgery.243 The authors reported that tumors located in the
lateral breast were more likely to have a false-negative SLN.
This may be explained by difficulty in discriminating the hot
spot in the axilla when the radioisotope has been injected at the
primary tumor site in the lateral breast. Those patients who had
undergone an excisional biopsy before the SLN procedure were
significantly more likely to have a false-negative SLN. This
report further confirms that surgeons should use needle biopsy
for diagnosis whenever possible and reserve excisional biopsy
for the rare situations in which needle biopsy findings are non-
diagnostic or discordant. Finally, removal of a larger number
of SLNs at surgery appears to reduce the false-negative rate. In
B-32, the false-negative rate was reduced from 17.7% to 10%
when two SLNs were recovered and to 6.9% when three SLNs
were removed. Yi and associates reported that the number of
SLNs that need to be removed for accurate staging is influenced
by individual patient and primary tumor factors.283
In the B-32 trial, SLNs were identified outside the levels I
and II axillary nodes in 1.4% of cases. This was significantly
influenced by the site of radioisotope injection. When a subareo-
lar or periareolar injection site was used, there were no instances
of SLNs identified outside the level I or II axilla, compared with
a rate of 20% when a peritumoral injection was used. This sup-
ports the overall concept that the SLN is the first site of drain-
age from the lymphatic vessels of the primary tumor. Although
many patients will have similar drainage patterns from injec-
tions given at the primary tumor site and at the subareolar
plexus, some patients will have extra-axillary drainage, either
alone or in combination with axillary node drainage, and this
is best assessed with a peritumoral injection of the radioiso-
tope. Kong et al reported that internal mammary node drain-
age on preoperative lymphoscintigraphy was associated with
worse distant disease-free survival in early-stage breast cancer
patients.284
Breast Conservation
Breast conservation involves resection of the primary breast
cancer with a margin of normal-appearing breast tissue, adju-
vant radiation therapy, and assessment of regional lymph node
status.285,286 Resection of the primary breast cancer is alterna-
tively called segmental mastectomy, lumpectomy, partial mas-
tectomy, wide local excision, and tylectomy. For many women
with stage I or II breast cancer, breast-conserving therapy (BCT)
is preferable to total mastectomy because BCT produces survival
rates equivalent to those after total mastectomy while preserv-
ing the breast.287 Six prospective randomized trials have shown
that overall and disease-free survival rates are similar with BCT
and mastectomy; however, three of the studies showed higher
local-regional failure rates in patients undergoing BCT. In two
of these studies, there were no clear criteria for histologically
negative margins.285-287 Data from the EBCTCG meta-analysis
revealed that the addition of radiation reduces recurrence by half
and improves survival at year 15 by about a sixth.288 When all
of this information is taken together, BCT is considered to be
oncologically equivalent to mastectomy.
In addition to being equivalent to mastectomy in terms of
oncologic safety, BCT appears to offer advantages over mas-
tectomy with regard to quality of life and aesthetic outcomes.
BCT allows for preservation of breast shape and skin as well as
preservation of sensation, and it provides an overall psychologic
advantage associated with breast preservation.
Breast conservation surgery is currently the standard treat-
ment for women with stage 0, I, or II invasive breast cancer.
Women with DCIS require only resection of the primary cancer
and adjuvant radiation therapy without assessment of regional
lymph nodes. When a lumpectomy is performed, a curvilinear
incision lying concentric to the nipple-areola complex is made
in the skin overlying the breast cancer when the tumor is in the
upper aspect of the breast. Radial incisions are preferred when
the tumor is in the lower aspect of the breast. Skin excision is
not necessary unless there is direct involvement of the overlying
skin by the primary tumor. The breast cancer is removed with
an envelope of normal-appearing breast tissue that is adequate
to achieve a cancer-free margin. Significant controversy has
existed on the appropriate margin width for BCT.260 However,
recently the SSO and ASTRO developed a consensus statement,
supported by data from a systematic review data, encouraging
“no tumor on ink” to be the standard definition of a negative
margin for invasive stages I and II breast cancer in patients who
undergo breast conserving surgery with whole-breast irradiation.
The meta-analysis found that increasing the margin width does
not affect local recurrence rates as long as the inked or transected
margin is microscopically negative.289-292 Specimen X-ray should
routinely be performed to confirm the lesion has been excised.
Specimen orientation is performed by the surgeon. Additional
margins from the surgical bed are taken as needed to provide
a histologically negative margin. Requests for determination of
ER, PR, and HER2 status are conveyed to the pathologist.
It is the surgeon’s responsibility to ensure complete
removal of cancer in the breast. Ensuring surgical margins that
are free of breast cancer will minimize the chances of local
recurrence and will enhance cure rates. If negative margins are
not obtainable with reexcision, mastectomy is required. SLN is
performed before removal of the primary breast tumor. When
indicated, intraoperative assessment of the sentinel node can 591
proceed while the segmental mastectomy is being performed.
The use of oncoplastic surgery can be entertained at the
time of segmental mastectomy or at a later time to improve the
overall aesthetic outcome. The use of oncoplastic techniques
range from a simple reshaping of breast tissue to local tissue
rearrangement to the use of pedicled flaps or breast reduction
techniques. The overall goal is to achieve the best possible aes-
thetic result. In determining which patients are candidates for
oncoplastic breast surgery, several factors should be considered,
CHAPTER 17 THE BREAST
including the extent of the resection of breast tissue necessary
to achieve negative margins, the location of the primary tumor
within the breast, and the size of the patient’s breast and body
habitus. Oncoplastic techniques are of prime consideration
when (a) a significant area of breast skin will need to be resected
with the specimen to achieve negative margins; (b) a large vol-
ume of breast parenchyma will be resected resulting in a signifi-
cant defect; (c) the tumor is located between the nipple and the
inframammary fold, an area often associated with unfavorable
cosmetic outcomes; or (d) excision of the tumor and closure of
the breast may result in malpositioning of the nipple.
Mastectomy and Axillary Dissection
A skin-sparing mastectomy removes all breast tissue, the
nipple-areola complex, and scars from any prior biopsy pro-
cedures.293,294 There is a recurrence rate of less than 6% to 8%,
comparable to the long-term recurrence rates reported with stan-
dard mastectomy, when skin-sparing mastectomy is used for
patients with Tis to T3 cancers. A total (simple) mastectomy
without skin sparing removes all breast tissue, the nipple-areola
complex, and skin. An extended simple mastectomy removes
all breast tissue, the nipple-areola complex, skin, and the level I
axillary lymph nodes. A modified radical (“Patey”) mastectomy
removes all breast tissue, the nipple-areola complex, skin, and
the levels I, II, and III axillary lymph nodes; the pectoralis minor
that was divided and removed by Patey may be simply divided,
giving improved access to level III nodes, and then left in situ,
or occasionally the axillary clearance can be performed with-
out dividing pectoralis minor. The Halsted radical mastectomy
removes all breast tissue and skin, the nipple-areola complex,
the pectoralis major and pectoralis minor muscles, and the levels
I, II, and III axillary lymph nodes. The use of systemic che-
motherapy and hormonal therapy as well as adjuvant radiation
therapy for breast cancer have nearly eliminated the need for the
radical mastectomy.
Nipple-areolar sparing mastectomy has been popularized
over the last decade especially for risk-reducing mastectomy
in high risk women. For those patients with a cancer diagno-
sis, many consider the following factors for eligibility: tumor
located more than 2 to 3 cm from the border of the areola,
smaller breast size, minimal ptosis, no prior breast surgeries
with periareolar incisions, body mass index less than 40 kg/m2,
no active tobacco use, no prior breast irradiation, and no evi-
dence of collagen vascular disease.
For a variety of biologic, economic, and psychosocial rea-
sons, some women desire mastectomy rather than breast con-
servation. Women who are less concerned about cosmesis may
view mastectomy as the most expeditious and desirable thera-
peutic option because it avoids the cost and inconvenience of
radiation therapy. Some women whose primary breast cancers
cannot be excised with a reasonable cosmetic result or those
who have extensive microcalcifications are best treated with
592
PART II
SPECIFIC CONSIDERATIONS
mastectomy. Similarly, women with large cancers that occupy
the subareolar and central portions of the breast and women with
multicentric primary cancers also undergo mastectomy.
Modified Radical Mastectomy
A modified radical mastectomy preserves the pectoralis major
muscle with removal of levels I, II, and III (apical) axillary
lymph nodes.293 The operation was first described by David
Patey, a surgeon at St Bartholomew’s Hospital London, who
reported a series of cases where he had removed the pectoralis
minor muscle allowing complete dissection of the level III axil-
lary lymph nodes while preserving the pectoralis major and the
lateral pectoral nerve. A modified radical mastectomy permits
preservation of the medial (anterior thoracic) pectoral nerve,
which courses in the lateral neurovascular bundle of the axilla
and usually penetrates the pectoralis minor to supply the lateral
border of the pectoralis major. Anatomic boundaries of the mod-
ified radical mastectomy are the anterior margin of the latissi-
mus dorsi muscle laterally, the midline of the sternum medially,
the subclavius muscle superiorly, and the caudal extension of
the breast 2 to 3 cm inferior to the inframammary fold inferiorly.
Skin-flap thickness varies with body habitus but ideally is 7 to
8 mm inclusive of skin and telasubcutanea (Fig. 17-35). Once
the skin flaps are fully developed, the fascia of the pectoralis
major muscle and the overlying breast tissue are elevated off the
underlying musculature, which allows for the complete removal
of the breast (Fig. 17-36).
Figure 17-35. Modified radical mastectomy: eleva-
tion of skin flaps. Skin flaps are 7 to 8 mm in thick-
ness, inclusive of the skin and telasubcutanea. (Visual
Art: © 2013. The University of Texas MD Anderson
Cancer Center.)
Subsequently, an axillary lymph node dissection is per-
formed. The most lateral extent of the axillary vein is identified,
and the areolar tissue of the lateral axillary space is elevated as
the vein is cleared on its anterior and inferior surfaces. The areo-
lar tissues at the junction of the axillary vein and the anterior
edge of the latissimus dorsi muscle, which include the lateral
and subscapular lymph node groups (level I), are cleared. Care
is taken to preserve the thoracodorsal neurovascular bundle. The
dissection then continues medially with clearance of the central
axillary lymph node group (level II). The long thoracic nerve
of Bell is identified and preserved as it travels in the investing
fascia of the serratus anterior muscle. Every effort is made to
preserve this nerve because permanent disability with a winged
scapula and shoulder weakness will follow denervation of the
serratus anterior muscle. Patey divided the pectoralis minor and
removed it to allow access right up to the apex of the axilla.
The pectoralis minor muscle is usually divided at the tendinous
portion near its insertion onto the coracoid process (Fig. 17-37
inset), which allows dissection of the axillary vein medially to
the costoclavicular (Halsted’s) ligament. Finally, the breast and
axillary contents are removed from the surgical bed and are sent
for pathologic assessment. In his modified radical mastectomy,
Patey removed the pectoralis minor muscle. Many surgeons
now divide only the tendon of the pectoralis minor muscle at
its insertion onto the coracoid process while leaving the rest of
the muscle intact, which still provides good access to the apex
of the axilla.
Figure 17-36. Modified radical mastectomy after
resection of breast tissue. The pectoralis major muscle
is cleared of its fascia as the overlying breast is elevated.
The latissimus dorsi muscle is the lateral boundary of the
dissection. (Visual Art: © 2013. The University of Texas
MD Anderson Cancer Center.)
 593

CHAPTER 17 THE BREAST

Figure 17-37. Modified radical mastectomy (Patey): axillary lymph node dissection. The dissection proceeds from lateral to medial, with
complete visualization of the anterior and inferior aspects of the axillary vein. Loose areolar tissue at the junction of the axillary vein and the
anterior margin of the latissimus dorsi muscle is swept inferomedially inclusive of the lateral (axillary) lymph node group (level I). Care is
taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space. The lateral lymph node group is resected in continuity
with the subscapular lymph node group (level I) and the external mammary lymph node group (level I). Dissection anterior to the axillary
vein allows removal of the central lymph node group (level II) and the apical (subclavicular) lymph node group (level III). The superomedial
limit of this dissection is the clavipectoral fascia (Halsted’s ligament). Inset depicts division of the insertion of the pectoralis minor muscle
at the coracoid process. The surgeon’s finger shields the underlying brachial plexus. (Reproduced with permission from Bland KI, Copeland
EMI: The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)

Seromas beneath the skin flaps or in the axilla represent
the most frequent complication of mastectomy and axillary
lymph node dissection, reportedly occurring in as many as 30%
of cases. The use of closed-system suction drainage reduces
the incidence of this complication. Catheters are retained in the
wound until drainage diminishes to <30 mL per day. Wound
infections occur infrequently after a mastectomy, and the
majority are a result of skin-flap necrosis. Cultures of speci-
mens taken from the infected wound for aerobic and anaerobic
organisms, debridement, and antibiotic therapy are effective
management. Moderate or severe hemorrhage in the postop-
erative period is rare and is best managed with early wound
exploration for control of hemorrhage and reestablishment of
closed-system suction drainage. The incidence of functionally
significant lymphedema after a modified radical mastectomy is
approximately 20% but can be as high as 50% to 60% when
postoperative radiation is employed. Extensive axillary lymph
node dissection, the delivery of radiation therapy, the presence
of pathologic lymph nodes, and obesity are predisposing factors.
Patients should be referred to physical therapy at the earliest
signs of lymphedema to prevent progression to the later stages.
The use of individually fitted compressive sleeves and complex
decongestive therapy may be necessary.
Reconstruction of the Breast and Chest Wall
The goals of reconstructive surgery after a mastectomy for breast
cancer are wound closure and breast reconstruction, which is
either immediate or delayed.295 In most cases, wound closure
after mastectomy is accomplished with simple approximation
of the wound edges. However, if a more radical removal of skin
and subcutaneous tissue is necessary, a pedicled myocutane-
ous flap from the latissimus dorsi muscle is generally the best
approach for wound coverage. A skin graft provides functional
coverage that will tolerate adjuvant radiation therapy; however,
this is not preferred because poor graft adherence may delay
delivery of radiation therapy. Breast reconstruction after risk-
reducing mastectomy or after mastectomy for early-stage breast
cancer may be performed at the same time as the mastectomy.
This allows for a skin-sparing mastectomy to be performed,
which offers the best overall cosmetic outcomes. Reconstruc-
tion can proceed with an expander/implant reconstruction or
with autologous tissue such as a pedicled myocutaneous flap
or a free flap using microvascular techniques. In patients with
locally advanced breast cancer, reconstruction is often delayed
until after completion of adjuvant radiation therapy to ensure
that local-regional control of disease is obtained. The expected
use of postmastectomy radiotherapy should also be considered
as a reason for delayed reconstruction as radiotherapy to a
reconstructed breast has been reported to result in inferior cos-
metic outcomes. Consideration can be made for placement of
a tissue expander to allow for skin-sparing, but this should be
discussed with the radiation oncologist and other members of
the treatment team. If chest wall coverage is needed to replace
a large skin or soft tissue defect, many different types of myo-
cutaneous flaps are employed, but the latissimus dorsi and
the rectus abdominis myocutaneous flaps are most frequently
used. The latissimus dorsi myocutaneous flap consists of a skin
paddle based on the underlying latissimus dorsi muscle, which
594 is supplied by the thoracodorsal artery with contributions from
the posterior intercostal arteries. A transverse rectus abdominis
myocutaneous (TRAM) flap consists of a skin paddle based on
the underlying rectus abdominis muscle, which is supplied by
vessels from the deep inferior epigastric artery. The free TRAM
flap uses microvascular anastomoses to establish blood supply
to the flap. When the bony chest wall is involved with cancer,
resection of a portion of the bony chest wall is indicated. If only
one or two ribs are resected and soft tissue coverage is pro-
vided, reconstruction of the bony defect is usually not necessary
because scar tissue will stabilize the chest wall. If more than two
ribs are sacrificed, it is advisable to stabilize the chest wall with
PART II
promising in highly selected low-risk populations, use of APBI
should be based on current guidelines or offered in the setting
of a prospective trial.304
Chemotherapy Adjuvant
Chemotherapy. The Early Breast Cancer Trialists’ Collabora-
tive Group overview analysis of adjuvant chemotherapy demon-
strated reductions in the odds of recurrence and death in women
≤70 years of age with stage I, IIA, or IIB breast cancer.123,305-309
For those ≥70 years of age, the lack of definitive clinical trial
data regarding adjuvant chemotherapy prevented definitive rec-
ommendations. Adjuvant chemotherapy is of minimal benefit

prosthetic material, which is then covered with soft tissue by
using a latissimus dorsi or TRAM flap.
NONSURGICAL BREAST CANCER THERAPIES
SPECIFIC CONSIDERATIONS
to women with negative nodes and cancers ≤0.5 cm in size and
is not recommended. Women with negative nodes and cancers
0.6 to 1.0 cm are divided into those with a low risk of recurrence
and those with unfavorable prognostic features that portend a
higher risk of recurrence and a need for adjuvant chemotherapy.

Radiation Therapy Adverse prognostic factors include blood vessel or lymph ves-
Radiation therapy is used for all stages of breast cancer sel invasion, high nuclear grade, high histologic grade, HER2/
depending on whether the patient is undergoing BCT or mas- neu overexpression, and negative hormone receptor status.
tectomy.296-302 Adjuvant radiation for patients with DCIS and American Society of Clinical Oncology guidelines suggest that
early-stage breast cancer have been described previously in this adjuvant chemotherapy should be considered for patients with
chapter. Those women treated with mastectomy who have cancer positive lymph nodes, HER2-positive disease, Adjuvant! Online
at the surgical margins are at sufficiently high risk for local mortality greater than 10%, grade 3 lymph node negative tumors
recurrence to warrant the use of adjuvant radiation therapy to >5 mm, triple-negative tumors, lympho-vascular invasion, or
the chest wall postoperatively. Women with metastatic disease estimated distant relapse risk of greater than 15% at 10 years
involving four or more axillary lymph nodes and premeno- based on 21 gene recurrence score.259 Adjuvant chemotherapy
pausal women with metastatic disease involving one to three is recommended by the NCCN guidelines for women with these
lymph nodes also are at increased risk for recurrence and are unfavorable prognostic features. Table 17-14 lists the frequently
candidates for the use of chest wall and supraclavicular lymph used chemotherapy regimens for breast cancer.
node radiation therapy. In advanced local-regional breast can- For women with hormone receptor-negative cancers
cer (stage IIIA or IIIB), women are at high risk for recurrent that are >1 cm in size, adjuvant chemotherapy is appropriate.
disease after surgical therapy, and adjuvant radiation therapy
is used to reduce the risk of recurrence. Current recommenda-
tions for stages IIIA and IIIB breast cancer are (a) adjuvant Table 17-14
radiation therapy to the breast and supraclavicular lymph nodes
after neoadjuvant chemotherapy and segmental mastectomy Adjuvant chemotherapy regimens for breast cancer
with or without axillary lymph node dissection, (b) adjuvant HER-2 NEGATIVE HER-2 POSITIVE
radiation therapy to the chest wall and supraclavicular lymph
nodes after neoadjuvant chemotherapy and mastectomy with Preferred AC → T + trastuzumab +/−
or without axillary lymph node dissection, and (c) adjuvant Dose dense AC → pertuzumab (T = paclitaxel)
radiation therapy to the chest wall and supraclavicular lymph Paclitaxel every TCH (docetaxel, carboplatin,
nodes after segmental mastectomy or mastectomy with axillary 2 weeks trastuzumab +/− pertuzumab)
lymph node dissection and adjuvant chemotherapy. Data from Dose dense AC → Other Regimens
the EBCTCG has shown improvements in local-regional con- Paclitaxel weekly AC → T + trastuzumab +/−
trol and survival in patients treated with mastectomy and post- TC (T = docetaxel) pertuzumab (T = docetaxel)
mastectomy radiation therapy for one to three positive axillary Other Regimens Docetaxel + cyclophosphamide +
lymph nodes.303 This data is based on clinical trials from the era CMF trastuzumab
of axillary lymph node dissection for staging prior to the routine AC → Docetaxel FEC → Docetaxel +
use of sentinel lymph node dissection. It is likely that the vol- every 3 weeks trastuzumab + pertuzumab
ume of disease in the earlier trials was greater overall than what AC → Paclitaxel weekly FEC → Paclitaxel +
is currently seen in patients who have small volume metastases TAC (T = docetaxel) trastuzumab + pertuzumab
detected at sentinel node dissection. It is important to include Paclitaxel + trastuzumab
all multidisciplinary team members (medical oncology, plastic Paclitaxel + trastuzumab +
surgery, radiation oncology, and surgical oncology) regarding pertuzumab → FEC
the risks and benefits of postmastectomy radiation therapy in Docetaxel + trastuzumab +
patients with one to three positive nodes. pertuzumab → FEC
The use of partial breast irradiation (APBI) for patients A = Adriamycin (doxorubicin); C = cyclophosphamide; E = epirubicin;
treated with breast-conserving surgery has also been previously F = 5-fluorouracil; M = methotrexate; T = Taxane (docetaxel or
described. APBI can be delivered via brachytherapy, external paclitaxel); → = followed by.
beam radiation therapy using 3D conformal radiation, or inten- Data from NCCN Practice Guidelines in Oncology. Fort Washington,
sity-modulated radiation therapy. Although initial results are PA: National Comprehensive Cancer Network, 2006.
However, women with node-negative hormone receptor–
positive cancers and T1 tumors are candidates for antiestrogen
therapy with or without chemotherapy. Assessment of overall
risk using known prognostic factors or additional testing such
as the 21-gene recurrence score assay can help to guide deci-
sion making regarding chemotherapy in patients with node-
negative, ER-positive breast cancer. For special-type cancers
(tubular, mucinous, medullary, etc), which are usually strongly
estrogen receptor positive, adjuvant antiestrogen therapy should
be advised for cancers >1 cm. For women with node-positive
tumors or with a special-type cancer that is >3 cm, the use of
chemotherapy is appropriate; those with hormone receptor-
positive tumors should receive antiestrogen therapy.
For stage IIIA breast cancer, preoperative chemotherapy
with an anthracycline and taxane-containing regimen followed
by either a modified radical mastectomy or segmental mastec-
tomy with axillary dissection followed by adjuvant radiation
therapy should be considered, especially for estrogen receptor
negative disease. While the same regimen may be considered
for estrogen receptor positive disease, it is known that these
tumors respond less well to chemotherapy with <10% pCR rate
overall and <3% pCR rate for lobular cancers. Other options
such as neoadjuvant endocrine therapy followed by local-
regional treatment or in some cases primary endocrine therapy
may be considered depending on other tumor characteristics and
the patient’s comorbid conditions and preference.
Neoadjuvant (Preoperative) Chemotherapy. In the early
1970s, the National Cancer Institute in Milan, Italy, initiated two
prospective randomized multimodality clinical trials for women
with T3 or T4 breast cancer.310 The best results were achieved
when surgery was interposed between chemotherapy courses,
with 82% local-regional control and 25% having a 5-year dis-
ease-free survival. The NSABP B-18 trial evaluated the role
of neoadjuvant chemotherapy in women with operable stages
II and III breast cancer.206 Women entered into this study were
randomly assigned to receive either surgery followed by che-
motherapy or neoadjuvant chemotherapy followed by surgery.
There was no difference in the 5-year disease-free survival rates
for the two groups, but after neoadjuvant chemotherapy there
was an increase in the number of lumpectomies performed and
a decreased incidence of node positivity. It was suggested that
neoadjuvant chemotherapy be considered for the initial manage-
ment of breast cancers judged too large for initial lumpectomy.
Several prospective clinical trials have evaluated the neo-
adjuvant approach, and two meta-analyses have been performed,
each showing that neoadjuvant vs. adjuvant chemotherapy are
equivalent in terms of OS.262,311 These analyses also evaluated
local-regional recurrence (LRR) and found that there was an
increase in LRR rates for patients receiving neoadjuvant chemo-
therapy when radiation therapy was used alone without surgery
after completion of chemotherapy. Mittendorf and colleagues
evaluated a contemporary series of almost 3000 patients treated
with breast conserving surgery and radiation therapy who
received either neoadjuvant or adjuvant chemotherapy for breast
cancer.312 They found that the risk of LRR was driven by bio-
logic factors and disease stage and was not impacted by
10 the timing of chemotherapy delivery. These data high-
light the importance of the multidisciplinary management of
patients with breast cancer in achieving the best outcomes.
The use of neoadjuvant chemotherapy offers the oppor-
tunity to observe the response of the intact primary tumor
and any regional nodal metastases to a specific chemotherapy 595
regimen.279 For patients whose tumors remain stable in size or
even progress with the initial neoadjuvant chemotherapy regi-
men, a new regimen may be considered that uses another class
of agents, although there is no randomized data confirming this
will improve outcome.
After treatment with neoadjuvant chemotherapy, patients
are assessed for clinical and pathologic response to the regimen.
Patients whose tumors achieve a pathologic complete response
to neoadjuvant chemotherapy have been shown to have statisti-
CHAPTER 17 THE BREAST
cally improved survival outcomes to those of patients whose
tumors demonstrate only a partial response, remain stable,
or progress on treatment. Researchers at MD Anderson Cancer
Center have shown that residual cancer burden (RCB)—
categorized into four classes, RCB-0 or pathologic complete
response, RCB-1, RCB-2, and RCB-3—is predictive of 10-year
relapse-free survival with neoadjuvant chemotherapy in triple
negative, ER-positive, and HER2-positive tumors.313 Patients
who experience progression of disease during neoadjuvant che-
motherapy have the poorest survival.314,315 This means that while
patients who achieve a pCR will have a better prognosis based
on their response to neoadjuvant chemotherapy. Equally other
patients will have a poorer prognosis compared to when they
started neoadjuvant therapy based on the nonresponse to treat-
ment. Consequently, the FDA has supported the use of the neo-
adjuvant platform and pathologic response rates as an endpoint
for mechanism of accelerated approval for new agents in high
risk early stage breast cancer, though the short-term endpoints
(i.e., pCR) have not been shown to correlate with long-term out-
comes (i.e., disease free survival and overall survival).
Current NCCN recommendations for treatment of oper-
able advanced local-regional breast cancer are neoadjuvant
chemotherapy with an anthracycline-containing or taxane-
containing regimen or both, followed by mastectomy or lumpec-
tomy with axillary lymph node dissection if necessary, followed
by adjuvant radiation therapy. For patients with HER2-positive
breast cancer, trastuzumab and pertuzumab can be combined
with chemotherapy in the preoperative setting to increase patho-
logic complete response rates. For inoperable stage IIIA and for
stage IIIB breast cancer, neoadjuvant chemotherapy is used to
decrease the local-regional cancer burden. This may then permit
subsequent modified radical or radical mastectomy, which is
followed by adjuvant radiation therapy.
Nodal Evaluation in Patients Receiving Neoadjuvant
Chemotherapy. The management of the axilla after neoadjuvant
chemotherapy has not been specifically addressed in randomized
trials. Standard practice has been to perform an axillary lymph
node dissection after chemotherapy or to perform a sentinel lymph
node dissection before chemotherapy for nodal staging before
chemotherapy is initiated. A number of small single-institution
studies, one multicenter study, and a recent meta-analysis have
explored the use of SLN dissection at the completion of chemo-
therapy. The published results from these studies have demon-
strated the feasibility of SLN dissection in breast cancer patients
after neoadjuvant chemotherapy. A review of 14 studies with 818
patients showed a false negative rate of 11% with an overall accu-
racy of 94%.280,281,316 While SLN dissection has been accepted for
assessment of the axilla in the clinically node-negative axilla after
neoadjuvant chemotherapy, clinicians have been slower to adopt
this approach for axillary staging after chemotherapy in patients
who started with initial node-positive disease. Several clinical
596 trials have been performed to evaluate the accuracy of SLN dis-
section in patients with documented axillary metastases at initial
presentation, including ACOSOG Z1071, SENTINA, and SN
FNAC. ACOSOG Z1071 (Alliance) analyzed women with clini-
cal T0-T4, N1-N2, M0 breast cancer who underwent both SLN
surgery and axillary lymph node dissection (ALND).317 The pri-
mary endpoint was the false-negative rate (FNR) of SLN surgery
after chemotherapy with clinically node-positive disease with a
prespecified endpoint of 10% considered to be an acceptable rate.
However, the FNR was found to be 12.6%, though it was lower
when dual-agent mapping technique was used and at least three or
more SLNs removed.317 The SENTINA and SN FNAC trials had
PART II
findings similar to Z1071. The results from Z1071 were further
analyzed to determine if a clip was placed in the positive node at
initial diagnosis and if the clipped node location at surgery (SLN
or ALND) was evaluated. Indeed, this showed that identification
of the clipped node during the surgical procedure further decreased
SPECIFIC CONSIDERATIONS
the FNR.318 The results from the ACOSOG Z1071 (Alliance) trial,
in cases presenting with cN1 disease and at least two SLN resec-
tions and clipped node was within the SLN specimen, showed that
the FNR was 6.8%.318 Caudle et al at MD Anderson Cancer Center
performed a prospective study of patients with biopsy-confirmed
nodal metastases with a clip placed in the biopsy-proven lymph
node, who were treated with neoadjuvant chemotherapy; at the
time of surgery these patients underwent SLN dissection with
targeting and removal of the clipped node (targeted axillary dis-
section [TAD]).319 TAD includes SLN surgery and selective local-
ization and removal of the clipped node, with the goal to determine
if pathologic changes in the clipped node accurately reflect the
status of the nodal basin, and proposing that TAD improves the
FNR compared to SLN surgery alone.319 In patients undergoing
SLN surgery and ALND (n = 118), the FNR was 10.1% (95%
CI, 4.2–19.8), and adding evaluation of the clipped node reduced
the FNR to 1.4% (95% CI, 0.03–7.3; P = .03). TAD followed by
ALND was performed in 85 patients, with an FNR of 2.0% (1 of
50; 95% CI, 0.05–10.7).319 Although the use of dual tracer tech-
nique, retrieval of three or more SLNs, and TAD improve axillary
staging after neoadjuvant chemotherapy, there is no long-term data
about the oncologic safety of omitting ALND in patients who con-
vert from cN1 to cN0 disease at this time.
Neoadjuvant Endocrine Therapy. While initially used in
elderly women who were deemed poor candidates for surgery
or cytotoxic chemotherapy, neoadjuvant endocrine therapy is
being increasingly evaluated in clinical trials. As clinicians
have gained experience with neoadjuvant treatment strategies,
it is now clear from examination of predictors of complete
pathologic response that ER-positive tumors do not shrink in
response to chemotherapy as readily as ER-negative tumors.320
Indeed, the pCR rate in ER-negative tumors is approximately
three times that of ER-positive tumors. Fisher et al examined
the results of the NSABP B-14 and B-20 trials and found that,
as age increased, women obtained less benefit from chemo-
therapy. They recommended that factors214 including tumor
estrogen receptor concentration, nuclear grade, histologic grade,
tumor type, and markers of proliferation should be considered in
these patients before choosing between the use of chemotherapy
and hormonal therapy. If in fact the tumor is estrogen-receptor
rich, these patients may benefit more from endocrine therapy in
the neoadjuvant setting than they might if they received stan-
dard chemotherapy. Neoadjuvant endocrine therapy has been
shown to shrink tumors, enabling breast-conserving surgery in
women with hormone receptor-positive disease who otherwise
would have to be treated with mastectomy, although long-term
recurrence rates have not been reported.265 The IMPACT trial
evaluated neoadjuvant use of tamoxifen or anastrozole or both
in combination in postmenopausal women with ER-positive
operable or locally advanced breast cancer.321 While there were
no significant differences in objective tumor response among
tamoxifen, anastrozole, or a combination of the two, in patients
who were initially deemed as mastectomy candidates, only 31%
had breast-conserving surgery with tamoxifen, whereas 44%
underwent breast-conserving surgery with anastrozole. Invasive
lobular cancers in particular have been shown to respond poorly
to neoadjuvant chemotherapy and may have better response to
neoadjuvant endocrine therapy.322-324 A meta-analysis evaluating
the response rate and rate of breast conservation surgery with
the use of neoadjuvant endocrine therapy compared to combi-
nation chemotherapy was recently reported. This meta-analysis
included nearly 3500 patients across 20 studies.325 Interestingly,
aromatase inhibitors had a similar response, and breast conserva-
tion rates in comparison with combination chemotherapy albeit
with lower toxicity suggest that neoadjuvant endocrine therapy
is an appropriate alternative in ER-positive breast cancers.
However, the incidence of complete pathological response was
low (<10%) with both approaches. Also, aromatase inhibitors
were associated with significantly higher response and breast
conservation rates compared with tamoxifen. The ALTER-
NATE (Alternate Approaches for Clinical Stage II or III Estro-
gen Receptor Positive Breast Cancer Neoadjuvant Treatment
in Postmenopausal Women) trial is currently evaluating neo-
adjuvant endocrine therapy with fulvestrant or anastrozole or
in combination.
Increasing knowledge of secondary resistance mecha-
nisms to endocrine therapy and cross talk between ER and the
PI3K/Akt/mTOR pathway have led to the evaluation of PI3K
pathway inhibitors in combination with endocrine therapy. Post-
menopausal women with ER-positive early breast cancers were
treated with letrozole or letrozole in combination with everoli-
mus, a mTOR inhibitor, in a randomized, phase 2 clinical trial.
Clinical response and antiproliferative response, characterized
by reduction in Ki67, was superior in the combination arm, sug-
gesting that everolimus can increase efficacy of neoadjuvant
letrozole.326 The LORLEI study is evaluating the use of taselisib,
a PI3K inhibitor in combination with letrozole compared with
letrozole alone. With the approval of CDK 4/6 inhibitors in the
metastatic setting, clinical trials are evaluating the use of CDK
inhibitors in combination with neoadjuvant endocrine therapy.
Neoadjuvant anastrozole in combination with palbociclib, a
CDK4/6 inhibitor, has been shown to significantly reduce Ki67,
suggesting that CDK4/6 inhibition can increase the efficacy of
neoadjuvant endocrine therapy.
With the use of neoadjuvant chemotherapy or endocrine
therapy, observation of the response of the intact tumor and/or
nodal metastases to a specific regimen could ultimately help to
define which patients will benefit from specific therapies in the
adjuvant setting. In adjuvant trials the primary endpoint is typi-
cally survival, whereas in neoadjuvant trials the endpoints have
more often been clinical or pathologic response rates. There are
a number of clinical trials underway comparing neoadjuvant
chemotherapy and endocrine therapy regimens with pretreat-
ment and posttreatment biopsy samples obtained from the pri-
mary tumors in all of the participants. These samples are being
subjected to intensive genomic and proteomic analyses that may
help to define a more personalized or individualized approach to
breast cancer treatment in the future.
Antiestrogen Therapy
Tamoxifen. Within the cytosol of breast cancer cells are spe-
cific proteins (receptors) that bind and transfer steroid moieties
into the cell nucleus to exert specific hormonal effects.308,327-331
The most widely studied hormone receptors are the estrogen
receptor and progesterone receptor. Hormone receptors are
detectable in >90% of well-differentiated ductal and lobular
invasive cancers. Although the receptor status may remain the
same between the primary cancer and metastatic disease in the
same patient in the majority of cases, there are instances where
the status is changed in the metastatic focus; therefore, biopsy
of newly diagnosed metastatic disease should be considered for
assessment of hormone receptor and HER2 status.
After binding to estrogen receptors in the cytosol, tamoxi-
fen blocks the uptake of estrogen by breast tissue. Clini-
cal responses to antiestrogen are evident in >60% of women
with hormone receptor-positive breast cancers but in <10%
of women with hormone receptor-negative breast cancers. A
meta-analysis by the Early Breast Cancer Trialists’ Collabora-
tive Group showed that adjuvant therapy with tamoxifen for
5 years reduced breast cancer mortality by about a third through
the first 15 years of follow-up.14 This mortality benefit contin-
ues to be statistically significant in the second and third 5-year
periods (i.e., years 5–9 and 10–15) when the patients are no
longer receiving endocrine treatment—the so-called carry-over
effect. The analysis also showed a 39% reduction in the risk
of cancer in the contralateral breast. The antiestrogens do have
defined toxicity, including bone pain, hot flashes, nausea, vom-
iting, and fluid retention. Thrombotic events occur in <3% of
treated women. Cataract surgery is more frequently performed
in patients receiving tamoxifen. The Stockholm trial showed
that 5 years of tamoxifen was associated with a significant
reduction in locoregional recurrences and distant metastasis
in postmenopausal women with ER-positive breast cancer.332
However, an increase in endometrial cancers was observed with
long-term tamoxifen use. The NSABP B14 trial evaluated 10
years of tamoxifen compared to 5 years.333 However, the study
was terminated based on interim analyses indicating no addi-
tional benefit from tamoxifen beyond 5 years. The ATLAS trial
also evaluated the use of tamoxifen for 5 years vs. 10 years
in nearly 13,000 women across the world. This study showed
that continuing tamoxifen for 10 years vs. 5 years produced a
significant reduction in recurrence and mortality.334 Interestingly,
the benefit was not seen in the second 5 years (i.e., years 5–9)
while the patients were on treatment, but it was seen from
years 10 to 15. One reason the NSABP B14 study was led to
conclude that 10 years of tamoxifen was not beneficial was that
the follow-up time was shorter. Results of the ATLAS study
were also corroborated by the aTTom study. Similarly, extended
adjuvant therapy with letrozole after 5 years of tamoxifen was
shown to improve disease-free survival without improvement in
overall survival except in node-positive patients.335
Tamoxifen therapy is also considered for women with
DCIS that is found to be ER-positive. The goals of such ther-
apy are to decrease the risk of an ipsilateral recurrence after
breast conservation therapy for DCIS and to decrease the risk
of a primary invasive breast cancer or a contralateral breast
cancer event. Consequently, tamoxifen is not recommended for
patients who have had bilateral mastectomies with ER-positive
DCIS. With the use of aromatase inhibitors in postmenopausal 597
women, use of adjuvant tamoxifen has increasingly been limited
to premenopausal women.
Aromatase Inhibitors. In postmenopausal women, aromatase
inhibitors are now considered first-line therapy in the adjuvant
setting. Currently, three third-generation aromatase inhibitors are
approved for clinical use: the reversible nonsteroidal inhibitors
anastrozole and letrozole and the irreversible steroidal inhibitor
exemestane. While all the aromatase inhibitors have been shown
to have similar efficacy with a similar spectrum of adverse
CHAPTER 17 THE BREAST
effects, the Early Breast Cancer Trialists’ Collaborative Group
meta-analyses of 31,920 postmenopausal women with ER-
positive early breast cancers treated with tamoxifen or aroma-
tase inhibitors demonstrated that 5 years of aromatase inhibitors
reduced the rate of recurrence by 30% and 10-year breast cancer
mortality by about 15% compared to 5 years of tamoxifen.336-339
The NSABP B42 study evaluated whether an additional 5 years
of letrozole improved disease-free survival in postmenopausal
women who have completed 5 years of tamoxifen or an aromatase
inhibitor. After a median follow-up of 6.9 years, while extended
letrozole significantly improved breast cancer-free interval, no
improvement in disease-free survival, the primary endpoint, was
observed. Recently, the results of the MA-17R study, designed
to assess the efficacy of adjuvant letrozole for 10 years, were
reported.340 Similar to NSABP B42, extended letrozole improved
disease-free survival without significant improvement in overall
survival. Patients who are node-positive, have received adjuvant
chemotherapy, with prior receipt of tamoxifen are likely to ben-
efit from long-term use of an aromatase inhibitor.
The aromatase inhibitors are less likely than tamoxifen to
cause endometrial cancer but do lead to changes in bone mineral
density that may result in osteoporosis and an increased rate of
fractures in postmenopausal women. The risk of osteoporosis
can be averted by treatment with bisphosphonates. Joint pains
are a side effect that affects a significant number of patients.
Node-negative and node-positive breast cancer patients whose
tumors express hormone receptors should be considered for
endocrine therapy in the adjuvant setting. Women with hormone
receptor–positive cancers achieve significant reduction in risk
of recurrence of breast cancer and mortality from breast cancer
through the use of endocrine therapies.
For postmenopausal women with ER-positive, HER2-
negative, metastatic breast cancer, available endocrine thera-
pies include nonsteroidal aromatase inhibitors (anastrozole and
letrozole); steroidal aromatase inhibitors (exemestane); serum
ER modulators (tamoxifen or toremifene); ER down-regulators
(fulvestrant); progestin (megestrol acetate); androgens
(fluoxymesterone); and high-dose estrogen (ethinyl estradiol).
A third generation nonsteroidal aromatase inhibitor or palbo-
ciclib, the CDK 4/6 inhibitor, in combination with letrozole
may be considered as a treatment option for first-line therapy.
Activation of CDK4/CDK6 cell cycle signaling axis has been
implicated in mediating endocrine resistance. Consequently,
PALOMA-1 evaluated the safety and efficacy of palbociclib in
combination with letrozole vs. letrozole alone as first-line treat-
ment for patients with ER-positive, HER2-negative advanced
breast cancer. Median progression-free survival (PFS) was
doubled with the combination compared to letrozole alone
(20.2 months vs. 10.2 months for the letrozole).341 Based on this,
the FDA approved palbociclib in combination with letrozole
for the treatment of postmenopausal women with ER-positive,
HER2-negative advanced breast cancer as initial treatment. The
598 benefit of palbociclib in combination with letrozole was sub-
sequently confirmed in a phase 3 trial (PFS 24.8 months vs.
14.5 months for letrozole).342 Two additional CDK4/6 inhibitors,
ribociclib and abemaciclib, have been approved for use in com-
bination with endocrine therapy for patients with hormone
receptor–positive advanced breast cancer.
On the other hand, PALOMA-3 compared the combina-
tion of palbociclib and fulvestrant to fulvestrant alone in pre- or
postmenopausal ER-positive, HER2-negative metastatic breast
cancer patients, whose disease progressed on prior endocrine
therapy. Premenopausal women also received the GNRH ago-
PART II
nist, goserelin. The median PFS was 9.2 months for the combi-
nation compared to 3.8 months with fulvestrant alone.343 Thus,
fulvestrant with palbociclib is a potential option for women with
metastatic breast cancer who have progressed on prior endo-
crine therapy. Additionally, abemaciclib in combination with
fulvestrant or as single agent is approved for use in ER-posi-
SPECIFIC CONSIDERATIONS
tive advanced breast cancers previously treated with endocrine
therapy.
In premenopausal women with stage IV ER-positive
breast cancer without previous exposure to endocrine therapy,
initial treatment with tamoxifen or ovarian suppression/ablation
plus aromatase inhibitor with or without CDK4/6 inhibitors are
reasonable options.
Activation of the PI3K/mammalian target of rapamycin
(mTOR) signal transduction pathway has also been implicated
in secondary resistance to estrogen targeting. BOLERO-2 eval-
uated the use of exemestane in combination with everolimus
in postmenopausal women with ER-positive tumors who had
progressed or recurred on a nonsteroidal aromatase inhibitor.344
An improvement in PFS was observed with combination com-
pared to exemestane alone (11 vs. 4.1 months) leading to FDA
approval. Similar improvement in PFS was observed with a
combination of tamoxifen and everolimus.345 However, a phase
3 trial of letrozole in combination with temsirolimus, an mTOR
inhibitor, did not show any improvement in PFS in aromatase
inhibitor–naive metastatic postmenopausal women.346 Trials
evaluating the adjuvant use of mTOR inhibitors and CDK 4/6
inhibitors are currently in progress.
Women whose tumors respond to an endocrine therapy
with either shrinkage of their breast cancer (objective response)
or long-term stabilization of disease (stable disease) are con-
sidered to represent “clinical benefit” and should receive addi-
tional endocrine therapy at the time of progression because
their chances of a further response remain high.294-296 Patients
whose tumors progress de novo on an endocrine agent have a
low rate of clinical benefit (<20%) to subsequent endocrine
therapy; the choice of endocrine or chemotherapy should be
considered based on the disease site and extent as well as the
patient’s general condition and treatment preference.294
The adjuvant use of aromatase inhibitors and recent
advances in tumor genome sequencing technologies have
enabled the identification of secondary ESR1 mutations.347,348
These mutations, typically present in the ligand binding
domains, lead to ligand-independent activation of the receptor,
mediate resistance to aromatase inhibitors, and are associated
with shorter survival.349 Reported incidence of these mutations
are variable (20%–30%) based on prior exposure to aroma-
tase inhibitors and are uncommon in primary breast cancers.
Clinical trials evaluating novel selective estrogen receptor
degraders with potential activity against these mutations are
in progress.
Ablative Endocrine Therapy
In the past, adrenalectomy and/or hypophysectomy were the pri-
mary endocrine modalities used to treat metastatic breast cancer,
but today these approaches are seldom used. In women who are
premenopausal at diagnosis, ovarian ablation can be accomplished
by oophorectomy or ovarian radiation. Ovarian suppression can
be accomplished by the use of gonadotrophin-hormone releasing
hormone agonists, such as goserelin or leuprolide. Evaluation of
the combination of goserelin with tamoxifen vs. cyclophospha-
mide/methotrexate/fluorouracil chemotherapy in premenopausal
ER-positive early-stage breast cancers showed that relapse-free
survival was superior with endocrine therapy combination, with
a similar trend in overall survival.350 Data from the SOFT and
TEXT trials on adjuvant endocrine therapy show that exemes-
tane plus ovarian suppression significantly reduces recurrences
as compared with tamoxifen plus ovarian suppression.351,352
In these trials, ovarian suppression was achieved with the use of
the gonadotropin-releasing hormone agonist triptorelin, oopho-
rectomy, or ovarian irradiation. The disease-free survival was
89% in the tamoxifen plus ovarian suppression group, while it
was 93% in exemestane plus ovarian suppression group; how-
ever, there was no significant differences in overall survival. In
the SOFT trial, while tamoxifen plus ovarian suppression was
not superior to tamoxifen alone in terms of disease-free survival,
improved outcomes were observed in ovarian suppression in
women with a high risk of recurrence. In women who received
no adjuvant chemotherapy, no meaningful benefit was obtained
with ovarian suppression. Thus, ovarian suppression in combi-
nation with an aromatase inhibitor can be considered in select
premenopausal women with high-risk features (age <40 years,
positive lymph nodes) who warranted adjuvant chemotherapy.
Anti-HER2 Therapy
The determination of tumor HER-2 expression or gene ampli-
fication for all newly diagnosed patients with breast cancer is
now recommended.353-356 It is used to assist in the selection of
adjuvant chemotherapy in both node-negative and node-positive
patients. Trastuzumab was initially approved for the treatment
of HER2/neu-positive breast cancer in patients with metastatic
disease. Once efficacy was demonstrated for patients with
metastatic disease, the NSABP and the North Central Cancer
Treatment Group conducted phase 3 trials that evaluated the
impact of adjuvant trastuzumab therapy in patients with early-
stage breast cancer. After approval from the FDA, these groups
amended their adjuvant trastuzumab trials (B-31 and N9831,
respectively), to provide for a joint efficacy analysis. The first
joint interim efficacy analysis demonstrated an improvement in
3-year disease-free survival from 75% in the control arm to 87%
in the trastuzumab arm (hazard ratio = 0.48, P <.0001). There
was an accompanying 33% reduction in mortality in the patients
who received trastuzumab (hazard ratio = 0.67, P = 0.015).
The magnitude of reduction in hazard for disease-free survival
events crossed prespecified early reporting boundaries, so the
data-monitoring committees for both groups recommended that
randomized accrual to the trials be ended, and the results were
subsequently published.181
While anthracycline-based adjuvant chemotherapy was
considered preferable in HER2-positive breast cancer, the
BCIRG 006 compared the use of anthracycline with taxane and
trastuzumab (AC-TH) versus taxane, carboplatin chemotherapy
with trastuzumab (TCH).182 With 10 years of follow-up, no
statistical significance with regard to disease-free and overall
survival was observed for anthracycline-based chemotherapy.
While anthracycline chemotherapy was numerically superior,
this was accompanied by an increase in the incidence of leu-
kemia and congestive heart failure. A year of adjuvant trastu-
zumab is considered standard of care. Two years of adjuvant
trastuzumab has been shown to be more effective, although it is
associated with more toxicity than 1 year of trastuzumab.357 On
the other hand, the PHARE trial examined 6 months vs. stan-
dard 12 months of trastuzumab. After 3.5 years of follow-up, the
study failed to demonstrate that 6 months was noninferior com-
pared to the standard therapy.358 Patients with HER2-positive
tumors benefit if trastuzumab is added to taxane chemotherapy.
Because of overlapping cardiotoxicities, trastuzumab is not usu-
ally given concurrently with anthracyclines.
Buzdar and colleagues reported the results of a random-
ized neoadjuvant trial of trastuzumab in combination with
sequential paclitaxel followed by FEC-75 (5-fluorouracil, epi-
rubicin, cyclophosphamide) vs. the same chemotherapy regimen
without trastuzumab in 42 women with early-stage operable
breast cancer. The pathologic complete response rates in this
trial increased from 25% to 66.7% when chemotherapy was
given concurrently with trastuzumab.301 A subsequent report
that included additional patients treated with concurrent chemo-
therapy and trastuzumab further confirmed the high pathologic
complete response rates and continued to show that cardiac
function was preserved.302
While novel agents have been approved for the treatment
of women with metastatic HER2-positive breast cancers, cur-
rently trastuzumab is the only HER2-targeted agent approved
for use in the adjuvant setting. Lapatinib is a dual tyrosine kinase
inhibitor that targets both HER2 and EGFR. It was approved
for use with capecitabine in patients with HER2-positive meta-
static disease. Adjuvant lapatinib was shown to be inferior to
trastuzumab, and the combination of lapatinib with trastuzumab
did yield a significant improvement in disease-free survival
compared to trastuzumab alone. Ado-trastuzumab emtansine
(T-DM1) is approved for HER2-positive metastatic breast
cancer patients who have previously received trastuzumab
and a taxane either separately or in combination. T-DM1 is an
antibody drug conjugate that incorporates the HER2 targeted
activity of trastuzumab with the cytotoxic activity of DM1, a
microtubule inhibitory agent leading to apoptosis.359
Pertuzumab is a humanized monoclonal antibody that
binds at a different epitope of the HER2 extracellular domain
(subdomain II) and prevents dimerization of HER2 with other
members of the family, primarily HER3. In the metastatic
setting, it is approved in combination with trastuzumab and
docetaxel for patients with metastatic HER2-positive breast
cancer who have not received prior HER2-targeted therapy
or chemotherapy for metastatic disease.360 In the neoadjuvant
setting, pertuzumab is approved in combination with trastu-
zumab and docetaxel in HER2-positive, early stage breast
cancers that are greater than 2 cm or node-positive. However,
this approval is based on improvement in pathologic complete
response rate, and not data based on improvement in event free
or overall survival.361,362 In the NeoSphere trial, neoadjuvant
use of pertuzumab with trastuzumab and docetaxel led to nearly
a 17% increase in pathologic complete response in the breast
(P = .0141).361 While in the TRYPHAENA study, pathologic
complete responses ranging from 57% to 66% were observed with
neoadjuvant pertuzumab and trastuzumab combination given
with anthracycline-containing or nonanthracycline-containing
chemotherapy.362 With the use of dual antibody therapy, cur- 599
rently there is significant interest in identifying patients who
can avoid chemotherapy and potentially be treated with HER2-
targeted agents alone. The NeoSphere study showed 27%
pathologic complete response in HER2-positive, ER-negative,
breast cancer patients treated with pertuzumab and trastuzumab
alone. Pertuzumab was recently FDA approved in combination
with trastuzumab and chemotherapy in the adjuvant setting in
HER2 amplified breast cancers with high risk of recurrence.
Approval is based on APHINITY trial showing that the addition
CHAPTER 17 THE BREAST
of pertuzumab improved invasive disease free survival (7.1%)
compared to placebo (8.7%) (HR 0.82, 95% CI: 0.67, 1.00;
p = 0.047). Overall survival data is not mature.
The ExteNET study evaluated the use of neratinib, an
irreversible inhibitor of EGFR, HER2, and HER4, in HER2-
positive early stage patients who have completed adjuvant
trastuzumab. A year of neratinib after completion of chemo-
therapy and trastuzumab-based adjuvant therapy significantly
improved 2-year disease-free survival, the primary endpoint.363
After two years, invasive disease free survival was 94.2% in
patients treated with neratinib compared with 91.9% in those
receiving placebo (HR 0.66; 95% CI: 0.49, 0.90, p = 0.008)
leading to FDA approval for HER2 amplified breast cancers
following a year of adjuvant trastuzumab.
In addition to amplifications or copy number alterations,
activating mutations or single nucleotide variants in HER2
have been described (2%).364 Typically observed in ER-positive
breast cancers, a higher prevalence of HER2 mutations have
been reported in invasive lobular carcinomas, particularly in
the pleomorphic subtype.365 These mutations, usually exclusive
with HER2 amplification, are observed in kinase or extracellular
domains and predict for responses or resistance to HER2-targeting
agents.366,367 A phase 2 trial of neratinib in HER2-mutated meta-
static breast cancers showed a clinical benefit rate of 36% with
one complete response and one partial response in a heavily pre-
treated population. A clinical trial evaluating the combination of
neratinib with fulvestrant, in HER2-mutated, ER-positive breast
cancers, is in progress.
SPECIAL CLINICAL SITUATIONS
Nipple Discharge
Unilateral Nipple Discharge. Nipple discharge is a finding
that can be seen in a number of clinical situations. It may be
suggestive of cancer if it is spontaneous, unilateral, localized
to a single duct, present in women ≥40 years of age, bloody,
or associated with a mass. A trigger point on the breast may
be present so that pressure around the nipple-areolar complex
induces discharge from a single duct. In this circumstance,
mammography and ultrasound are indicated for further evalu-
ation. A ductogram also can be useful and is performed by can-
nulating a single discharging duct with a small nylon catheter
or needle and injecting 1.0 mL of water-soluble contrast solu-
tion. Nipple discharge associated with a cancer may be clear,
bloody, or serous. Testing for the presence of hemoglobin is
helpful, but hemoglobin may also be detected when nipple dis-
charge is secondary to an intraductal papilloma or duct ecta-
sia. Definitive diagnosis depends on excisional biopsy of the
offending duct and any associated mass lesion. A 3.0 lacrimal
duct probe can be used to identify the duct that requires exci-
sion. Another approach is to inject methylene blue dye within
600 the duct after ductography. The nipple must be sealed with
collodion or a similar material so that the blue dye does not
discharge through the nipple but remains within the distended
duct facilitating its localization. Localization with a wire or
seed is performed when there is an associated mass that lies
>2.0 to 3.0 cm from the nipple.
Bilateral Nipple Discharge. Nipple discharge is suggestive
of a benign condition if it is bilateral and multiductal in origin,
occurs in women ≤39 years of age, or is milky or blue-green.
Prolactin-secreting pituitary adenomas are responsible for bilat-
eral nipple discharge in <2% of cases. If serum prolactin levels
PART II
are repeatedly elevated, plain radiographs of the sellaturcica are
indicated, and thin section CT scan is required. Optical nerve
compression, visual field loss, and infertility are associated with
large pituitary adenomas.
Axillary Lymph Node Metastases in the
SPECIFIC CONSIDERATIONS
Setting of an Unknown Primary Cancer
A woman who presents with an axillary lymph node metasta-
sis that is consistent with a breast cancer metastasis has a 90%
probability of harboring an occult breast cancer.303 However,
axillary lymphadenopathy is the initial presenting sign in only
1% of breast cancer patients. Fine-needle aspiration biopsy or
core-needle biopsy can be used to establish the diagnosis when
an enlarged axillary lymph node is identified. When metastatic
cancer is found, immunohistochemical analysis may classify
the cancer as epithelial, melanocytic, or lymphoid in origin.
The presence of hormone receptors (estrogen or progesterone
receptors) suggests metastasis from a breast cancer but is not
diagnostic. The search for a primary cancer includes careful
examination of the thyroid, breast, and pelvis, including the
rectum. The breast should be examined with diagnostic mam-
mography, ultrasonography, and MRI to evaluate for an occult
primary lesion. Further radiologic and laboratory studies should
include chest radiography and liver function studies. Additional
imaging of the chest, abdomen, and skeleton may be indicated
if the extent of nodal involvement is consistent with stage III
breast cancer. Suspicious findings on mammography, ultra-
sonography, or MRI necessitate breast biopsy. When a breast
cancer is found, treatment consists of an axillary lymph node
dissection with a mastectomy or preservation of the breast fol-
lowed by whole-breast radiation therapy. Chemotherapy and
endocrine therapy should be considered.
Breast Cancer During Pregnancy
Breast cancer occurs in 1 of every 3000 pregnant women, and
axillary lymph node metastases are present in up to 75% of
these women.368 The average age of the pregnant woman with
breast cancer is 34 years. Fewer than 25% of the breast nodules
developing during pregnancy and lactation will be cancerous.
Ultrasonography and needle biopsy specimens are used in the
diagnosis of these nodules. Mammography is rarely indicated
because of its decreased sensitivity during pregnancy and lac-
tation; however, the fetus can be shielded if mammography is
needed. Approximately 30% of the benign conditions encoun-
tered will be unique to pregnancy and lactation (galactoceles,
lobular hyperplasia, lactating adenoma, and mastitis or abscess).
Once a breast cancer is diagnosed, complete blood count, chest
radiography (with shielding of the abdomen), and liver function
studies are performed.
Because of the potential deleterious effects of radiation
therapy on the fetus, radiation cannot be considered until the
fetus is delivered. A modified radical mastectomy can be per-
formed during the first and second trimesters of pregnancy, even
though there is an increased risk of spontaneous abortion after
first-trimester anesthesia. During the third trimester, lumpec-
tomy with axillary node dissection can be considered if adju-
vant radiation therapy is deferred until after delivery. Lactation
is suppressed. Chemotherapy administered during the first tri-
mester carries a risk of spontaneous abortion and a 12% risk of
birth defects. There is no evidence of teratogenicity resulting
from administration of chemotherapeutic agents in the second
and third trimesters. For this reason, many clinicians now con-
sider the optimal strategy to be delivery of chemotherapy in the
second and third trimesters as a neoadjuvant approach, which
allows local therapy decisions to be made after the delivery of
the baby. Pregnant women with breast cancer often present at
a later stage of disease because breast tissue changes that occur
in the hormone-rich environment of pregnancy obscure early
cancers. However, pregnant women with breast cancer have a
prognosis, stage by stage, that is similar to that of nonpregnant
women with breast cancer.
Male Breast Cancer
Fewer than 1% of all breast cancers occur in men.369,370 The inci-
dence appears to be highest among North Americans and the
British, in whom breast cancer constitutes as much as 1.5% of
all male cancers. Jewish and African-American men have the
highest incidence. Male breast cancer is preceded by gyneco-
mastia in 20% of men. It is associated with radiation exposure,
estrogen therapy, testicular feminizing syndromes, and Kline-
felter’s syndrome (XXY). Breast cancer is rarely seen in young
males and has a peak incidence in the sixth decade of life. A
firm, nontender mass in the male breast requires investigation.
Skin or chest wall fixation is particularly worrisome.
DCIS makes up <15% of male breast cancer, whereas infil-
trating ductal carcinoma makes up >85%. Special-type cancers,
including infiltrating lobular carcinoma, have occasionally been
reported. Male breast cancer is staged in the same way as female
breast cancer, and stage by stage, men with breast cancer have the
same survival rate as women. Overall, men do worse because of
the more advanced stage of their cancer (stage II, III or IV) at the
time of diagnosis. The treatment of male breast cancer is surgi-
cal, with the most common procedure being a modified radical
mastectomy. SLN dissection has been shown to be feasible and
accurate for nodal assessment in men presenting with a clinically
node-negative axilla. Adjuvant radiation therapy is appropriate in
cases in which there is a high risk for local-regional recurrence.
Approximately 80% of male breast cancers are hormone recep-
tor–positive, and adjuvant tamoxifen is considered. Systemic che-
motherapy is considered for men with hormone receptor-negative
cancers and for men with large primary tumors, multiple positive
nodes, and locally advanced disease.
Phyllodes Tumors
The nomenclature, presentation, and diagnosis of phyllodes
tumors (including cystosarcoma phyllodes) have posed many
problems for surgeons.371 These tumors are classified as benign,
borderline, or malignant. Borderline tumors have a greater
potential for local recurrence.
Mammographic evidence of calcifications and morpho-
logic evidence of necrosis do not distinguish between benign,
borderline, and malignant phyllodes tumors. Consequently, it
is difficult to differentiate benign phyllodes tumors from the
malignant variant and from fibroadenomas. Phyllodes tumors
are usually sharply demarcated from the surrounding breast
tissue, which is compressed and distorted. Connective tissue
composes the bulk of these tumors, which have mixed gelati-
nous, solid, and cystic areas. Cystic areas represent sites of
infarction and necrosis. These gross alterations give the gross
cut tumor surface its classical leaf-like (phyllodes) appearance.
The stroma of a phyllodes tumor generally has greater cellular
activity than that of a fibroadenoma. After microdissection to
harvest clusters of stromal cells from fibroadenomas and from
phyllodes tumors, molecular biology techniques have shown the
stromal cells of fibroadenomas to be either polyclonal or mono-
clonal (derived from a single progenitor cell), whereas those of
phyllodes tumors are always monoclonal.
Most malignant phyllodes tumors (Fig. 17-38) contain
liposarcomatous or rhabdomyosarcomatous elements rather than
fibrosarcomatous elements. Evaluation of the number of mitoses
and the presence or absence of invasive foci at the tumor mar-
gins may help to identify a malignant tumor. Small phyllodes
tumors are excised with a margin of normal-appearing breast
tissue. When the diagnosis of a phyllodes tumor with suspicious
A
Figure 17-38. A. Malignant phyllodes tumor (cystosarcoma-
phyllodes). B. Histologic features of a malignant phyllodes tumor
(hematoxylin and eosin stain, ×100).
malignant elements is made, reexcision of the biopsy specimen 601
site to ensure complete excision of the tumor with a 1-cm mar-
gin of normal-appearing breast tissue is indicated. Large phyl-
lodes tumors may require mastectomy. Axillary dissection is not
recommended because axillary lymph node metastases rarely
occur.
Inflammatory Breast Carcinoma
Inflammatory breast carcinoma (stage IIIB) accounts for <3% of
breast cancers. This cancer is characterized by the skin changes
of brawny induration, erythema with a raised edge, and edema
CHAPTER 17 THE BREAST
(peau d’orange).372 Permeation of the dermal lymph vessels by
cancer cells is seen in skin biopsy specimens. There may be
an associated breast mass (Fig. 17-39). The clinical differentia-
tion of inflammatory breast cancer may be extremely difficult,
especially when a locally advanced scirrhous carcinoma invades
dermal lymph vessels in the skin to produce peau d’orange and
lymphangitis (Table 17-15). Inflammatory breast cancer also
may be mistaken for a bacterial infection of the breast. More
than 75% of women who have inflammatory breast cancer
present with palpable axillary lymphadenopathy, and distant
metastases also are frequently present. A PET-CT scan should
be considered at the time of diagnosis to rule out concurrent
metastatic disease. A report of the SEER program described
distant metastases at diagnosis in 25% of white women with
inflammatory breast carcinoma.
Surgery alone and surgery with adjuvant radiation therapy
have produced disappointing results in women with inflamma-
tory breast cancer. However, neoadjuvant chemotherapy with an
anthracycline-containing regimen may affect dramatic regres-
sions in up to 75% of cases. Tumors should be assessed for
HER2 and hormone receptors with treatment dictated based on
receptor status. Modified radical mastectomy is performed after
demonstrated response to systemic therapy to remove residual
cancer from the chest wall and axilla. Adjuvant chemotherapy
may be indicated depending on final pathologic assessment of
the breast and regional nodes. Finally, the chest wall and the
Figure 17-39. Inflammatory breast carcinoma. Stage IIIB cancer
of the breast with erythema, skin edema (peau d’orange), nipple
retraction, and satellite skin nodules.
602 Table 17-15
Inflammatory vs. noninflammatory breast cancer
INFLAMMATORY NONINFLAMMATORY
Dermal lymph vessel invasion Inflammatory changes are
is present with or without present without dermal
inflammatory changes. lymph vessel invasion.
Cancer is not sharply Cancer is better delineated.
delineated.
Erythema and edema Erythema is usually confined
PART II
frequently involve >33% to the lesion, and edema is
of the skin over the breast. less extensive.
Lymph node involvement is Lymph nodes are involved in
present in >75% of cases. approximately 50% of the
cases.
SPECIFIC CONSIDERATIONS
Distant metastases are more Distant metastases are less
common at the initial common at presentation.  palpable axillary lymphadenopathy. Treatment depends on the
presentation (25% of
cases).
Modified with permission from Bland KI, Copeland ED: The Breast:
Comprehensive Management of Benign and Malignant Diseases, 2nd ed.
Philadelphia, PA: Elsesvier/Saunders; 1998.
supraclavicular, internal mammary, and axillary lymph node
basins receive adjuvant radiation therapy. This multimodal
approach results in 5-year survival rates that approach 30%.
Patients with inflammatory breast cancer should be encouraged
to participate in clinical trials.
Rare Breast Cancers
Squamous Cell (Epidermoid) Carcinoma. Squamous
cell (epidermoid) carcinoma is a rare cancer that arises from
metaplasia within the duct system and generally is devoid of
distinctive clinical or radiographic characteristics.373 Regional
metastases occur in 25% of patients, whereas distant metastases
are rare.
Adenoid Cystic Carcinoma. Adenoid cystic carcinoma is very
rare, accounting for <0.1% of all breast cancers. It is typically
indistinguishable from adenoid cystic carcinoma arising in sali-
vary tissues. These cancers are generally 1 to 3 cm in diameter
at presentation and are well circumscribed. Axillary lymph node
metastases are rare, but deaths from pulmonary metastases have
been reported.
Apocrine Carcinomas. Apocrine carcinomas are well-
differentiated cancers that have rounded vesicular nuclei and
prominent nucleoli. There is a very low mitotic rate and little
variation in cellular features. However, apocrine carcinomas
may display an aggressive growth pattern.
Sarcomas. Sarcomas of the breast are histologically similar
to soft tissue sarcomas at other anatomic sites. This diverse
group includes fibrosarcoma, malignant fibrous histiocytoma,
liposarcoma, leiomyosarcoma, malignant schwannoma, rhab-
domyosarcoma, osteogenic sarcoma, and chondrosarcoma. The
clinical presentation is typically that of a large, painless breast
mass with rapid growth. Diagnosis is by core-needle biopsy or by
open incisional biopsy. Sarcomas are graded based on cellular-
ity, degree of differentiation, nuclear atypia, and mitotic activity.
Primary treatment is wide local excision, which may necessitate
mastectomy. Axillary dissection is not indicated unless there is
biopsy proven lymph node involvement. Angiosarcomas are
classified as de novo, as postradiation, or as arising in associa-
tion with postmastectomy lymphedema. In 1948, Stewart and
Treves described lymphangiosarcoma of the upper extremity in
women with ipsilateral lymphedema after radical mastectomy.374
Angiosarcoma is now the preferred name. The average interval
between modified radical or radical mastectomy and the devel-
opment of an angiosarcoma is 7 to 10 years. Sixty percent of
women developing this cancer have a history of adjuvant radia-
tion therapy. Forequarter amputation may be necessary to palli-
ate the ulcerative complications and advanced lymphedema.
Lymphomas. Primary lymphomas of the breast are rare, and
there are two distinct clinicopathologic variants. One type occurs
in women ≤39 years of age, is frequently bilateral, and has the
histologic features of Burkitt’s lymphoma. The second type is
seen in women ≥40 years of age and is usually of the B-cell type.
Breast involvement by Hodgkin’s lymphoma has been reported.
An occult breast lymphoma may be diagnosed after detection of
stage of disease. Lumpectomy or mastectomy may be required.
Axillary dissection for clearance of disease may be necessary.
Recurrent or progressive local-regional disease is best man-
aged by chemotherapy and radiation therapy. The prognosis is
favorable, with 5- and 10-year survival rates of 74% and 51%,
respectively. More recently anaplastic large cell lymphoma has
been described in association with breast implants for cosmetic
or reconstructive purposes. This disease is treated with complete
excision of the implant capsule with any associated soft tissue
mass. More advanced cases may require systemic therapy and
radiation treatment.
REFERENCES
Entries highlighted in bright blue are key references.
1. Breasted JH. The Edwin Smith Surgical Papyrus. University
of Chicago Press, 1930;405.
2. Celsus AC. De Medicina (ed Loeb Classical Library Ed).
Cambridge: Harvard University Press; 1935;131.
3. Beenken SW. History of the therapy of breast cancer. In:
Copeland BA, ed. The Breast: Comprehensive Manage-
ment of Benign and Malignant Disorder. Philadelphia:
Saunders;2004;5.
4. Le Dran F. Mémoire avec une précis de plusieurs observa-
tions sur le. Mem Acad Roy Chir Paris. 1757;3:1.
5. Moore C. On the influence of inadequate operations on the
theory of cancer. R Med Chir Soc. 1867;1:244.
6. Halsted WS I. The results of operations for the cure of cancer
of the breast performed at the Johns Hopkins Hospital from
June, 1889, to January, 1894. Ann Surg. 1894;20:497-555.
7. Haagensen CD, Stout AP. Carcinoma of the breast. II-criteria
of operability. Ann Surg. 1943;118:1032-1051.
8. Patey DH, Dyson WH. The prognosis of carcinoma of the
breast in relation to the type of operation performed. Br J
Cancer. 1948;2:7-13.
9. Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year
follow-up of a randomized trial comparing radical mas-
tectomy, total mastectomy, and total mastectomy followed
by irradiation. N Engl J Med. 2002;347:567-575.
10. Keynes G. Conservative treatment of cancer of the breast.
Br Med J. 1937;2(3):643-666.
11. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up
of a randomized trial comparing total mastectomy, lumpec-
tomy, and lumpectomy plus irradiation for the treatment of
invasive breast cancer. N Engl J Med. 2002;347:1233-1241.
12. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy
and of differences in the extent of surgery for early breast
cancer on local recurrence and 15-year survival: an overview
of the randomised trials. Lancet. 2005;366:2087-2106.
13. Peto R, Davies C, Godwin J, et al. Comparisons between dif-
ferent polychemotherapy regimens for early breast cancer:
meta-analyses of long-term outcome among 100,000 women
in 123 randomised trials. Lancet. 2012;379:432-444.
14. Davies C, Godwin J, Gray R, et al. Relevance of breast cancer
hormone receptors and other factors to the efficacy of adju-
vant tamoxifen: patient-level meta-analysis of randomised
trials. Lancet. 2011;378:771-784.
15. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression
patterns of breast carcinomas distinguish tumor subclasses
with clinical implications. Proc Natl Acad Sci U S A.
2001;98:10869-10874.
16. Bland KI, Romrell LJ. Congenital and acquired disturbances
of breast development and growth. In: Bland KI, Cope-
land EMI, eds. The Breast: Comprehensive Management of
Benign and Malignant Diseases. Philadelphia: WB Saunders;
1998:214.
17. Lonnerdal B. Nutritional and physiologic significance of
human milk proteins. Am J Clin Nutr. 2003;77:1537S-1543S.
18. Rosenbloom AL. Breast physiology: normal and abnormal
development and function. In: Bland KI, Copeland EMI,
eds. The Breast: Comprehensive Management of Benign and
Malignant Diseases. Philadelphia: WB Saunders; 1998:38.
19. Van de Perre P. Transfer of antibody via mother’s milk.
Vaccine. 2003;21(24):3374-3376.
20. Bland KI, Graves TA. Gynecomastia. In: Bland KI, Copeland
EMI, eds. The Breast: Comprehensive Management of
Benign and Malignant Diseases. Philadelphia: WB Saunders;
1998:153.
21. Dixon JM. Outpatient treatment of non-lactational breast
abscesses. Br J Surg. 1992;79:56-57.
22. Furlong AJ, al-Nakib L, Knox WF, et al. Periductal inflamma-
tion and cigarette smoke. J Am Coll Surg. 1994;179:417-420.
23. Zuska JJ, Crile G, Jr., Ayres WW. Fistulas of lactifierous
ducts. Am J Surg. 1951;81:312-317.
24. Dixon JM. Infection in surgical practice. In: Taylor EW,
ed. Breast Surgery. Oxford: Oxford Medical Publications;
1992;187.
25. Dixon JM. Periductal mastitis and duct ectasia: an update.
Breast. 1998;7:128-130.
26. Dixon JM, Kohlhardt SR, Dillon P. Total duct excision.
Breast. 1998;7:216-219.
27. Frykberg ER, Bland KI. Current concepts on the biology and
management of in situ (Tis, stage 0) breast carcinoma. In:
Bland KI, Copeland EMI, eds. The Breast: Comprehensive
Management of Benign and Malignant Diseases. Philadel-
phia: WB Saunders; 1998:1020.
28. Camiel MR. Mondor’s disease in the breast. Am J Obstet
Gynecol. 1985;152:879-881.
29. Mondor H. Tronculite sous-cutanée subaiguë de la paroi
thoracique antero-latérale. Mem Acad Chir Paris. 1939;
65:1271.
30. Hughes LE, Mansel RE, Webster DJ. Aberrations of normal
development and involution (ANDI): a new perspective on
pathogenesis and nomenclature of benign breast disorders.
Lancet. 1987;2:1316-1319.
31. Archer F, Omar M. The fine structure of fibro adenoma of the
human breast. J Pathol. 1969;99:113-117.
32. Page DL, Anderson TJ. Diagnostic Histopathology of the
Breast. Edinburgh: Churchill Livingstone; 1987.
33. Page DL, Simpson JF. Benign, high-risk, and premalignant
lesions of the breast. In: Bland KI, Copeland EMI, eds. The
Breast: Comprehensive Management of Benign and Malig-
nant Diseases. Philadelphia: WB Saunders; 1998:191.
34. Haagensen CD. Diseases of the Breast. 3rd ed. Philadelphia: 603
WB Saunders; 1986.
35. Haagensen CD, Lane N, Lattes R, et al. Lobular neoplasia
(so-called lobular carcinoma in situ) of the breast. Cancer.
1978;42:737-769.
36. Gadd MA, Souba WW. Evaluation and treatment of benign
breast disorders. In: Bland KI, Copeland EMI, eds. The
Breast: Comprehensive Management of Benign and Malig-
nant Diseases. Philadelphia: WB Saunders; 1998:233.
37. Marchant DJ. Benign breast disease. Obstet Gynecol Clin
North Am. 2002;29:1-20.
CHAPTER 17 THE BREAST
38. Nurko J, Mabry CD, Whitworth P, et al. Interim results from
the FibroAdenoma Cryoablation Treatment Registry. Am J
Surg. 2005;190:647-651; discussion 651-652.
39. Dixon JM. Conservative management of fibroadenoma of the
breast. Br J Surg. 1996;83:1798-1799.
40. Atkins HJ. Mammillary fistula. Br Med J. 1955;2:1473-1474.
41. Dixon JM, Thompson AM. Effective surgical treatment for
mammary duct fistula. Br J Surg. 1991;78:1185-1186.
42. Bernstein L, Henderson BE, Hanisch R, et al. Physical exer-
cise and reduced risk of breast cancer in young women. J
Natl Cancer Inst. 1994;86:1403-1408.
43. Blackburn GL, Copeland T, Khaodhiar L, et al. Diet and
breast cancer. J Womens Health (Larchmt). 2003;12:
183-192.
44. Goss PE, Sierra S. Current perspectives on radiation-induced
breast cancer. J Clin Oncol. 1998;16:338-347.
45. Hulka BS. Epidemiologic analysis of breast and gynecologic
cancers. Prog Clin Biol Res. 1997;396:17-29.
46. Pujol P, Galtier-Dereure F, Bringer J: Obesity and breast
cancer risk. Hum Reprod. 1997;12(1):116-125.
47. Singletary SE. Rating the risk factors for breast cancer. Ann
Surg. 2003;237:474-482.
48. Wynder EL, Cohen LA, Muscat JE, et al. Breast cancer:
weighing the evidence for a promoting role of dietary fat.
J Natl Cancer Inst. 1997;89:766-775.
49. Baan R, Straif K, Grosse Y, et al. Carcinogenicity of alcoholic
beverages. Lancet Oncol. 2007;8:292-293.
50. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer
Statistics Review, 1975-2010, National Cancer Institute, based
on November 2012 SEER data submission. Bethesda; 2013.
51. Domchek SM, Eisen A, Calzone K, et al. Application of
breast cancer risk prediction models in clinical practice. J
Clin Oncol. 2003;21:593-601.
52. Gail MH, Brinton LA, Byar DP, et al. Projecting individu-
alized probabilities of developing breast cancer for white
females who are being examined annually. J Natl Cancer
Inst. 1989;81:1879-1886.
53. Edwards BK, Brown ML, Wingo PA, et al. Annual report
to the nation on the status of cancer, 1975-2002, featuring
population-based trends in cancer treatment. J Natl Cancer
Inst. 2005;97:1407-1427.
54. Chen J, Pee D, Ayyagari R, et al. Projecting absolute invasive
breast cancer risk in white women with a model that includes
mammographic density. J Natl Cancer Inst. 2006;98:1215-1226.
55. Claus EB, Risch N, Thompson WD. The calculation of breast
cancer risk for women with a first degree family history of
ovarian cancer. Breast Cancer Res Treat. 1993;28:115-120.
56. Kerlikowske K, Ichikawa L, Miglioretti DL, et al. Longitudi-
nal measurement of clinical mammographic breast density to
improve estimation of breast cancer risk. J Natl Cancer Inst.
2007;99:386-395.
57. Berry DA, Parmigiani G, Sanchez J, et al. Probability of car-
rying a mutation of breast-ovarian cancer gene BRCA1 based
on family history. J Natl Cancer Inst. 1997;89:227-238.
58. Parmigiani G, Berry D, Aguilar O. Determining carrier prob-
abilities for breast cancer-susceptibility genes BRCA1 and
BRCA2. Am J Hum Genet. 1998;62:145-158.
604 59. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction
model incorporating familial and personal risk factors. Stat
Med. 2004;23:1111-1130.
60. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxi-
fen for prevention of breast cancer: report of the National
Surgical Adjuvant Breast and Bowel Project P-1 Study. J
Natl Cancer Inst. 1998;90:1371-1388.
61. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmeno-
pausal hormone therapy and mortality. N Engl J Med.
1997;336:1769-1775.
62. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilat-
eral prophylactic mastectomy in women with a family history
of breast cancer. N Engl J Med. 1999;340:77-84.
PART II
63. Kerlikowske K, Grady D, Rubin SM, et al. Efficacy of screening
mammography. A meta-analysis. JAMA. 1995;273:149-154.
64. Rowe TC, Chen GL, Hsiang YH, et al. DNA damage by anti-
tumor acridines mediated by mammalian DNA topoisomer-
ase II. Cancer Res. 1986;46:2021-2026.
SPECIFIC CONSIDERATIONS
65. Sakorafas GH. The management of women at high risk for
the development of breast cancer: risk estimation and preven-
tative strategies. Cancer Treat Rev. 2003;29:79-89.
66. Schrag D, Kuntz KM, Garber JE, et al. Decision analysis—
effects of prophylactic mastectomy and oophorectomy on life
expectancy among women with BRCA1 or BRCA2 mutations.
N Engl J Med. 1997;336:1465-1471.
67. Vogel VG. Management of the high-risk patient. Surg Clin
North Am. 2003;83:733-751.
68. Wu K, Brown P. Is low-dose tamoxifen useful for the treat-
ment and prevention of breast cancer? J Natl Cancer Inst.
2003;95:766-767.
69. Collaborative Group on Hormonal Factors in Breast Cancer.
Breast cancer and hormone replacement therapy: collabora-
tive reanalysis of data from 51 epidemiological studies of
52,705 women with breast cancer and 108,411 women with-
out breast cancer. Lancet. 1997;350:1047-1059.
70. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of
estrogen plus progestin on breast cancer and mammography
in healthy postmenopausal women: the Women’s Health Ini-
tiative Randomized Trial. JAMA. 2003;289:3243-3253.
71. Beral V. Breast cancer and hormone-replacement therapy in
the Million Women Study. Lancet. 2003;362:419-427.
72. Glasziou P, Houssami N. The evidence base for breast cancer
screening. Prev Med. 2011;53:100-102.
73. Olsen O, Gotzsche PC. Cochrane review on screening for breast
cancer with mammography. Lancet. 2001;358:1340-1342.
74. Siu AL. Screening for Breast Cancer: U.S. Preventive Ser-
vices Task Force recommendation statement. Ann Intern
Med. 2016;164:279-296.
75. Oeffinger KC, Fontham ET, Etzioni R, et al. Breast can-
cer screening for women at average risk: 2015 guide-
line update from the American Cancer Society. JAMA.
2015;314:1599-1614.
76. National Comprehensive Cancer Network. Breast cancer
screening and diagnosis, version 1.2016. Available at: https://
www.nccn.org/professionals/physician_gls/pdf/breast-
screening.pdf. Accessed July 9, 2018.
77. US Preventive Services Task Force. Screening for breast
cancer: US Preventive Services Task Force recommenda-
tion statement. Ann Intern Med. 2009;151:716-726, W-236.
78. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-
year follow-up of the Royal Marsden randomized, double-
blinded tamoxifen breast cancer prevention trial. J Natl
Cancer Inst. 2007;99:283-290.
79. Independent UK Panel on Breast Cancer Screening. The ben-
efits and harms of breast cancer screening: an independent
review. Lancet. 2012;380:1778-1786.
80. Nyström L, Andersson I, Bjurstam N, Frisell J, Norden-
skjöld B, Rutqvist LE. Long-term effects of mammography
screening: updated overview of the Swedish randomised trials.
Lancet. 2002;359:909-919.
81. Moss S, Thomas I, Evans A, Thomas B, Johns, L. Ran-
domised controlled trial of mammographic screening in
women from age 40: results of screening in the first 10 years.
Br J Cancer. 2005;92:949-954.
82. Veronesi U, Maisonneuve P, Sacchini V, Rotmensz N, Boyle
P. Tamoxifen for breast cancer among hysterectomised
women. Lancet. 2002;359:1122-1124.
83. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of
tamoxifen prophylaxis for breast cancer–96-month follow-up
of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99:
272-282.
84. Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and
benefits of tamoxifen treatment for preventing breast cancer.
J Natl Cancer Inst. 1999;91:1829-1846.
85. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of
tamoxifen vs. raloxifene on the risk of developing inva-
sive breast cancer and other disease outcomes: the NSABP
Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA.
2006;295:2727-2741.
86. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the
National Surgical Adjuvant Breast and Bowel Project Study
of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing
breast cancer. Cancer Prev Res (Phila). 2010;3:696-706.
87. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for
breast-cancer prevention in postmenopausal women. N Engl
J Med. 2011;364:2381-2391.
88. Cuzick J. IBIS II: a breast cancer prevention trial in post-
menopausal women using the aromatase inhibitor anastro-
zole. Expert Rev Anticancer Ther. 2008;8:1377-1385.
89. Sestak I, Singh S, Cuzick J, et al. Changes in bone mineral
density at 3 years in postmenopausal women receiving anas-
trozole and risedronate in the IBIS-II bone substudy: an inter-
national, double-blind, randomised, placebo-controlled trial.
Lancet Oncol. 2014;15:1460-1468.
90. Jenkins VA, Ambroisine LM, Atkins L, et al. Effects of anas-
trozole on cognitive performance in postmenopausal women:
a randomised, double-blind chemoprevention trial (IBIS II).
Lancet Oncol. 2008;9:953-961.
91. Nelson HD, Smith ME, Griffin JC, et al. Use of medications
to reduce risk for primary breast cancer: a systematic review
for the U.S. Preventive Services Task Force. Ann Intern Med.
2013;158:604-614.
92. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmaco-
logic interventions for breast cancer risk reduction: american
society of clinical oncology clinical practice guideline. J Clin
Oncol. 2013;31:2942-2962.
93. Domchek SM, Friebel TM, Singer CF, et al. Association
of risk-reducing surgery in BRCA1 or BRCA2 mutation
carriers with cancer risk and mortality. JAMA. 2010;304:
967-975.
94. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity
and penetrance analysis of the BRCA1 and BRCA2 genes in
breast cancer families. The Breast Cancer Linkage Consor-
tium. Am J Hum Genet. 1998;62:676-689.
95. Gowen LC, Avrutskaya AV, Latour AM, et al. BRCA1
required for transcription-coupled repair of oxidative DNA
damage. Science. 1998;281:1009-1012.
96. Martin AM, Weber BL. Genetic and hormonal risk factors in
breast cancer. J Natl Cancer Inst. 2000;92:1126-1135.
97. Oddoux C, Struewing JP, Clayton CM, et al. The carrier
frequency of the BRCA2 6174delT mutation among Ash-
kenazi Jewish individuals is approximately 1%. Nat Genet.
1996;14:188-190.
98. Roa BB, Boyd AA, Volcik K, et al. Ashkenazi Jewish pop-
ulation frequencies for common mutations in BRCA1 and
BRCA2. Nat Genet. 1996;14:185-187.
 99. Rosen EM, Fan S, Pestell RG, et al. BRCA1 gene in breast
cancer. J Cell Physiol. 2003;196:19-41.
100. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J
Med. 2003;348:2339-2347.
101. Petrij-Bosch A, Peelen T, van Vliet M, et al. BRCA1 genomic
deletions are major founder mutations in Dutch breast cancer
patients. Nat Genet. 1997;17:341-345.
102. Gorski B, Byrski T, Huzarski T, et al. Founder mutations in
the BRCA1 gene in Polish families with breast-ovarian can-
cer. Am J Hum Genet. 2000;66:1963-1968.
103. Sarantaus L, Huusko P, Eerola H, et al. Multiple founder
effects and geographical clustering of BRCA1 and BRCA2
families in Finland. Eur J Hum Genet. 2000;8:757-763.
104. Gayther SA, Harrington P, Russell P, et al. Frequently
occurring germ-line mutations of the BRCA1 gene in
ovarian cancer families from Russia. Am J Hum Genet.
1997;60:1239-1242.
105. Szabo CI, King MC. Population genetics of BRCA1 and
BRCA2. Am J Hum Genet. 1997;60:1013-1020.
106. Abeliovich D, Kaduri L, Lerer I, et al. The founder muta-
tions 185delAG and 5382insC in BRCA1 and 6174delT in
BRCA2 appear in 60% of ovarian cancer and 30% of early-
onset breast cancer patients among Ashkenazi women. Am J
Hum Genet. 1997;60:505-514.
107. Johannesdottir G, Gudmundsson J, Bergthorsson JT, et al.
High prevalence of the 999del5 mutation in Icelandic breast
and ovarian cancer patients. Cancer Res. 1996;56:3663-3665.
108. Hakansson S, Johannsson O, Johansson U, et al. Moder-
ate frequency of BRCA1 and BRCA2 germ-line mutations
in Scandinavian familial breast cancer. Am J Hum Genet.
1997;60:1068-1078.
109. Infante M, Duran M, Acedo A, et al. The highly prevalent BRCA2
mutation c.2808_2811del (3036delACAA) is located in a
mutational hotspot and has multiple origins. Carcinogenesis.
2013;34:2505-2511.
110. Warner E, Foulkes W, Goodwin P, et al. Prevalence and pen-
etrance of BRCA1 and BRCA2 gene mutations in unselected
Ashkenazi Jewish women with breast cancer. J Natl Cancer
Inst. 1999;91:1241-1247.
111. Khatcheressian JL, Hurley P, Bantug E, et al. Breast can-
cer follow-up and management after primary treatment:
American Society of Clinical Oncology clinical practice
guideline update. J Clin Oncol. 2013;31:961-965.
112. Schneider KA. Genetic counseling for BRCA1/BRCA2 test-
ing. Genet Test. 1997;1:91-98.
113. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI
and mammography for breast-cancer screening in women
with a familial or genetic predisposition. N Engl J Med.
2004;351:427-437.
114. Saslow D, Boetes C, Burke W, et al. American Cancer Soci-
ety guidelines for breast screening with MRI as an adjunct to
mammography. CA Cancer J Clin. 2007; 57:75-89.
115. King MC, Wieand S, Hale K, et al. Tamoxifen and breast
cancer incidence among women with inherited mutations in
BRCA1 and BRCA2: National Surgical Adjuvant Breast and
Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.
JAMA. 2001;286:2251-2256.
116. Antoniou AC, Foulkes WD, Tischkowitz M. Breast-cancer
risk in families with mutations in PALB2. N Engl J Med.
2014;371(17):497-506.
117. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA
Cancer J Clin. 2016;66:7-30.
118. Clarke CA, Glaser SL, Uratsu CS, et al. Recent declines in hor-
mone therapy utilization and breast cancer incidence: clinical
and population-based evidence. J Clin Oncol. 2006;24:e49-e50.
119. Ferlay J, Bray F, Pisani P, Parkin DM. Globocan 2002:
Cancer Incidence, Mortality and Prevalence Worldwide.
Lyon, France: IARC Press; 2004.
120. National Cancer Institute. SEER Cancer Statistics Review, 605
1975-2002. Available at: https://seer.cancer.gov/archive/
csr/1975_2002/. Accessed July 8, 2018.
121. Fregene A, Newman LA. Breast cancer in sub-Saharan
Africa: how does it relate to breast cancer in African-Ameri-
can women? Cancer. 2005;103:1540-1550.
122. Bloom HJ, Richardson WW, Harries EJ. Natural history
of untreated breast cancer (1805-1933). Comparison of
untreated and treated cases according to histological grade of
malignancy. Br Med J. 1962;2:213-221.
123. Early Breast Cancer Trialists’ Collaborative Group. Tamoxi-
CHAPTER 17 THE BREAST
fen for early breast cancer. an overview of the randomised
trials. Lancet. 1998;351:1451-1467.
124. Saphner T, Tormey DC, Gray R. Annual hazard rates of recur-
rence for breast cancer after primary therapy. J Clin Oncol.
1996;14:2738-2746.
125. Sestak I, Dowsett M, Zabaglo L, et al. Factors predicting late
recurrence for estrogen receptor-positive breast cancer. J Natl
Cancer Inst. 2013;105:1504-1511.
126. Gonzalez-Angulo AM, Cristofanilli M, Strom EA, et al.
Central nervous system metastases in patients with high-
risk breast carcinoma after multimodality treatment. Cancer.
2004;101:1760-1766.
127. Carey LA, Ewend MG, Metzger R, et al. Central nervous
system metastases in women after multimodality ther-
apy for high risk breast cancer. Breast Cancer Res Treat.
2004;88:273-280.
128. Evans AJ, James JJ, Cornford EJ, et al. Brain metastases from
breast cancer: identification of a high-risk group. Clin Oncol
(R Coll Radiol). 2004;16:345-349.
129. Broders AC. Carcinoma in situ contrasted with benign pen-
etrating epithelium. JAMA. 1932;99:1670.
130. Foote FW, Stewart FW. Lobular carcinoma in situ: a rare form
of mammary cancer. Am J Pathol. 1941;17:491-496.
131. Consensus conference on the classification of ductal carci-
noma in situ. Hum Pathol. 1997; 28:1221-1225.
132. Recht A, Rutgers EJ, Fentiman IS, et al. The fourth EORTC
DCIS Consensus meeting (Chateau Marquette, Heemskerk,
The Netherlands, 23-24 January 1998)–conference report.
Eur J Cancer. 1998;34:1664-1669.
133. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status,
tumor characteristics, and prognosis: a prospective cohort of
breast cancer patients. Breast Cancer Res. 2007;9:R6.
134. McDivitt RW, Boyce W, Gersell D. Tubular carcinoma of the
breast. Clinical and pathological observations concerning 135
cases. Am J Surg Pathol. 1982;6:401-411.
135. Jatoi I. Screening clinical breast examination. Surg Clin
North Am. 2003;83:789-801.
136. Rosato FE, Rosato EL. Examination techniques: roles of the
physician and patient evaluating breast diseases. In: Bland KI,
Copeland EMI, eds. The Breast: Comprehensive Management
of Benign and Malignant Diseases. Philadelphia: WB Saunders;
1998:615.
137. Bassett LW. Breast imaging. In: Bland KI, Copeland EMI,
eds. The Breast: Comprehensive Management of Benign
and Malignant Diseases. Philadelphia: WB Saunders;
1998:648.
138. Fletcher SW, Elmore JG. Clinical practice. Mammographic
screening for breast cancer. N Engl J Med. 2003;348:1672-1680.
139. Miller AB. Screening and detection. In: Bland KI, Cope-
land EMI, eds. The Breast: Comprehensive Management of
Benign and Malignant Diseases. Philadelphia: WB Saunders;
1998:625.
140. Schnall MD. Breast MR imaging. Radiol Clin North Am.
2003;41:43-50.
141. Seidman H, Gelb SK, Silverberg E, et al. Survival experience
in the Breast Cancer Detection Demonstration Project. CA
Cancer J Clin. 1987;37:258-290.
606 142. Bevers T, Bibbins-Domingo K, Oeffinger KC, Smith ML.
Controversies in breast cancer screening strategies. J Natl
Compr Canc Netw. 2016;14:651-653.
143. Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic perfor-
mance of digital versus film mammography for breast-cancer
screening. N Engl J Med. 2005;353:1773-1783.
144. Helvie MA. Digital mammography imaging: breast tomo-
synthesis and advanced applications. Radiol Clin North Am.
2010;48:917-929.
145. Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer
screening using tomosynthesis in combination with digital
mammography. JAMA. 2014;311:2499-2507.
146. Bernardi D, Macaskill P, Pellegrini M, et al. Breast cancer
PART II
screening with tomosynthesis (3D mammography) with
acquired or synthetic 2D mammography compared with 2D
mammography alone (STORM-2): a population-based pro-
spective study. Lancet Oncol. 2016;17(8):1105-1113.
147. Ciatto S, Houssami N, Bernardi D, et al. Integration of 3D
SPECIFIC CONSIDERATIONS
digital mammography with tomosynthesis for population
breast-cancer screening (STORM): a prospective comparison
study. Lancet Oncol. 2013;14:583-589.
148. Helvie MA. Digital mammography imaging: breast tomo-
synthesis and advanced applications. Radiol Clin North Am.
2010;48:917-929.
149. Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer
screening using tomosynthesis in combination with digital
mammography. JAMA. 2014;311:2499-2507.
150. Bernardi D, Macaskill P, Pellegrini M, et al. Breast cancer
screening with tomosynthesis (3D mammography) with
acquired or synthetic 2D mammography compared with 2D
mammography alone (STORM-2): a population-based pro-
spective study. Lancet Oncol. 2016;17(8):1105-1113.
151. Jochelson MS, Dershaw DD, Sung JS, et al. Bilateral con-
trast-enhanced dual-energy digital mammography: feasibility
and comparison with conventional digital mammography and
MR imaging in women with known breast carcinoma. Radi-
ology. 2013;266(3):743-751.
152. Jochelson MS, Dershaw DD, Sung JS, et al. Bilateral con-
trast-enhanced dual-energy digital mammography: feasibility
and comparison with conventional digital mammography and
MR imaging in women with known breast carcinoma. Radi-
ology. 2013;266(3):743-751.
153. Krishnamurthy S, Sneige N, Bedi DG, et al. Role of ultra-
sound-guided fine-needle aspiration of indeterminate and
suspicious axillary lymph nodes in the initial staging of
breast carcinoma. Cancer. 2002;95:982-988.
154. Turnbull L, Brown S, Harvey I, et al. Comparative effective-
ness of MRI in breast cancer (COMICE) trial: a randomised
controlled trial. Lancet. 2010;375:563-571.
155. Houssami N, Turner R, Morrow M. Preoperative magnetic
resonance imaging in breast cancer: meta-analysis of surgical
outcomes. Ann Surg. 2013;257:249-255.
156. Robinson DS, Sundaram M. Stereotactic imaging and breast
biopsy. In: Bland KI, Copeland EMI, eds. The Breast: Com-
prehensive Management of Benign and Malignant Diseases.
Philadelphia: WB Saunders; 1998:698.
157. Wilkinson EJ, Masood S. Cytologic needle samplings of the
breast: techniques and end results. In: Bland KI, Copeland EMI,
eds. The Breast: Comprehensive Management of Benign and
Malignant Diseases. Philadelphia: WB Saunders; 1998:705.
158. Greene FL, Page DL, Fleming ID, eds. Breast. AJCC Cancer
Staging Manual. 6th ed. New York: Springer-Verlag: 2002.
159. Britton PD, Goud A, Godward S, et al. Use of ultrasound-
guided axillary node core biopsy in staging of early breast
cancer. Eur Radiol. 2009;19:561-569.
160. Fisher B, Slack NH. Number of lymph nodes examined and
the prognosis of breast carcinoma. Surg Gynecol Obstet.
1970;131:79-88.
161. Giuliano AE, et al. Breast cancer—major changes in the
American Joint Committee on Cancer eighth edition cancer
staging manual. CA Cancer J Clin. 2017;67:290-303.
162. Du Toit RS, Locker AP, Ellis IO, Elston CW, Blamey RW.
Evaluation of the prognostic value of triple node biopsy in
early breast cancer. Br J Surg. 77:163-167.
163. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL,
Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. France:
Springer; 2010.
164. Dillon DA. Molecular markers in the diagnosis and staging
of breast cancer. Semin Radiat Oncol. 2002;12:305-318.
165. Esteva FJ, Sahin AA, Cristofanilli M, et al. Molecular prog-
nostic factors for breast cancer metastasis and survival. Semin
Radiat Oncol. 2002;12:319-328.
166. Haffty BG. Molecular and genetic markers in the localre-
gional management of breast cancer. Semin Radiat Oncol.
2002;12:329-340.
167. Morabito A, Magnani E, Gion M, et al. Prognostic and pre-
dictive indicators in operable breast cancer. Clin Breast Can-
cer. 2003;3:381-390.
168. Rogers CE, Loveday RL, Drew PJ, et al. Molecular prog-
nostic indicators in breast cancer. Eur J Surg Oncol.
2002;28:467-478.
169. Rampaul R, Ellis IO, Robertson JFR. Prognostic indices in
breast cancer. In: Autier BP, Adebamowo C, Anderson BO,
et al, eds. World Breast Cancer Report. iPRI:2012:
323-332.
170. Athanassiadou PP, Veneti SZ, Kyrkou KA, et al. Presence
of epidermal growth factor receptor in breast smears of cyst
fluids: relationship to electrolyte ratios and pH concentration.
Cancer Detect Prev. 1992;16:113-118.
171. Tsutsumi Y, Naber SP, DeLellis RA, et al. Neu oncogene
protein and epidermal growth factor receptor are indepen-
dently expressed in benign and malignant breast tissues. Hum
Pathol. 1990;21:750-758.
172. van de Vijver MJ, Peterse JL, Mooi WJ, et al. Neu-protein
overexpression in breast cancer. Association with com-
edotype ductal carcinoma in situ and limited prognostic
value in stage II breast cancer. N Engl J Med. 1988;319:
1239-1245.
173. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:
correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science. 1987;235:177-182.
174. Gusterson BA, Gelber RD, Goldhirsch A, et al. Prognostic
importance of c-erbB-2 expression in breast cancer. Interna-
tional (Ludwig) Breast Cancer Study Group. J Clin Oncol.
1992;10:1049-1056.
175. McCann AH, Dervan PA, O’Regan M, et al. Prognostic sig-
nificance of c-erbB-2 and estrogen receptor status in human
breast cancer. Cancer Res. 1991;51:3296-3303.
176. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the
HER-2/neu proto-oncogene in human breast and ovarian
cancer. Science. 1989;244:707-712.
177. Wright C, Angus B, Nicholson S, et al. Expression of
c-erbB-2 oncoprotein: a prognostic indicator in human breast
cancer. Cancer Res. 1989;49:2087-2090.
178. Dabbs DJ, Klein ME, Mohsin SK, Tubbs RR, Shuai Y,
Bhargava R. High false-negative rate of HER2 quantita-
tive reverse transcription polymerase chain reaction of the
Oncotype DX test: an independent quality assurance study.
J Clin Oncol. 2011;29(32):4279-4285.
179. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and
safety of trastuzumab as a single agent in first-line treatment
of HER2-overexpressing metastatic breast cancer. J Clin
Oncol. 20;(3):719-726.
180. Piccart-Gebhart MJ, Proctor M, Leyland-Jones B, et al.
Trastuzumab after adjuvant chemotherapy in HER2-positive
breast cancer. N Engl J Med. 2005;353(16):1659-1672.
181. Romond EH, Perez EA, Bryant J, et al. Trastuzumab
plus adjuvant chemotherapy for operable HER2-positive
breast cancer. N Engl J Med. 2005;353:1673-1684.
182. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastu-
zumab in HER2-positive breast cancer. N Engl J Med.
2011;365:1273-1283.
183. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of
trastuzumab after adjuvant chemotherapy in HER2-posi-
tive breast cancer: a randomised controlled trial. Lancet.
2007;369:29-36.
184. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastu-
zumab in HER2-positive breast cancer. N Engl J Med.
2011;365:1273-1283.
185. Dahabreh IJ, Linardou H, Siannis F, et al. Trastuzumab in the
adjuvant treatment of early-stage breast cancer: a systematic
review and meta-analysis of randomized controlled trials.
Oncologist. 2008;13:620-630.
186. Monaghan P, Perusinghe NP, Nicholson RI, et al. Growth fac-
tor stimulation of proliferating cell nuclear antigen (PCNA)
in human breast epithelium in organ culture. Cell Biol Int
Rep. 1991;15:561-570.
187. Siitonen SM, Isola JJ, Rantala IS, et al. Intratumor varia-
tion in cell proliferation in breast carcinoma as determined
by antiproliferating cell nuclear antigen monoclonal anti-
body and automated image analysis. Am J Clin Pathol.
1993;99:226-231.
188. Tuccari G, Rizzo A, Muscara M, et al. PCNA/cyclin expres-
sion in breast carcinomas: its relationships with Ki-67, ER,
PgR immunostainings and clinico-pathologic aspects. Patho-
logica. 1993;85:47-55.
189. van Dierendonck JH, Wijsman JH, Keijzer R, et al. Cell-
cyclerelated staining patterns of anti-proliferating cell
nuclear antigen monoclonal antibodies. Comparison with
BrdUrd labeling and Ki-67 staining. Am J Pathol. 1991;138:
1165-1172.
190. Cuzick J, Dowsett M, Pineda S, et al. Prognostic value of a
combined estrogen receptor, progesterone receptor, Ki-67,
and human epidermal growth factor receptor 2 immunohis-
tochemical score and comparison with the Genomic Health
recurrence score in early breast cancer. J Clin Oncol. 2011;29:
4273-4278.
191. Brown LF, Berse B, Jackman RW, et al. Expression of vas-
cular permeability factor (vascular endothelial growth factor)
and its receptors in breast cancer. Hum Pathol. 1995;26:86-91.
192. Gasparini G, Toi M, Gion M, et al. Prognostic significance
of vascular endothelial growth factor protein in node-negative
breast carcinoma. J Natl Cancer Inst. 1997;89:139-147.
193. Schneider BP, Gray RJ, Radovich M, et al. Prognostic and
predictive value of tumor vascular endothelial growth factor
gene amplification in metastatic breast cancer treated with
paclitaxel with and without bevacizumab; results from ECOG
2100 trial. Clin Cancer Res. 2013;19(5):1281-1289.
194. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevaci-
zumab versus paclitaxel alone for metastatic breast cancer.
N Engl J Med. 2007;357:2666-2676.
195. Allan DJ, Howell A, Roberts SA, et al. Reduction in apop-
tosis relative to mitosis in histologically normal epithelium
accompanies fibrocystic change and carcinoma of the pre-
menopausal human breast. J Pathol. 1992;167:25-32.
196. Bargou RC, Daniel PT, Mapara MY, et al. Expression of the
bcl-2 gene family in normal and malignant breast tissue: low
bax-alpha expression in tumor cells correlates with resistance
towards apoptosis. Int J Cancer. 1995;60:854-859.
197. Binder C, Marx D, Binder L, Schaurer A, Hiddemann W.
Expression of Bax in relation to Bcl-2 and other predictive
parameters in breast cancer. Ann Oncol. 1996;7:129-133.
198. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer
program to assist in making decisions about adjuvant
therapy for women with early breast cancer. J Clin Oncol. 607
2001;19:980-991.
199. Blamey RW, Ellis IO, Pinder SE, et al. Survival of inva-
sive breast cancer according to the Nottingham Prognos-
tic Index in cases diagnosed in 1990-1999. Eur J Cancer.
2007;43:1548-1555.
200. Blamey RW, Pinder SE, Ball GR, et al. Reading the prog-
nosis of the individual with breast cancer. Eur J Cancer.
2007;43:1545-1547.
201. Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT:
a new UK prognostic model that predicts survival follow-
CHAPTER 17 THE BREAST
ing surgery for invasive breast cancer. Breast Cancer Res.
2010;12:R1.
202. Perou CM, Jeffrey SS, van de Rijn M, et al. Distinctive gene
expression patterns in human mammary epithelial cells and
breast cancers. Proc Natl Acad Sci U S A. 1999;96:9212-9217.
203. Paik S, Shak S, Tang G, et al. A multigene assay to pre-
dict recurrence of tamoxifen-treated, node-negative breast
cancer. N Engl J Med. 2004:351:2817-2826.
204. Sparano JA, Gray RJ, Makower DF, et al. Prospective valida-
tion of a 21-gene expression assay in breast cancer. N Engl J
Med. 2015;373(21):2005-2014.
205. Albain KS, Barlow WE, Shak S, et al. Prognostic and pre-
dictive value of the 21-gene recurrence score assay in
postmenopausal women with node-positive, oestrogen-
receptor-positive breast cancer on chemotherapy: a ret-
rospective analysis of a randomised trial. Lancet Oncol.
2010;11(1):55-65.
206. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter
study of the impact of the 21-gene recurrence score assay on
medical oncologist and patient adjuvant breast cancer treat-
ment selection. J Clin Oncol. 2010;28(10):1671-1676.
207. Drukker CA, Bueno-de-Mesquita JM, Retèl VP, et al. A
prospective evaluation of a breast cancer prognosis sig-
nature in the observational RASTER study. Int J Cancer.
2013;133(4):929-936.
208. Cardoso F, van’t Veer LI, Bogaerts J, et al. 70-gene signature
as an aid to treatment decisions in early-stage breast cancer.
N Engl J Med. 2016;375:717-729.
209. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-
conserving treatment for ductal carcinoma in situ: first results
of the EORTC randomised phase III trial 10853. EORTC
Breast Cancer Cooperative Group and EORTC Radiotherapy
Group. Lancet. 2000;355:528-533.
210. Lagios MD, Margolin FR, Westdahl PR, et al. Mammo-
graphically detected duct carcinoma in situ. Frequency of
local recurrence following tylectomy and prognostic effect of
nuclear grade on local recurrence. Cancer. 1989;63:618-624.
211. Rosai J. Borderline epithelial lesions of the breast. Am J Surg
Pathol. 1991;15:209-221.
212. Schnitt SJ, Connolly JL, Tavassoli FA, et al. Interobserver
reproducibility in the diagnosis of ductal proliferative
breast lesions using standardized criteria. Am J Surg Pathol.
1992;16:1133-1143.
213. Silverstein MJ, Lagios MD, Groshen S, et al. The influence
of margin width on local control of ductal carcinoma in situ
of the breast. N Engl J Med. 1999;340:1455-1461.
214. Tan-Chiu E. The effect of tamoxifen on benign breast dis-
ease: Findings from the National Surgical Adjuvant Breast
and Bowel Project (NSABP) breast cancer prevention trial
(BCPT). Breast Cancer Res Treat. 2001;69:abstract 7.
215. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radi-
ation therapy for the treatment of intraductal breast cancer:
findings from National Surgical Adjuvant Breast and Bowel
Project B-17. J Clin Oncol. 1998;16:441-452.
216. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving
treatment with or without radiotherapy in ductal carci-
noma-in-situ: ten-year results of European Organisation for
608 Research and Treatment of Cancer randomized phase III
trial 10853–a study by the EORTC Breast Cancer Coopera-
tive Group and EORTC Radiotherapy Group. J Clin Oncol.
2006;24:3381-3387.
217. Houghton J, George WD, Cuzick J, et al. Radiotherapy and
tamoxifen in women with completely excised ductal carcinoma
in situ of the breast in the UK, Australia, and New Zealand: ran-
domised controlled trial. Lancet. 2003;362:95-102.
218. Emdin SO, Granstrand B, Ringberg A, et al. SweDCIS:
Radiotherapy after sector resection for ductal carcinoma
in situ of the breast. Results of a randomised trial in a
population offered mammography screening. Acta Oncol.
2006;45:536-543.
PART II
219. Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncol-
ogy–American Society for Radiation Oncology–American Soci-
ety of Clinical Oncology consensus guideline on margins for
breast-conserving surgery with whole-breast irradiation in ductal
carcinoma in situ. J Clin Oncol. 2016;34(33):4040-4046.
SPECIFIC CONSIDERATIONS
220. Marinovich ML, Azizi L, Macaskill P, Irwig L, et al. The
Association of Surgical Margins and Local Recurrence in
Women with Ductal Carcinoma In Situ Treated with Breast-
Conserving Therapy: A Meta-Analysis. Ann Surg Oncol.
2016;23(12):3811-3821.
221. Mansel RE, Fallowfield L, Kissin M, et al. Randomized mul-
ticenter trial of sentinel node biopsy versus standard axillary
treatment in operable breast cancer: the ALMANAC Trial.
J Natl Cancer Inst. 2006;98:599-609.
222. Hughes LL, Wang M, Page DL, et al. Local excision alone
without irradiation for ductal carcinoma in situ of the
breast: a trial of the Eastern Cooperative Oncology Group.
J Clin Oncol. 2009;27:5319-5324.
223. McCormick B. RTOG 9804: a prospective randomized
trial for “good risk” ductal carcinoma in situ (DCIS), com-
paring radiation (RT) to observation (OBS). J Clin Oncol.
2012;30(suppl):abstr 1004.
224. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a pro-
spective randomized trial for good-risk ductal carcinoma in
situ comparing radiotherapy with observation. J Clin Oncol.
2015;33(7):709-715.
225. Rakovitch E, Nofech-Mozes S, Hanna W, et al. A population-
based validation study of the DCIS Score predicting recur-
rence risk in individuals treated by breast-conserving surgery
alone. Breast Cancer Res Treat. 2015;152(2):389-398.
226. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treat-
ment of intraductal breast cancer: National Surgical Adjuvant
Breast and Bowel Project B-24 randomised controlled trial.
Lancet. 1999;353:1993-2000.
227. Effects of radiotherapy and surgery in early breast cancer. An
overview of the randomized trials. Early Breast Cancer Trialists’
Collaborative Group. N Engl J Med. 1995;333:1444-1455.
228. Arriagada R, Le MG, Rochard F, et al. Conservative treatment
versus mastectomy in early breast cancer: patterns of failure
with 15 years of follow-up data. Institut Gustave-Roussy
Breast Cancer Group. J Clin Oncol. 1996;14:1558-1564.
229. Cooke T, Reeves J, Lanigan A, et al. HER2 as a prognos-
tic and predictive marker for breast cancer. Ann Oncol.
2001;12(suppl 1):S23-S28.
230. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and
results after 12 years of follow-up in a randomized clinical
trial comparing total mastectomy with lumpectomy with or
without irradiation in the treatment of breast cancer. N Engl
J Med. 1995;333:1456-1461.
231. Gump FE, Jicha DL, Ozello L. Ductal carcinoma in situ
(DCIS): a revised concept. Surgery. 102:790-795.
232. Paik S, Bryant J, Tan-Chiu E, et al. HER2 and choice of adju-
vant chemotherapy for invasive breast cancer: National Surgi-
cal Adjuvant Breast and Bowel Project Protocol B-15. J Natl
Cancer Inst. 2000;92:1991-1998.
233. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year fol-
lowup of a randomized study comparing breast-conserving
surgery with radical mastectomy for early breast cancer.
N Engl J Med. 2002;347:1227-1232.
233a. Hughes KS, Schnaper LA, Berry D, et al: Lumpectomy plus
tamoxifen with or without irradiation in women 70 years of
age or older with early breast cancer. N Engl J Med 351:971-
7, 2004.
234. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM;
PRIME II investigators. Breast-conserving surgery with or
without irradiation in women aged 65 years or older with
early breast cancer (PRIME II): a randomised controlled trial.
Lancet Oncol. 2015;16(3):266-273.
235. Vaidya J, Wenz F, Bulsara M, et al. Abstract S4-2: Targeted
intraoperative radiotherapy for early breast cancer: TARGIT-
A trial-updated analysis of local recurrence and first analysis
of survival. Cancer Res. 2012;72:S4-2-S4-2.
236. Corica T, Nowak AK, Saunders CM, et al. Cosmesis and breast-
related quality of life outcomes after intraoperative radiation
therapy for early breast cancer: a substudy of the TARGIT-A
trial. Int J Radiat Oncol Biol Phys. 2016;96(1):55-64.
237. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted
intraoperative radiotherapy versus whole-breast radiotherapy
for breast cancer: 5-year results for local control and over-
all survival from the TARGIT-A randomised trial. Lancet.
2014;383:603-613.
238. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated par-
tial breast irradiation consensus statement from the American
Society for Radiation Oncology (ASTRO). J Am Coll Surg.
2009;209:269-277.
239. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a
randomized clinical trial comparing radical mastectomy and
total mastectomy with or without radiation. N Engl J Med.
1985;12:674-681.
240. Krag D, Weaver DL, Alex JC, et al. Surgical resection and
radiolocalization of the sentinel lymph node in breast cancer
using a gamma probe. Surg Oncol. 1993;2:335-339.
241. Giuliano AE, Dale PS, Turner RR, et al. Improved axillary
staging of breast cancer with sentinel lymphadenectomy. Ann
Surg. 1995;222:394-399; discussion 399-401.
242. Giuliano AE, Kirgan DM, Guenther JM, et al. Lymphatic
mapping and sentinel lymphadenectomy for breast cancer.
Ann Surg. 1994;220:391-398; discussion 398-401.
243. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes
of sentinel-lymph-node resection and conventional axillary
lymph-node dissection in patients with clinically node-
negative breast cancer: results from the NSABP B-32 ran-
domised phase III trial. Lancet Oncol. 2007;8:881-888.
244. Veronesi U, Paganelli G, Viale G, et al. A randomized com-
parison of sentinel-node biopsy with routine axillary dissec-
tion in breast cancer. N Engl J Med. 2003;349:546-553.
245. Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node
biopsy in breast cancer: ten-year results of a randomized con-
trolled study. Ann Surg. 2010;251:595-600.
246. Ashikaga T, Krag DN, Land SR, et al. Morbidity results
from the NSABP B-32 trial comparing sentinel lymph
node dissection versus axillary dissection. J Surg Oncol.
2010;102:111-118.
247. Giuliano AE, Hawes D, Ballman KV, et al. Association of
occult metastases in sentinel lymph nodes and bone marrow
with survival among women with early-stage invasive breast
cancer. JAMA. 2011;306:385-393.
248. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dis-
section vs no axillary dissection in women with invasive
breast cancer and sentinel node metastasis: a randomized
clinical trial. JAMA. 2011;305:569-575.
249. Giuliano AE, Ballman KV, McCall L, et al. Effect of axil-
lary dissection vs no axillary dissection on 10-year overall
 survival among women with invasive breast cancer and senti-
nel node metastasis: the ACOSOG Z0011 (Alliance) random-
ized clinical trial. JAMA. 2017;318(10):918-926.
250. Giuliano AE, Ballman KV, McCall L, et al. Locoregional
recurrence after sentinel lymph node dissection with or with-
out axillary dissection in patients with sentinel lymph node
metastases: long-term follow-up from the American College
of Surgeons Oncology Group (Alliance) ACOSOG Z0011
randomized trial. Ann Surg. 2016;264:413-420.
251. Wilke LG, McCall LM, Posther KE, et al. Surgical compli-
cations associated with sentinel lymph node biopsy: results
from a prospective international cooperative group trial. Ann
Surg Oncol. 2006;13:491-500.
252. Lucci A, McCall LM, Beitsch PD, et al. Surgical complica-
tions associated with sentinel lymph node dissection (SLND)
plus axillary lymph node dissection compared with SLND
alone in the American College of Surgeons Oncology Group
Trial Z0011. J Clin Oncol. 2007;25:3657-3663.
253. The American Society of Breast Surgeons position state-
ment on management of the axilla in patients with invasive
breast cancer. Available at: http://www.breastsurgeons.org/
statements/PDF_Statements/Axillary_Management.pdf.
Accessed February, 26, 2014.
254. Galimberti V, Cole BF, Zurrida S, et al. Axillary dissection
versus no axillary dissection in patients with sentinel-node
micrometastases (IBCSG 23-01): a phase 3 randomised con-
trolled trial. Lancet Oncol. 2013;14:297-305.
255. Julian TB, Blumencranz P, Deck K, et al. Novel intraop-
erative molecular test for sentinel lymph node metastases
in patients with early-stage breast cancer. J Clin Oncol.
2008;26:3338-3345.
256. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomo-
gram for predicting the likelihood of additional nodal metas-
tases in breast cancer patients with a positive sentinel node
biopsy. Ann Surg Oncol. 2003;10:1140-1151.
257. Lyman GH, Giuliano AE, Somerfield MR, et al. American
Society of Clinical Oncology guideline recommendations for
sentinel lymph node biopsy in early-stage breast cancer. J
Clin Oncol. 2005:23:7703-7720.
258. Lyman GH, Somerfield MR, Giuliano AE. Sentinel lymph
node biopsy for patients with early-stage breast cancer:
American Society of Clinical Oncology Clinical Practice
guideline update. J Clin Oncol. 2017;35:561-564.
259. Henry P, Wasserstein D, Paterson M, Kreder H, Jenkinson R.
Risk factors for reoperation and mortality after the operative
treatment of tibial plateau fractures in Ontario, 1996-2009.
J Orthop Trauma. 2015;29:182-188.
260. Hortobagyi GN, Singletary SE, et al. Treatment of locally
advanced and inflammatory breast cancer. In: Harris JR, et
al, eds. Diseases of the Breast. Philadelphia: Lippincott Wil-
liams Wilkins: 2000:645.
261. Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast con-
servation after neoadjuvant chemotherapy: the MD Anderson
cancer center experience. J Clin Oncol. 2004;22:2303-2312.
262. Mieog JS, Van Der Hage JA, Van de Velde CJ. Neoadju-
vant chemotherapy for operable breast cancer. Br J Surg.
2007;94:1189-1200.
263. Mathew J, Agrawal A, Asgeirsson KS, et al. Primary endo-
crine therapy in locally advanced breast cancers–the Not-
tingham experience. Breast Cancer Res Treat. 2009;113:
403-407.
264. Ellis MJ, Suman VJ, Hoog J, et al. Ki67 proliferation index
as a tool for chemotherapy decisions during and after neoad-
juvant aromatase inhibitor treatment of breast cancer: results
from the American College of Surgeons Oncology Group
Z1031 trial (Alliance). J Clin Oncol. 2017;35:1061-1069.
265. Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase ii
neoadjuvant comparison between letrozole, anastrozole, and
exemestane for postmenopausal women with estrogen recep- 609
tor-rich stage 2 to 3 breast cancer: clinical and biomarker
outcomes and predictive value of the baseline PAM50-
based intrinsic subtype-ACOSOG Z1031. J Clin Oncol.
2011;29:2342-2349.
266. Favret AM, Carlson RW, Goffinet DR, et al. Locally advanced
breast cancer: is surgery necessary? Breast J. 2001;7:131-137.
267. Khan SA, Stewart AK, Morrow M. Does aggressive local
therapy improve survival in metastatic breast cancer? Sur-
gery. 2002;132:620-626; discussion 626-627.
268. Gnerlich J, Jeffe DB, Deshpande AD, et al. Surgical removal
CHAPTER 17 THE BREAST
of the primary tumor increases overall survival in patients
with metastatic breast cancer: analysis of the 1988-2003
SEER data. Ann Surg Oncol. 2007;14:2187-2194.
269. Khan SA, DesJardin ESM. Readdressing the role of surgery
of the primary tumor in de novo stage IV breast cancer. Can-
cer Treat Res. 2018;173:73-88.
270. Howlader N, Cronin KA, Kurian AW, Andridge R. Dif-
ferences in breast cancer survival by molecular subtypes
in the United States. Cancer Epidemiol Biomarkers Prev.
2018;27(6):619-626.
271. Bass SS, Lyman GH, McCann CR, et al. Lymphatic mapping
and sentinel lymph node biopsy. Breast J. 1999;5(5):288-295.
272. Cox CE, Nguyen K, Gray RJ, et al. Importance of lymphatic
mapping in ductal carcinoma in situ (DCIS): why map DCIS?
Am Surg. 2001;67:513-519; discussion 519-521.
273. Dupont E, Cox C, Shivers S, et al. Learning curves and breast
cancer lymphatic mapping: institutional volume index. J Surg
Res. 2001;97:92-96.
274. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in
breast cancer—a multicenter validation study. N Engl J Med.
1988;339:941-946.
275. McMasters KM, Giuliano AE, Ross MI, et al. Sentinel-
lymphnode biopsy for breast cancer—not yet the standard of
care. N Engl J Med. 1998;339:990-995.
276. O’Hea BJ, Hill AD, El-Shirbiny AM, et al. Sentinel lymph
node biopsy in breast cancer: initial experience at Memo-
rial Sloan-Kettering Cancer Center. J Am Coll Surg.
1998;186:423-427.
277. Souba WW, Bland KI. Indications and techniques for biopsy.
In: Bland KI, Copeland EMI, eds. The Breast: Comprehen-
sive Management of Benign and Malignant Diseases. Phila-
delphia: WB Saunders; 1998:802.
278. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node
biopsy to avoid axillary dissection in breast cancer with clini-
cally negative lymph-nodes. Lancet. 1997;349:1864-1867.
279. Wilke LG, Giuliano A: Sentinel lymph node biopsy in
patients with early-stage breast cancer: status of the National
Clinical Trials. Surg Clin North Am. 2003;83:901-910.
280. Xing Y, Foy M, Cox DD, et al. Meta-analysis of sentinel
lymph node biopsy after preoperative chemotherapy in
patients with breast cancer. Br J Surg. 2006;93:539-546.
281. Hunt KK, Yi M, Mittendorf EA, et al. Sentinel lymph node
surgery after neoadjuvant chemotherapy is accurate and
reduces the need for axillary dissection in breast cancer
patients. Ann Surg. 2009;250:558-566.
282. Tan VK, Goh BK, Fook-Chong S, et al. The feasibility and
accuracy of sentinel lymph node biopsy in clinically noden-
egative patients after neoadjuvant chemotherapy for breast
cancer—a systematic review and meta-analysis. J Surg
Oncol. 2011;104:97-103.
283. Yi M, Meric-Bernstam F, Ross MI, et al. How many sentinel
lymph nodes are enough during sentinel lymph node dissec-
tion for breast cancer? Cancer. 2008;113:30-37.
284. Kong AL, Tereffe W, Hunt KK, et al. Impact of internal mam-
mary lymph node drainage identified by preoperative lym-
phoscintigraphy on outcomes in patients with stage I to III
breast cancer. Cancer. 2012;118:6287-6296.
610 285. Fisher B. Lumpectomy (segmental mastectomy and axillary
dissection). In: Bland KI, Copeland EMI, eds. The Breast:
Comprehensive Management of Benign and Malignant
Diseases. Philadelphia: WB Saunders; 1998:917.
286. Newman LA, Washington TA. New trends in breast conserva-
tion therapy. Surg Clin North Am. 2003;83:841-883.
287. NIH consensus conference. Treatment of early-stage breast
cancer. JAMA. 1991;265:391-395.
288. Group EBCTC. Effect of radiotherapy after breast-conserv-
ing surgery on 10-year recurrence and 15-year breast cancer
death: meta-analysis of individual patient data for 10 801
women in 17 randomised trials. Lancet. 2011;378:1707-1716.
289. Houssami N, Macaskill P, Marinovich ML, et al. Meta-
PART II
analysis of the impact of surgical margins on local recurrence
in women with early-stage invasive breast cancer treated with
breast-conserving therapy. Eur J Cancer. 2010;46:3219-3232.
290. Moran MS, Schnitt SJ Giuliano AE, et al. Society of Surgical
Oncology–American Society for Radiation Oncology con-
SPECIFIC CONSIDERATIONS
sensus guideline on margins for breast-conserving surgery
with whole-breast irradiation in stages I and II invasive breast
cancer. Int J Radiat Oncol Biol Phys. 2014;88(3):553-564.
291. Houssami N, Macaskill P, Marinovich ML, Morrow M.
The association of surgical margins and local recurrence in
women with early-stage invasive breast cancer treated with
breast-conserving therapy: a meta-analysis. Ann Surg Oncol.
2014;21:717-730.
292. Moran MS, Schnitt SJ Giuliano AE, et al. Society of Surgi-
cal Oncology–American Society for Radiation Oncology
consensus guideline on margins for breast-conserving sur-
gery with whole-breast irradiation in stages I and II inva-
sive breast cancer. Int J Radiat Oncol Biol Phys. 2014;88(3):
553-564.
293. Bland KI, Chang HR. Modified radical mastectomy and total
(simple) mastectomy. In: Bland KI, Copeland EMI, eds. The
Breast: Comprehensive Management of Benign and Malig-
nant Diseases. Philadelphia: WB Saunders;1998:881.
294. Simmons RM, Adamovich TL. Skin-sparing mastectomy.
Surg Clin North Am. 2003;83:885-899.
295. McCraw JB, Papp C. Breast reconstruction following mas-
tectomy, In: Bland KI, Copeland EMI, eds. The Breast: Com-
prehensive Management of Benign and Malignant Diseases.
Philadelphia: WB Saunders;1998:96.
296. Fortin A, Dagnault A, Larochelle M, et al. Impact of locore-
gional radiotherapy in node-positive patients treated by
breast-conservative treatment. Int J Radiat Oncol Biol Phys.
2003;56:1013-1022.
297. Hellman S. Stopping metastases at their source. N Engl J
Med. 1997;337:996-997.
298. Overgaard M, Hansen PS, Overgaard J, et al. Postopera-
tive radiotherapy in high-risk premenopausal women with
breast cancer who receive adjuvant chemotherapy. Danish
Breast Cancer Cooperative Group 82b Trial. N Engl J Med.
1997;337:949-955.
299. Overgaard M, Jensen MB, Overgaard J, et al. Postopera-
tive radiotherapy in high-risk postmenopausal breast-cancer
patients given adjuvant tamoxifen: Danish Breast Cancer
Cooperative Group DBCG 82c randomised trial. Lancet.
1999;353:1641-1648.
300. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and
chemotherapy in node-positive premenopausal women with
breast cancer. N Engl J Med. 1997;337:956-962.
301. Recht A, Edge SB. Evidence-based indications for postmas-
tectomy irradiation. Surg Clin North Am. 2003;83:995-1013.
302. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radio-
therapy: clinical practice guidelines of the American Society
of Clinical Oncology. J Clin Oncol. 2001;19:1539-1569.
303. EBCTCG (Early Breast Cancer Trialists’ Collabora-
tive Group); McGale P, Taylor C, Correa C, et al. Effect
of radiotherapy after mastectomy and axillary surgery on
10-year recurrence and 20-year breast cancer mortality:
meta-analysis of individual patient data for 8135 women in
22 randomised trials. Lancet. 2014;383:2127-2135.
304. Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for
the whole breast: Executive summary of an American Society
for Radiation Oncology (ASTRO) evidence-based guideline.
Pract Radiat Oncol. 2018;8:145-152.
305. Polychemotherapy for early breast cancer: an overview of the
randomised trials. Early Breast Cancer Trialists’ Collabora-
tive Group. Lancet. 352:930-942.
306. Fisher B, Brown AM, Dimitrov NV, et al. Two months of
doxorubicin-cyclophosphamide with and without interval
reinduction therapy compared with 6 months of cyclophos-
phamide, methotrexate, and fluorouracil in positive-node
breast cancer patients with tamoxifen-nonresponsive tumors:
results from the National Surgical Adjuvant Breast and Bowel
Project B-15. J Clin Oncol. 1990;8:1483-1496.
307. Kelleher M, Miles D. 21. The adjuvant treatment of breast
cancer. Int J Clin Pract. 2003;57:195-199.
308. Loprinzi CL, Thome SD. Understanding the utility of adju-
vant systemic therapy for primary breast cancer. J Clin Oncol.
2001;19:972-979.
309. Wood WC, Budman DR, Korzun AH, et al. Dose and dose
intensity of adjuvant chemotherapy for stage II, node-positive
breast carcinoma. N Engl J Med. 1994;330:1253-1259.
310. Bonadonna G, Bignami P, Buzzoni R, et al. New adjuvant trials
for resectable breast cancer at the Istituto Nazionale Tumori of
Milan. Recent Results. Cancer Res. 1984;91:210-213.
311. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adju-
vant systemic treatment in breast cancer: a meta-analysis.
J Natl Cancer Inst. 2005;97:188-194.
312. Mittendorf EA, Buchholz TA, Tucker SL, et al. Impact of
chemotherapy sequencing on local-regional failure risk in
breast cancer patients undergoing breast-conserving therapy.
Ann Surg. 257:173-179.
313. Symmans WF, Wei C, Gould R, et al. Long-term prognos-
tic risk after neoadjuvant chemotherapy associated with
residual cancer burden and breast cancer subtype. J Clin
Oncol. 2017;35(10):1049-1060.
314. Kuerer HM, Newman LA, Smith TL, et al. Clinical course
of breast cancer patients with complete pathologic primary
tumor and axillary lymph node response to doxorubicin-based
neoadjuvant chemotherapy. J Clin Oncol. 1999;17:460-469.
315. Caudle AS, Gonzalez-Angulo AM, Hunt KK, et al. Predictors
of tumor progression during neoadjuvant chemotherapy in
breast cancer. J Clin Oncol. 2010;28:1821-1828.
316. Mamounas EP, Brown A, Anderson S, et al. Sentinel node
biopsy after neoadjuvant chemotherapy in breast cancer:
results from National Surgical Adjuvant Breast and Bowel
Project Protocol B-27. J Clin Oncol. 2005;23:2694-2702.
317. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel
lymph node surgery after neoadjuvant chemotherapy in
patients with node-positive breast cancer: the ACOSOG
Z1071 (Alliance) clinical trial. JAMA. 2013;310:1455-1461.
318. Boughey JC, Ballman KV, Le-Petross HT, et al. Identification
and resection of clipped node decreases the false-negative
rate of sentinel lymph node surgery in patients presenting
with node-positive breast cancer (T0–T4, N1–N2) who
receive neoadjuvant chemotherapy: results from ACOSOG
Z1071 (Alliance). Ann Surg. 2016;263(4):802-807.
319. Caudle AS, Yang WT, Krishnamurthy S, et al. Improved axil-
lary evaluation following neoadjuvant therapy for patients
with node-positive breast cancer using selective evaluation
of clipped nodes: implementation of targeted axillary dissec-
tion. J Clin Oncol. 2016;34:1072-1078.
320. Guarneri V, Broglio K, Kau SW, et al. Prognostic value of
pathologic complete response after primary chemotherapy in
 relation to hormone receptor status and other factors. J Clin
Oncol. 24:1037-1044.
321. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment
of postmenopausal breast cancer with anastrozole, tamoxifen,
or both in combination: the Immediate Preoperative Anastro-
zole, Tamoxifen, or Combined with Tamoxifen (IMPACT)
multicenter double-blind randomized trial. J Clin Oncol.
2005;23(22):5108-5116.
322. Delpech Y, Coutant C, Hsu L, et al. Clinical benefit from
neoadjuvant chemotherapy in oestrogen receptor-positive
invasive ductal and lobular carcinomas. Br J Cancer.
2013;108(2):285-291.
323. Joh JE, Esposito NN, Kiluk JV, et al. Pathologic tumor
response of invasive lobular carcinoma to neo-adjuvant che-
motherapy. Breast J. 2012;18(6):569-574.
324. Dixon JM, Renshaw L, Dixon J, Thomas J. Invasive lobular
carcinoma: response to neoadjuvant letrozole therapy. Breast
Cancer Res Treat. 2011;130:871-877.
325. Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant
endocrine therapy for estrogen receptor-positive breast can-
cer: a systematic review and meta-analysis. JAMA Oncol.
2016;2(11):1477-1486.
326. Baselga J, Semiglazov V, van Dam P, et al. Phase II random-
ized study of neoadjuvant everolimus plus letrozole compared
with placebo plus letrozole in patients with estrogen receptor-
positive breast cancer. J Clin Oncol. 2009;27:2630-2637.
327. Baum M, Buzdar A. The current status of aromatase inhibi-
tors in the management of breast cancer. Surg Clin North Am.
83:973-994.
328. Bonneterre J, Thurlimann B, Robertson JF, et al. Anastrozole
versus tamoxifen as first-line therapy for advanced breast
cancer in 668 postmenopausal women: results of the Tamoxi-
fen or Arimidex Randomized Group Efficacy and Tolerability
study. J Clin Oncol. 2000;18:3748-3757.
329. Buzdar A, Douma J, Davidson N, et al. Phase III, multicenter,
double-blind, randomized study of letrozole, an aromatase
inhibitor, for advanced breast cancer versus megestrol ace-
tate. J Clin Oncol. 2001;19:3357-3366.
330. Buzdar AU, Jonat W, Howell A, et al. Anastrozole ver-
sus megestrol acetate in the treatment of postmenopausal
women with advanced breast carcinoma: results of a sur-
vival update based on a combined analysis of data from
two mature phase III trials. Arimidex Study Group. Cancer.
1998;83:1142-1152.
331. Campos SM, Winer EP. Hormonal therapy in postmenopausal
women with breast cancer. Oncology. 2003;64:289-299.
332. Rutqvist LE, Johansson H; Stockholm Breast Cancer
Study Group. Long-term follow-up of the randomized
Stockholm trial on adjuvant tamoxifen among postmeno-
pausal patients with early stage breast cancer. Acta Oncol.
2007;46(2):133-145.
333. Fisher B, Dignam J, Bryant J, et al. Five versus more than
five years of tamoxifen therapy for breast cancer patients with
negative lymph nodes and estrogen receptor-positive tumors.
J Natl Cancer Inst. 1996;88(21):1529-1542.
334. Davies C, Pan H, Godwin J, et al. Long-term effects of
continuing adjuvant tamoxifen to 10 years versus stop-
ping at 5 years after diagnosis of oestrogen receptor-pos-
itive breast cancer: ATLAS, a randomised trial. Lancet.
2013;381(9869):805-816.
335. Goss PE, Ingle JN, Martino S, et al. Randomized trial of
letrozole following tamoxifen as extended adjuvant therapy
in receptor-positive breast cancer: updated findings from
NCIC CTG MA.17. J Natl Cancer Inst. 2005;97:1262-1271.
336. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anas-
trozole in postmenopausal women with early breast cancer:
NCIC CTG MA.27—a randomized controlled phase III trial.
J Clin Oncol. 2013;31(11):1398-1404.
337. Goss PE, Hershman DL, Cheung AM, et al. Effects of adju- 611
vant exemestane versus anastrozole on bone mineral density
for women with early breast cancer (MA.27B): a compan-
ion analysis of a randomised controlled trial. Lancet Oncol.
2014;15(4):474-482.
338. Smith I, Yardley D, Burris H, et al. Comparative efficacy and
safety of adjuvant letrozole versus anastrozole in postmeno-
pausal patients with hormone receptor-positive, node-positive
early breast cancer: final results of the randomized phase III
Femara Versus Anastrozole Clinical Evaluation (FACE) trial.
J Clin Oncol. 2017;35(10):1041-1048.
CHAPTER 17 THE BREAST
339. Early Breast Cancer Trialists’ Collaborative Group. Aro-
matase inhibitors versus tamoxifen in early breast cancer:
patient-level meta-analysis of the randomised trials. Lancet.
2015;386(10001):1341-1352.
340. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-
inhibitor adjuvant therapy to 10 years. N Engl J Med.
2016;375:209-219.
341. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent
kinase 4/6 inhibitor palbociclib in combination with letro-
zole versus letrozole alone as first-line treatment of oestrogen
receptor-positive, HER2-negative, advanced breast cancer
(PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet
Oncol. 2015;16(1): 25-35.
342. Finn RS, Martin M, Rugo HS, et al. Palbociclib and
letrozole in advanced breast cancer. N Engl J Med.
2016;375(20):1925-1936.
343. Cristofanilli M, Turnr NC, Bondarenko I, et al. Fulvestrant
plus palbociclib versus fulvestrant plus placebo for treatment
of hormone-receptor-positive, HER2-negative metastatic
breast cancer that progressed on previous endocrine therapy
(PALOMA-3): final analysis of the multicentre, double-
blind, phase 3 randomised controlled trial. Lancet Oncol.
2016;17(4):425-439.
343a. Goetz, M. P., et al. (2017). MONARCH 3: Abemaciclib As
Initial Therapy for Advanced Breast Cancer. J Clin Oncol.
35(32): 3638-3646.
343b. Sledge, G. W., Jr., et al. (2017). MONARCH 2: Abemaci-
clib in Combination With Fulvestrant in Women With HR+/
HER2- Advanced Breast Cancer Who Had Progressed
While Receiving Endocrine Therapy. J Clin Oncol. 35(25):
2875-2884.
344. Baselga J, Campone M, Piccart M, et al. Everolimus in
postmenopausal hormone-receptor-positive advanced breast
cancer. N Engl J Med. 2012;366:520-529.
345. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II
trial of everolimus in combination with tamoxifen in patients
with hormone receptor-positive, human epidermal growth
factor receptor 2-negative metastatic breast cancer with prior
exposure to aromatase inhibitors: a GINECO study. J Clin
Oncol. 2012;30(22):2718-2724.
346. Wolff AC, Lazar AA, Bondarenko I, et al. Randomized
phase III placebo-controlled trial of letrozole plus oral tem-
sirolimus as first-line endocrine therapy in postmenopausal
women with locally advanced or metastatic breast cancer.
J Clin Oncol. 2013;31(2):195-202.
347. Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of
ESR1 mutation in circulating tumor DNA demonstrates evo-
lution during therapy for metastatic breast cancer. Sci Transl
Med. 2015;7(313):313ra182.
348. Robinson DR, Wu YM, Vats P, et al. Activating ESR1 muta-
tions in hormone-resistant metastatic breast cancer. Nat
Genet. 2013;45(12):1446-1451.
349. Toy W, Weir H, Razavi P, et al. Activating ESR1 mutations
differentially affect the efficacy of ER antagonists. Cancer
Discov. 2017;7(3):277-287.
350. Jakesz R, Hausmaninger H, Kubista E, et al. Random-
ized adjuvant trial of tamoxifen and goserelin versus
612 cyclophosphamide, methotrexate, and fluorouracil: evidence
for the superiority of treatment with endocrine blockade in pre-
menopausal patients with hormone-responsive breast cancer—
Austrian Breast and Colorectal Cancer Study Group Trial 5.
J Clin Oncol. 2002;20(24):4621-4627.
351. Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovar-
ian suppression in premenopausal breast cancer. N Engl J
Med. 2015;372(5):436-446.
352. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemes-
tane with ovarian suppression in premenopausal breast
cancer. N Engl J Med. 2014;371:107-118.
353. Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG). Effects of chemotherapy and hormonal ther-
PART II
apy for early breast cancer on recurrence and 15-year
survival: an overview of the randomised trials. Lancet.
2005;365:1687-1717.
354. Paik S, Bryant J, Tan-Chiu E, et al. Real-world performance of
HER2 testing—National Surgical Adjuvant Breast and Bowel
SPECIFIC CONSIDERATIONS
Project experience. J Natl Cancer Inst. 2002;94:852-854.
355. Press MF, Slamon DJ, Flom KJ, et al. Evaluation of HER-2/
neu gene amplification and overexpression: comparison
of frequently used assay methods in a molecularly char-
acterized cohort of breast cancer specimens. J Clin Oncol.
2002;20:3095-3105.
356. Volpi A, De Paola F, Nanni O, et al. Prognostic significance
of biologic markers in node-negative breast cancer patients:
a prospective study. Breast Cancer Res Treat. 63:181-192.
357. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years
versus 1 year of adjuvant trastuzumab for HER2-positive
breast cancer (HERA): an open-label, randomised controlled
trial. Lancet. 2013;382(9897):1021-1028.
358. Pivot X, Romieu G, Debled M, et al. 6 months versus
12 months of adjuvant trastuzumab for patients with HER2-
positive early breast cancer (PHARE): a randomised phase 3
trial. Lancet Oncol. 2013;14(8):741-748.
359. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine
for HER2-positive advanced breast cancer. N Engl J Med.
2012;367:1783-1791.
360. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastu-
zumab plus docetaxel for metastatic breast cancer. N Engl J
Med. 2012;366(2):109-119.
361. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety
of neoadjuvant pertuzumab and trastuzumab in women
with locally advanced, inflammatory, or early HER2-
positive breast cancer (NeoSphere): a randomised multi-
centre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):
25-32.
362. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab
plus trastuzumab in combination with standard neoad-
juvant anthracycline-containing and anthracycline-free
chemotherapy regimens in patients with HER2-positive
early breast cancer: a randomized phase II cardiac safety
study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284.
362a. Von Minckwitz, G., et al. (2017). Adjuvant Pertuzumab
and Trastuzumab in Early HER2-Positive Breast Cancer.
N Engl J Med. 377(2): 122-131.
363. Chan A, Delaloge S, Holmes FA, et al. Neratinib after
trastuzumab-based adjuvant therapy in patients with
HER2-positive breast cancer (ExteNET): a multicentre,
randomised, double-blind, placebo-controlled, phase 3
trial. Lancet Oncol. 2016;17(3):367-377.
364. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2
mutations in HER2 gene amplification negative breast cancer.
Cancer Discov. 2013;3(2):224-237.
365. Lien HC, Chen YL, Juang YL, Jeng YM. Frequent alterations
of HER2 through mutation, amplification, or overexpression
in pleomorphic lobular carcinoma of the breast. Breast Can-
cer Res Treat. 2015;150:447-455.
366. Ben-Baruch NE, Bose R, Kavuri SM, Ma CX, Ellis
MJ. HER2-mutated breast cancer responds to treatment
with single-agent neratinib, a second-generation HER2/
EGFR tyrosine kinase inhibitor. J Natl Compr Canc Netw.
2015;13:1061-1064.
367. Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of
neratinib in combination with temsirolimus in patients with
human epidermal growth factor receptor 2-dependent and
other solid tumors. J Clin Oncol. 2014;32(2):68-75.
368. Robinson DS, Sundaram M, et al. Carcinoma of the breast
in pregnancy and lactation. In: Bland KI, Copeland EMI,
eds. The Breast: Comprehensive Management of Benign and
Malignant Diseases. Philadelphia: WB Saunders; 1998:1433.
369. Giordano SH, Buzdar AU, Hortobagyi GN: Breast cancer in
men. Ann Intern Med. 2002;137:678-687.
370. Wilhelm MC. Cancer of the male breast. In: Bland KI, Cope-
land EMI, eds. The Breast: Comprehensive Management of
Benign and Malignant Diseases. Philadelphia: WB Saunders;
1998:1416.
371. Khan SA, Badve S. Phyllodes tumors of the breast. Curr
Treat Options Oncol. 2001;2:139-147.
372. Chittoor SR, Swain SM. Locally advanced breast cancer:
Role of medical oncology. In: Bland KI, Copeland EMI,
eds. The Breast: Comprehensive Management of Benign and
Malignant Diseases. Philadelphia: WB Saunders; 1998:1403.
373. Mies C. Mammary sarcoma and lymphoma. In: Bland KI,
Copeland EMI, eds. The Breast: Comprehensive Management
of Benign and Malignant Diseases. Philadelphia: WB Saunders;
1998:307.
374. Stewart FW, Treves N. Lymphangiosarcoma in postmas-
tectomy lymphedema; a report of six cases in elephantiasis
chirurgica. Cancer. 1948;1:64-81.