Breast Cancer

Raymond Reilly University Health Network, Toronto, Canada

ã 2007 Elsevier Inc. All rights reserved.

Introduction

The growth of epithelial cells lining the ducts of the breast is controlled by growth-
stimulatory and differentiation signals as well as promotion/inhibition of cell death
pathways. Breast cancer may arise when these homeostatic mechanisms are disrupted.

Definition

Breast cancer is an uncontrolled growth of epithelial cells originating in the ducts or

breast lobules Carbone et al (1993). The disorder includes early, noninvasive breast
cancer, such as ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS),
breast cancer that has invaded the surrounding breast stroma (primary invasive breast
cancer); and breast cancer that has spread to the draining lymph nodes or to distant organs
(advanced or metastatic breast cancer). The disease is differentiated from benign breast
pathologies, such as fibroadenoma, fibrocystic disease, or benign hyperplasia.

Classification

Infiltrating ductal carcinoma is the most common pathology, accounting for 70–80% of
cases of breast cancer, while infiltrating lobular carcinoma comprises 10% of cases. The
remainder of cases include medullary carcinoma (5%) and papillary, cirrhous, or comedo,
which respresent 5–10% Carbone et al (1993). Breast cancer in males accounts for <1%
of all cases. The disease is staged according to the TNM (tumor, nodes, metastases)
system. Stage 0 is carcinoma in situ, and Stage I primary breast cancer with no nodal
involvement or metastases. Stage II is primary breast cancer (tumor size 1–5 cm diameter)
but with nodal involvement, primary breast cancer (tumor size >5 cm) with no nodal
infiltration or, rarely, no evidence of primary tumor but nodal involvement detected. Stage
III is primary breast cancer with infiltrated nodes with adhesion to other structures, or any
sized tumor with adhesion to the chest wall or skin with involved nodes. Stage IV is
defined as breast cancer that has metastasized to distant organs. The disease stage affects
the treatment strategies and long-term prognosis.

Consequences

Early breast cancer is treated with a combination of surgery, local radiation of the breast,
and, in some cases, adjuvant chemotherapy or hormonal therapy. This combination of
treatments in early stage disease provides an excellent long-term prognosis Fields Jones
and Burris (1996). Advanced metastatic breast cancer is treated in a similar manner, but
cannot be cured. Those diagnosed with advanced breast cancer eventually die of the
condition. Complications of advanced breast cancer include skeletal metastases, brain
metastases, bone marrow infiltration, hypercalcemia, abdominal metastases, lung
1
2 Breast Cancer

metastases, and pleural effusions. Skeletal metastases are painful and predispose to
fractures. Brain metastases may cause headaches, lethargy, confusion, memory loss,
seizures, nausea and vomiting, difficulty in walking, and papilledema. Hypercalcemia
may result from osteolytic bone metastases or hyperparathyroidism. Abdominal metas-
tases may be located in the liver, ovaries, or adrenals. Lung metastases are common and
may cause pleural effusions with associated respiratory insufficiency.

Associated Disorders

There is a high risk of ovarian cancer in women with mutations in the BRCA1 tumor
suppressor gene Ford et al (1994). Li-Fraumeni syndrome is a familial cancer-prone
syndrome that predisposes young women to breast cancer and other malignancies. It is
associated with a germ-line mutation in the tumor-suppressor gene, p53 Srivastava et al
(1990).

Etiology

While the precise cause of breast cancer is unknown, the disorder is associated with
genetic, hormonal, and environmental risk factors. Women with a first-degree relative
with breast cancer have a 2–4 fold greater risk of developing the condition. Mutations in
the BRCA1 tumor suppressor gene on chromosome-17 are associated with a 70–75% risk
of developing breast cancer, as well as a greater risk than the general population to
develop ovarian cancer Ford et al (1994). BRCA1 mutations are present in <5% of all
breast cancers. Most breast cancers appear to be sporadic in nature and not familial.
Mutations in the BRCA2 gene on chromosome 13 are also associated with breast cancer.
Benign breast disease, particularly atypical hyperplasia, may predispose a woman to breast
cancer. There is a 4–6 fold greater risk for breast cancer in women with increased breast
density measured mammographically Boyd et al (1998). Hormonal factors are important,
with women experiencing early menarche or late menopause having a higher risk of
developing breast cancer Carbone et al (1993). Whereas pregnancy before age 35
decreases the risk, estrogenic hormones, including oral contraceptives, increase the risk
for breast cancer. There is a direct correlation between a high-fat diet and risk for the
disease, with a higher incidence of breast cancer in obese, post-menopausal women.
Alcohol use and exposure to ionizing radiation may also increase the risk for developing
breast cancer.

Epidemiology

The incidence of breast cancer is dependent on age and nationality. In Western countries,
such as the United States, the annual incidence ranges from 5 cases/100,000 at age 25 to
150 cases/100,000 at age 50, then rises slowly to 200 cases/100,000 at age 75. Although
pre-menopausal incidence rates in Japanese women are similar to those in Western
countries, post-menopausal rates are much lower in Japan. The reported risk for a
woman developing breast cancer over her lifetime is 11% (1 in 9). Breast cancer is the
second most common cause of cancer death in women, exceeded only by lung cancer. Less
than 1% of all cases of breast cancer each year occur in men.
 Breast Cancer 3

Pathophysiology

Breast cancer appears to develop through a series of nonobligatory pathological stages

from atypical hyperplasia, to carcinoma in situ, to invasive breast cancer and metastasis
Bergstein (1999). Molecular changes that occur include amplification of the transcription
factor c-myc (20–30% of cases), overexpression of cyclin D1 (35–50% of cases) and cyclin
E (25% of cases), HER-2/neu overexpression (20–30% of cases), and overexpression of
epidermal growth factor receptors (EGFR) (30–60% of cases). Breast cancer cells pro-
duce and secrete TGFa, an autocrine peptide ligand for the EGF R. Overexpression of
EGFR is inversely correlated with estrogen receptor (ER) expression and is seen in >90%
of ER-negative tumors Klijn et al (1992). Although there are no reported mutations in the
gene for p21WAF-1/CIP-1, a cyclin-dependent kinase inhibitor, a decrease in p21WAF-1/CIP-1
or p27 expression correlates with a poor outcome. Mutations in the tumor suppressor
gene p53 are found in 25–50% of cases, and in the protein in 15–35% of cases. Germ line
mutations in the BRCA1 and BRCA2 tumor suppressor genes are responsible for a large
proportion of familial breast cancer. There is a decrease in expression of bcl-2, an
antiapoptotic protein, as breast cancer progresses from >95% in normal breast epithe-
lium, to 80–90% on ductal carcinoma in situ, to 45–80% in invasive ductal carcinoma.
This paradoxical decrease is thought to be due to de-differentiation of breast cancer cells
as the disease advances.

Signs and Symptoms

Patients may present with a lump, thickening, or pain in the breast that may be detected
by self-examination or examination by a physician. More recently, breast cancer is often
detected in asymptomatic patients by mammographic screening. Mammographic findings
include microcalcifications characterized by an irregular margin that may be associated
with distortion of normal breast architecture. Mammography has high sensitivity, but low
specificity, for detecting breast cancer, with abnormalities most often being nonmalignant,
such as benign breast disease (fibroadenoma or fibrocystic disease). Ultrasound is useful to
distinguish between fibrocystic breast disease and solid breast lesions. Fine-needle aspi-
ration, or excisional biopsy, is ultimately required to confirm a diagnosis of breast cancer.
Radiological examinations, including CT, chest X-ray, bone scan, and PET scan, are
useful to stage the patient and evaluate the extent of metastasis.

Standard Therapies

Breast cancer is treated first by surgery, including modified radical mastectomy or

lumpectomy, to excise the primary lesion and to dissect the axillary lymph nodes for
staging of the disease Fields Jones and Burris (1996) Henderson (1994), Carbone et al
(1993). Intraoperative detection of the sentinel node, which is the first node in the
lymphatic chain draining the tumor, using radioactive colloids or dyes with pathological
examination is under investigation as an alternate means of evaluating nodal involvement
to avoid complete nodal dissection Ell and Keshtgar (1999). Surgery is followed by local
radiation to the anterior chest wall and axilla to eradicate residual local microdisease and
prevent recurrence. Depending on staging and hormonal receptor status, patients may be
treated with systemic chemotherapy or hormonal therapy to treat known metastatic
deposits or to eradicate undetected micrometastatic disease (adjuvant therapy). In some
cases, patients are treated with chemotherapy or hormonal therapy prior to surgery to
4 Breast Cancer

decrease the size of the tumor to permit breast-conserving surgery as an alternative to

mastectomy (neoadjuvant therapy).

Agent Name Discussion

Surgery Breast conserving surgery, defined as lumpectomy or partial mastectomy,

combined with axillary node dissection and local radiotherapy may be
used for early stage (Stage I and II) breast cancer. Ten-year follow-up of
patients with early stage breast cancer treated with breast conserving
surgery compared to mastectomy showed no significant difference in
survival Jacobson et al (1995). For more advanced stages of the disease,
a modified radical mastectomy is required. While ductal carcinoma in situ
was previously treated with mastectomy, it is now more commonly
treated by breast conserving surgery sometimes combined with local
radiotherapy Morrow et al (2002).
Radiotherapy Post-surgical radiation therapy involves irradiation of the anterior chest
wall, the ipsilateral internal mammary lymph nodes, the apex of the axilla,
and the supraclavicular node. The total dose administered is 40–50 Gy
(4,000–5,000 rads) over 4–5 weeks. The goal of radiation therapy is to
eradicate microscopic disease in the breast and draining lymph nodes.
Cyclophosphamide An alkylating agent, cyclophosphamide cross-links DNA, which causes a
misreading of the DNA template or promotion of degradation by
nucleases and cell death. Cyclophosphamide is inactive until converted
in the liver and peripheral tissues to its active metabolites,
phosphoramide mustard, and acrolein. Cyclophosphamide is
administered orally at 80–100 mg/m2 for days 1–14 of a 4-week cycle in
combination with methotrexate and 5-fluorouracil or doxorubicin (e.g.,
CMF, CAF, FAC). The most common adverse effects are
myelosuppression, nausea, vomiting, hemorrhagic cystitis, alopecia,
and immunosuppression Schnell et al (2002).
Doxorubicin and Anthracyclines, such as doxorubicin, exert their cytotoxic effects by a
related combination of DNA intercalation, interference with topoisomerase II,
anthracyclines formation of free radicals, chelation of metals, and damage to cell
(daunorubicin, membranes. Doxorubicin is administered intravenously in a dose of
epirubicin, idarubicin) 40–50 mg/m2 on day 1, or days 1 and 8 of a 4-week cycle in combination
with cyclophosphamide and 5-fluorouracil (e.g., CAF, FAC, or AC). The
most common adverse effects associated with doxorubicin therapy are
myelosuppression, alopecia, nausea, vomiting, mucositis, and dose-
limiting cardiotoxicity. Severe cardiotoxicity is <10% for total cumulative
doses <550 mg/m2.
Methotrexate Methotrexate is an inhibitor of dihydrofolate reductase, an enzyme
required to maintain the supply of reduced folates for DNA and RNA
synthesis. Methotrexate is administered intravenously in a dose of 20 mg/
m2 weekly, or 60 mg/m2 on days 1 and 8 of a 4-week cycle, usually in
combination with cyclophosphamide and 5-fluorouracil (e.g., CMF). The
most frequent adverse effects are myelosuppression, mucositis, nausea,
vomiting, diarrhea, rash, and photosensitivity Schnell et al (2002). Renal
toxicity may occur with high doses, as well as a rare acute interstitial
pneumonitis.
5-Fluorouracil (5-FU) 5-fluorouracil (5-FU) is a fluorinated pyrimidine that exerts its cytotoxic
effects through incorporation into RNA as fluorouridine triphosphate
(FUTP). This incorporation interferes with RNA synthesis and function.
Moreover, as fluorodeoxyuridine monophosphate (FdUMP), it interferes
with thymidylate synthetase, an enzyme required for DNA synthesis. 5-FU
is administered intravenously in a dose of 500–600 mg/m2 on days 1 and
8 of a 4-week cycle in combination with cyclophosphamide and
methotrexate or doxorubicin (e.g., CMF, CAF, FAC). The most frequent
adverse effect associated with 5-FU is myelosuppression, with
gastrointestinal toxicity, cerebellar syndrome, hyperpigmentation of the
skin, photosensitivity, alopecia, and conjunctivitis being less common
Schnell et al (2002).
 Breast Cancer 5

Vincristine Vincristine is a vinca alkaloid derived from the periwinkle plant that exerts a
cytotoxic effect by binding to tubulin and preventing its polymerization.
This action interferes with the formation of the mitotic spindle and mitosis.
Vincristine is administered intravenously in a dose of 1 mg/m2 weekly in
a 4-week cycle in combination with cyclophosphamide, methotrexate, 5-
FU, and prednisone (e.g., CMFVP). The most frequent adverse effect is a
neurological toxicity that limits the single dose to <1.4 mg/m2.
Mitomycin C Mitomycin C is a second-line agent for the treatment of advanced breast
cancer. It is metabolized in vivo to an alkylating agent that binds to DNA
and inhibits DNA synthesis. Mitomycin-C is administered intravenously at
a dose of 10–15 mg/m2 every 6 weeks. The most frequent adverse effect
of mitomycin C is myelosuppression.
Mitoxantrone Mitoxantrone is a second-line agent for the treatment of advanced breast
cancer. It interferes with DNA synthesis by intercalation with DNA or by
inhibiting topoisomerase II. Mitoxantrone is administered intravenously
in a dose of 12–14 mg/m2 every 3 weeks. The most frequent adverse
effects of mitoxantrone are myelosuppression, nausea, vomiting,
alopecia, and cardiotoxicity.
Paclitaxel Paclitaxel is a second-line agent for the treatment of advanced breast
cancer. It causes mitotic arrest in cells by stabilizing polymerized tubulin
and the mitotic spindle. Paclitaxel is administered by intravenous infusion
in a dose of 175 mg/m2. The most frequent adverse effects are acute
hypersensitivity reactions, including anaphylaxis, which are minimized
by pre-treatment with antihistamines or corticosteroids. Neutropenia
and mucositis are dose-limiting. Other side effects include alopecia,
thromocytopenia, nausea, and vomiting.
VP-16 (etoposide) Etoposide (VP-16) is an epipodophyllotoxin second-line agent for the
treatment of advanced breast cancer. It causes DNA strand breaks in
cells by binding to topoisomerase II and preventing re-joining of DNA
strands. VP-16 may be administered by intravenous infusion at 50–100
mg/m2 daily for 5 days, or orally as a capsule in a dose of 100–200 mg/m2
daily for 5 days. The most frequent adverse effects of VP-16 are
myelosuppression, including leukopenia and thrombocytopenia, nausea,
vomiting, alopecia, and a mild peripheral neuropathy. Rapid intravenous
administration may cause acute arterial hypotension.
LHRH analogs Goserelin is a synthetic peptide analog of LHRH that is used as palliative
treatment for pre-menopausal women with estrogen and/or progesterone
receptor positive metastatic breast cancer. Goserelin, 3.6 mg, is
administered subcutaneously every 28 days. The most common adverse
effects of this agent are hot flashes, tumor flare, nausea, edema, malaise,
and vomiting.
Tamoxifen Tamoxifen is a nonsteroidal antiestrogen that competitively inhibits the
binding of 17-beta-estradiol to the estrogen receptor (ER), thereby
blocking the growth-stimulatory properties of the hormone. Tamoxifen is
indicated primarily for the treatment of ER-positive breast cancer, with
response rate as high as 89% Newby et al (1997). In addition, about 10%
of ER-negative tumors respond to tamoxifen by an unknown mechanism.
Tamoxifen may decrease the production of TGFalpa by ER-positive
tumor cells Noguchi et al (1993). TGFalpha is an autocrine peptide
growth-factor ligand for the epidermal growth-factor receptor (EGFR).
Tamoxifen is a first-line treatment for advanced breast cancer in both pre-
and post-menopausal women, and may also be used in an adjuvant
setting post-surgery and during radiotherapy for early stage disease.
Tamoxifen is administered orally in a dose of 10–20 mg twice daily. The
duration of treatment is dependent on the clinical response. Several
months of treatment may be required to observe an initial therapeutic
effect. The most frequent adverse effects associated with tamoxifen
therapy are hot flashes, nausea, and vomiting. Less frequent side effects
include vaginal bleeding, vaginal discharge, and skin rash. While
increased bone and tumor pain have been associated with tamoxifen
treatment, they may be indicative of a good tumor response. As
6 Breast Cancer

tamoxifen has partial estrogenic activity, it may increase the risk of

developing endometrial cancer.
Letrozole The aromatase inhibitors anastrozole and letrozole block estrogen
synthesis by inhibiting cytochrome P-450 aromatase Assikis and Buzdar
(2002). In post-menopausal women, estrogens, which are major growth
factors for breast cancer cells, are derived mainly from the aromatase-
mediated conversion of the androgens androstenedione and
testosterone to estrone and estradiol. Letrozole is indicated for
treatment of advanced breast cancer in post-menopausal women. The
dose of letrozole is 2.5 mg of per day, or 1 mg of anastrozole per day
administered orally. Side effects of these drugs include hot flashes,
vaginal dryness, hair thinning, nausea, vomiting, diarrhea, joint pain/
stiffness, headache, and rash Schnell et al (2002).
Anastrozole The aromatase inhibitors anastrozole and letrozole block estrogen
synthesis by inhibiting cytochrome P-450 aromatase Assikis and Buzdar
(2002). In post-menopausal women, estrogens, which are major growth
factors for breast cancer cells, are derived mainly from the aromatase-
mediated conversion of the androgens androstenedione and
testosterone to estrone and estradiol. Letrozole is indicated for
treatment of advanced breast cancer in post-menopausal women. The
dose of letrozole is 2.5 mg of per day, or 1 mg of anastrozole per day
administered orally. Side effects of these drugs include hot flashes,
vaginal dryness, hair thinning, nausea, vomiting, diarrhea, joint pain/
stiffness, headache, and rash Schnell et al (2002).
Trastuzumab Trastuzumab is a humanized, monoclonal antibody that binds specifically
to the HER-2/neu growth factor receptor present on 20–30% of breast
cancers. The antibody acts by blocking the ligand activation of the HER-
2/neu-mediated signal-transduction pathway or by activating antibody-
dependent cellular cytotoxicity (ADCC). HER-2/neu expression, which is
quantified by immunohistochemical staining, by using the HercepTest
(Dako), or by fluorescence in situ hybridization (FISH), is a selection
criterion for treatment with trastuzumab Field et al (2001). The usual
regimen of trastuzumab therapy consists of a loading dose of 4 mg/kg
administered as an intravenous infusion, followed by a maintenance dose
of 2 mg/kg. Although a slight increase in hematological toxicity was
observed in patients treated with a combination of trastuzumab and
chemotherapy, hematological toxicity is rare after treatment with
trastuzumab alone. The most common side effects associated with
infusion of trastuzumab alone are diarrhea, chills and fever, nausea,
vomiting, rigors, headache, cough, dizziness, and rash Schnell et al
(2002). Trastuzumab may cause cardiotoxicity, particularly when used in
combination with anthracyclines such as doxorubicin.

Experimental Therapies

Agent Name Discussion

High-dose High-dose chemotherapy combined with bone marrow transplant is under

chemotherapy with investigation as a treatment for advanced breast cancer, although there is
bone marrow currently no definitive evidence that it offers a survival advantage over
transplant conventional chemotherapy Gerrero et al (2002). In one recently reported
study Schrama et al (2001), 41 patients with advanced hormone-resistant
breast cancer were treated with high-dose chemotherapy consisting of
cyclophosphamide 4000 mg/m2, thiotepa 320 mg/m2, and carboplatin
1060 mg/m2 administered over 4 days. Second and third courses of
treatment were given after bone marrow transplant. Major toxicities
included hemorrhagic cystitis, prolonged gastrointestinal toxicity, and
 Breast Cancer 7

veno-occlusive disease, as well as one therapy-related death.

Approximately 49% of the patients achieved a complete response, nine
patients achieved a partial response, and three patients had stable
disease. The median follow-up period was 43 months. Six patients
remain in complete remission after 3 years.
Gene therapy Gene therapy is under investigation for the treatment of advanced breast
cancer. One approach is the use of cationic liposomes to deliver the
adenovirus type 5 E1A gene into breast cancer cells. The E1A adenovirus
gene represses oncogene transcription, modulates gene expression,
promotes cellular differentiation, and induces apoptosis in cancer cells. In
one study Yoo et al (2001), nine patients with recurrent and unresectable
primary breast cancer and nine patients with head and neck cancer
were injected intratumorally with liposomal E1 A. No toxicity was
observed and gene transfer was documented in 14/15 patients tested.
Down-regulation of HER-2/neu was observed in 2/5 patients who
overexpressed HER-2/neu at the start of treatment. No evidence of
residual tumor was found in one patient 12 weeks after treatment.
Breast cancer Breast cancer vaccines are under investigation as potential treatments for
therapeutic vaccines this condition. A randomized, double-blind, Phase III clinical trial is
currently in progress investigating the efficacy and safety of a vaccine
against the sialyl-Tn antigen present in breast cancer ( www.biomira.com ).
The trial involves 1,030 women with metastatic breast cancer. Interim
analysis of the data revealed no significant safety issues. Another cancer
vaccine consists of T-cell epitopes of the HER-2/neu receptor combined
with GM-CS F. In one study Disis et al (2002), 64 patients with HER-2/neu
positive breast, ovarion, or nonsmall-cell lung cancer were injected
intradermally with HER-2/neu peptide vaccines. T-cell immunity to HER-2/
neu peptides developed in 92% of patients. At 1 year post-vaccination,
HER-2/neu immunity was detected in 38% of patients and epitope
spreading was observed. The efficacy of this approach remains to be
established.
Targeted With radioimmunotherapy, monoclonal antibodies are conjugated to
radioimmunotherapy radioisotopes that bind to tumor-associated antigens on cancer cells,
thereby killing the disseminated cancer cells with radiation while sparing
normal tissues. In one Phase I study Wong et al (1999), 7 patients with
metastatic breast cancer received 27–46 mCi of yttrium-90 (90Y)
conjugated antiCEA monoclonal antibody T84.66 combined with
autologous stem-cell support. One patient had stable disease for 4
months, one patient had stable disease with a reduction in bone pain for 3
months, a third patient had >50% reduction in size of an ovarian
metastasis, resolution of pleural effusion, stable pleural metastases, and
a stable bone scan for 14 months. There were no dose-limiting toxicities
and all patients demonstrated hematopoietic recovery after stem cell
infusion.

Animal Models

Cell Lines:
Numerous human breast cancer cell lines established from metastatic breast cancer
specimens are available through the American Type Culture Collection (ATCC). The
most studied is MCF-7, an estrogen receptor (ER)-positive cell line derived from a
pleural effusion in a patient with breast cancer. Other ER-positive cell lines include
ZR-75-1 and BT-474. Breast cancer cell lines that are ER-negative, but are epidermal
growth factor receptor (EGFR) positive, include MDA-MB-468 and MDA-MB-231
Fitzpatrick et al (1984), Filmus et al (1985). A normal breast cell line is HBL-100.
8 Breast Cancer

Animal Models:
Human breast cancer cell lines may be implanted subcutaneously in athymic mice or
severe combined immunodeficiency (SCID) mice to establish a tumor xenograft model of
disease. Examples of breast cancer cell lines that form tumors in mice are MDA-MB-468,
MDA-MB-231, MCF-7 and BT-474, and MCF-7 and BT-474l. These tumors require
estrogen supplementation to grow in athymic mice. Implantation into immunocompro-
mised mice of primary breast cancer specimens obtained directly from patients has not
been generally successful. However, there have been reports of successful implantation of
primary tumor xenografts of ductal carcinoma in situ of the breast into athymic mice
Holland et al (1997), Chan et al (2001). A mammary carcinogenesis model can be
established in rats by treatment with dimethylbenzanthracene (DMBA) Costa et al (2002).

Other Information – Web Sites

Susan G. Komen Breast Cancer Foundation: http://www.komen.org. This is a private

foundation web site providing information on breast cancer and soliciting donations for
breast cancer research and education.
Canadian Cancer Society: http://www.cancer.ca. This is a public health web site
providing information on cancer, including breast cancer and soliciting donations for
cancer research and education.
American Cancer Society: http://www.cancer.org. This is a public health web site
providing information on breast cancer and soliciting donations for cancer research and
education.
CancerNet: http://www.cancer.gov/cancerinfo. This is a public health web site providing
information on cancer, incuding breast cancer.
Breastcancer.org: http://www.breastcancer.org. This is a private foundation web site
providing information on breast cancer.
CenterWatch Clinical Trials Listing Service: http://www.centerwatch.com. This is a web
site providing information on clinical trials of new treatments for various medical condi-
tions, including cancer.
American Type Culture Collection: http://www.atcc.org This is a web site for sources of
cancer cell lines.

Journal Citations

Assikis, V.J., Buzdar, A., 2002. Recent advances in aromatase inhibitor therapy for breast cancer. Seminars
in Oncol., 29(3 Suppl. 11), 120–128.
Boyd, N.F., Lockwood, G.A., Byng, J.W., et al. 1998. Mammographic densities and breast cancer risk.
Cancer Epidemiology Biomarkers and Prevention, 7(12), 1133–1144.
Chan, K.C., Knox, W.E., Gandhi, A., Slamon, D.J., Potten, C.S., Bundred, N.J., 2001. Blockade of growth
factor receptors in ductal carcinoma in situ inhibits epithelial proliferation. Br. J. Surg., 88(3), 412–418.
Costa, I., Solanas, M., Escrich, E., 2002. Histopathologic characterization of mammary neoplastic lesions
induced with 7,12-dimethylbenz(alpha)anthracene in the rat: a comparative analysis with human breast
tumors. Arch. Pathol. Lab. Med., 126(8), 915–927.
Disis, M.L., Gooley, T.A., Rinn, K., David, D., Piepkorn, M., Cheever, M.A., Knutson, K.L., Schiffman, K.,
2002. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu
peptide based vaccines. J. Clin. Oncol., 20(11), 2624–2632.
Ell, P.J., Keshtgar, M.R.S., 1999. The sentinel node and lymphoscintigraphy in breast cancer. Nucl. Med.
Commun., 20, 303–316.
Field, A.S., Chamebrlain, N.L., Tran, D., Morey, A.L., 2001. Suggestions for HER-2/neu testing in breast
carcinoma, based on a comparison of immunohistochemistry and fluorescence in situ hybridisation.
Pathology, 33(3), 278–282.
Ford, D., Easton, D.F., Bishop, D.T., Narod, S.A., Goldgar, D.E., 1994. Risk of cancer in BRCA1 mutation
carriers. Lancet, 343, 692–695.
 Breast Cancer 9

Gerrero, R.M., Stein, S., Stadtmauer, E.A., 2002. High-dose chemotherapy and stem cell support for breast
cancer: where are we now? Drugs and Aging, 19(7), 475–485.
Holland, P.A., Knox, W.F., Potten, C.S., Howell, A., Anderson, E., Baildam, A.D., Bundred, N.J., 1997.
Assessment of hormone-dependence of comedo ductal carcinoma in situ of the breast. J. Natl. Cancer
Inst., 89, 1059–1065.
Jacobson, J.A., Danforth, D.N., Cowan, K.H., d’Angelo, T., Steinberg, S.M., Pierce, L., Lippman, M.E.,
Lichter, A.S., Glatstein, E., Okunieff, P., 1995. Ten-year results of a comparison of conservation with
mastectomy in the treatment of Stage I and II breast cancer. N. Engl. J. Med., 332, 907–911.
Klijn, J.G.M., Berns, P.M.J.J., Schmitz, P.I.M., Foekens, J.A., 1992. The clinical significance of epidermal
growth factor receptor (EGF-R) in human breast cancer: a review on 5,232 patients. Endocr. Rev., 13,
3–17.
Morrow, M., Strom, E.A., Bassett, L.W., Dershaw, D.D., Fowble, B., Harris, J.R., O’Malley, F., Schnitt, S.J.,
Singletary, S.E., Winchester, D.P., 2002. Standard for the management of ductal carcinoma in situ of the
breast (DCIS). CA Cancer J. Clin., 52, 256–276.
Newby, J.C., Johnston, S.R.D., Smith, I.E., Dowsett, M., 1997. Expression of epidermal growth factor
receptor and ce-erbB2 during the development of tamoxifen resistance in human breast cancer. Clin.
Cancer. Res., 3, 1643–1651.
Noguchi, S., Motomura, K., Inaji, H., Imaoka, S., Koyama, H., 1993. Down-regulation of transforming
growth factor-a by tamoxifen in human breast cancer. Cancer, 72, 131–136.
Schrama, J.G., Baars, J.W., Holtkamp, M.J., Schornagel, J.H., Beijnen, J.H., Rodenhuis, S., 2001. Phase II
study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa,
and carboplatin in stage IV breast cancer. Bone Marrow Transplantation, 28(2), 173–180.
Srivastava, S., Zou, Z., Pirollo, K., Blattner, W., Chang, E., 1990. Germ-line transmission of a mutated p53
gene in a cancer-prone family with Li-Fraumeni syndrome. Nature, 348(6303), 747–749.
Wong, J.Y., Somlo, G., Odom-Maryon, T., Williams, L.E., Liu, A., Yamauchi, D., Wu, A.M., Yazaki, P.,
Wilczynski, S., Shively, J.E., Forman, S., Doroshow, J.H., Raubitschek, A.A., 1999. Initial clinical
experience evaluating Yttrium-90-chimeric T84.66 anticarcinoembryonic antigen antibody and
autologous hematopoietic stem cell support in patients with carcinoembryonic antigen-producing
metastatic breast cancer. Clin. Cancer Res., 5(10 Suppl.), 3224s–3231s.
Fitzpatrick, S.L., LaChance, M.P., Schultz, G.S., 1984. Characterization of epidermal growth factor receptor
and action on human breast cancer cells in culture. Cancer Res., 44, 3442–3447.
Filmus, J., Pollak, M.N., Cailleau, R., Buick, R.N., 1985. A human breast cancer cell line with a high number
of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited
by EGF. Biochem. Biophys. Res. Commun., 128, 898–905.
Yoo, G.H., Hung, M.C., Lopez-Berestein, G., LaFollette, S., Ensley, J.F., Carey, M., Batson, E., Reynolds, T.
C., Murray, J.L., 2001. Phase I trial of intratumoral liposome E1A gene therapy in patients with recurrent
breast and head and neck cancer. Clin. Cancer Res., 7(5), 1237–1245.

Book Citations

Fields Jones, S.M., Burris, H.A., 1996. Breast Cancer. Herfindal, E.T., Gourley, D.R. (Ed.), Textbook of
Therapeutics: Drug and Disease Management, Edition 6, pp. 1533–1547, Williams and Wilkins, Baltimore,
MD.
Henderson, I.C., 1994. Breast Cancer. Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.
S., Kasper, D.L. (Ed.), Harrison’s Principles of Internal Medicine, Edition 13, pp. 1840–1853, McGraw-Hill,
Inc., New York.
Carbone, P.P., Jordan, V.C., Bonadonna, G., 1993. Neoplasms of the Breast. Calabresi, P., Schein, P.S.
(Ed.), Medical Oncology. Basic Principles and Clinical Management of Cancer, Edition 2, pp. 819–849,
McGraw-Hill, Inc., New York.
Anonymous 2002 Product monographs for etoposide (VepesidW), tamoxifen (NolvadexW), trastuzumab
(HerceptinW), letrozole (FemaraW) and goserelin (ZoladexW). Schnell, B.R., et al. (eds.) Compendium of
Pharmaceuticals and Specialties, pp. 1806–1807; 1140-1141; 726-728; 628-629; 1927-1929, Can.
Pharmacists Assoc., Toronto.
Bergstein, I., 1999. Molecular Alterations in Breast Cancer. Bowcock, A.M. (Ed.), Breast Cancer: Molecular
Genetics, Pathogenesis and Therapeutics, Edition 1, pp. 143–170, Humana Press, Totowa, NJ.