Oxford Textbook of Fundamentals of Surgery

William E. G. Thomas (ed.) et al.

https://doi.org/10.1093/med/9780199665549.001.0001
Published: 2016 Online ISBN: 9780191810817 Print ISBN: 9780199665549

CHAPTER

2.6.3 Non-surgical treatment of breast cancer 

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Mymoona Alzouebi, Matthew Q. F. Hatton

https://doi.org/10.1093/med/9780199665549.003.0039 Pages 319–326

Published: July 2016

Abstract
Breast cancer has been the most common cancer in the United Kingdom since 1997 and is the
commonest malignant disease in women with an annual incidence of nearly 50 000 new cases in the
United Kingdom. One woman in nine will develop breast cancer during her lifetime and it is the leading
cause of death from malignant disease in Western women. Surgery is key in the management of the
primary tumour in early breast cancer. The main aim is to ensure adequate control of locoregional
disease. However, with increased understanding that patients with breast cancer die not from
uncontrolled local disease but from blood-borne metastases, there is now much greater emphasis on
additional pre- and postoperative therapies to reduce risk of recurrence and improve long-term
survival. These treatments include chemotherapy, radiotherapy, hormones, and molecular-targeted
therapies. This chapter discusses di erent treatment modalities for breast cancer and their
indications.

Keywords: breast cancer, adjuvant treatment, radiotherapy, chemotherapy, hormonal treatment

Subject: Surgery, Breast Surgery, Urology, Paediatric Surgery, Cardiothoracic Surgery, Peri-operative Care,
Trauma and Orthopaedic Surgery, Upper Gastrointestinal Surgery, Colorectal Surgery, Surgical Oncology,
Neurosurgery, Transplant Surgery, Vascular Surgery, Surgical Skills
Series: Oxford Textbooks in Surgery
Treatment modalities

Radiotherapy
Radiotherapy is the use of high-energy ionizing radiation such as X-rays, electrons, and protons to kill
tumour cells with DNA being the principal target for the biological e ects. Radiation causes direct damage
by inducing breaks in the DNA helical structure and indirect damage by the production of unstable, highly
reactive, and short-lived free radicals that in turn damage the normal DNA. Radiation-induced damage can
either be lethal and irreversible, which leads to cell death, or sublethal, in which case the cellular damage

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can be partially or completely repaired. The probability of a lethal cell injury is dependent on the amount of
radiation energy deposited in the tissues and the ‘type’ of radiation used (i.e. X-ray, electrons, or other
particles).

The early development of radiation treatment showed one large radiation dose had profound e ects on
tumours, but equally profound e ects on normal tissues, limiting clinical usefulness. This limitation led to
the development of fractionated treatments, utilizing the radiobiological principles of repair, redistribution,
resistance, repopulation, and re-oxygenation to enhance the radiation e ects on rapidly dividing tumour
cells in comparison to more slowly dividing normal tissues. These factors have led to the classical radiation
schedule, delivering 1 fraction per day (1.8–2 Gy per fraction), 5 days per week, over 5–6 weeks with the
outcome of treatment depending on the total dose delivered.

Total dose is the main determinant of the e ects of radiotherapy but increasing the radiation dose is a
challenge for the radiotherapist due to the tolerance of several vital normal tissues—lung, heart, and
brachial plexus—that must be taken into account. Most early side e ects are predictable (tiredness, skin
erythema, and local discomfort) but it is the irreversible late treatment e ects causing signi cant morbidity
(e.g. cardiac mortality and radiation neuropathy) which give most concern. Total dose is the main
determinant of the risk of late-e ects, but these risks are made greater by increasing treatment volume and
fraction size.

Improvements in radiotherapy schedules centre on reduction of the risk of late e ects and aim to improve
the local control rates leading to a reduction in distant metastasis and improved survival. Non-conventional
fractionation schedules, initially developed on an empirical basis, look to take advantage of di erent
radiobiological properties of tumour and normal tissues and, combined with new technologies reducing the
volume of normal tissue being treated, to maintain (or increase) the biological tumour dose.

Chemotherapy
The systemic treatment of cancer is a critical component of management and reduces the risk of local
recurrence and systemic metastasis. Chemotherapy is treatment using speci c cytotoxic agents targeted at
dividing cancer cells and distinguished from the forms of systemic treatment that have speci c cellular
targets (e.g. hormone therapy).

Cytotoxic drugs produce their e ect by direct DNA damage, prevention of DNA synthesis and replication, or
inhibition of cell division through damage to the mitotic spindle. As cytotoxic drugs have speci c actions,
the e ectiveness of treatment can be increased by combining drugs to synergize killing e ects by acting on
di erent phases of the cell cycle. Like radiotherapy, chemotherapy is ‘fractionated’ to maximize tumour kill
as normal tissue is expected to repair and recover before the tumour. Therefore, chemotherapy regimens are
often administered at 3-weekly intervals using a combination of drugs that have been selected to give the
optimal dose of each individual drug without overlapping toxicity. The use of therapeutic doses of cytotoxic
drugs will involve the development of side e ects which can be immediate (e.g. nausea, vomiting, and
allergic reactions), acute (e.g. neutropenia, diarrhoea, and stomatitis) or late as a result of prolonged use of
drugs (e.g. nephro-, cardio-, and neurotoxicity).

Targeted systemic treatments

Molecular-targeted cancer therapies are drugs that stop the growth and spread of cancer by interfering with
speci c molecular targets. As Figure 2.6.3.1 demonstrates, the pathways which promote cancer cell growth
are complex and by identifying the speci c molecular changes in these pathways targeted cancer therapies
may prove more e ective and less harmful to normal cells than cytotoxic chemotherapy. Hormonal

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treatment has a long history of use in breast cancer and recent developments have increased the range of
targets for which we now have drugs that can interfere with cell growth signalling, tumour blood vessel
development, promote apoptosis, stimulate the immune system, or target the delivery of toxic drugs to
cancer cells. Figure 2.6.3.1 shows some of the pathways implicated in breast cancer and its management.

Fig. 2.6.3.1

Pathways and molecular targets in breast cancer.

Hormone therapy
George Beatson pioneered ‘systemic’ treatment when he reported regression of breast tumours after
oophorectomy. This rst hormonal manipulation deprived cancer cells of an oestrogenic proliferative
stimulus by lowering plasma oestrogen levels. Oestrogen is a steroid hormone that in premenopausal
women is made primarily in the ovaries. The smaller amounts made by other tissues, including the adrenals
and adipose tissue, become the primary sources in postmenopausal women. Oestrogen crosses the plasma
membrane of cells and enters the nucleus to bind with the oestrogen receptor (ER) proteins. This ER
complex then binds to speci c sequences of DNA and regulates the expression of numerous genes involved
in cell growth. By lowering of oestrogen levels or by blocking their action at a receptor level, hormone-
dependant tumour cell proliferation is reduced and apoptotic (programmed cell death) pathways increased.

Approximately two-thirds of women with breast cancer have oestrogen-positive tumours and it is this
presence or absence of the ER that predicts responsiveness of a tumour to hormone treatment. Current
treatment options still include ovarian ablation which can be achieved by oophrectomy, radiation
treatment, or the use of analogues of luteinizing hormone-releasing hormone such as goserelin. More
commonly used alternatives are the selective oestrogen receptor modulators (SERMs) such as tamoxifen,
which compete with oestrogen and selectively bind to the cytoplasmic component of the oestrogen receptor.
Further options are the pure antioestrogens (e.g. fulvestrant) which downregulate ER without the oestrogen
agonist e ects that can be seen with SERMs and aromatase inhibitors in postmenopausal women where
oestrogen production is by the peripheral conversion of androgens mediated by aromatase enzymes.

Other molecularly targeted therapies

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Manipulations of other driver pathways that have been identi ed in breast cancer have found applications
in diagnosis and staging (e.g. immunohistochemistry and radio-immunodetection) as well as treatment.
The HER2/neu (erbB2) receptor pathway and over-expression of this epidermal growth factor receptor is
1
seen in around 20% of breast cancers and associated with a more aggressive form of the disease. Drugs
targeting the HER2 pathway include trastuzumab, a humanized monoclonal antibody. Trastuzumab targets
the extracellular domain of HER2, inhibiting signal transduction, and is the established treatment in this
form of the disease. Other pathways for which there are targeted treatments in current use include vascular
endothelial growth factor inhibitors such as bevacizumab and the activation of the mechanistic target of
rapamycin (mTOR) intracellular signalling pathway as a mechanism of resistance to endocrine therapy with
evidence for the use of mTOR inhibitors (e.g. everolimus) in combination with aromatase inhibitors in that
2
situation.

Treatment of breast cancer

A number of terms are used to describe the intent of non-surgical cancer therapy. Neoadjuvant (primary)
treatment given in the preoperative period to ‘downstage’ the primary tumour, local lymph involvement,
and treat any distant microscopic disease. Adjuvant therapy refers to treatment given after the macroscopic
disease has been resected to remove any residual microscopic tumour cells. Palliative treatment is used to
prolong and maintain quality of life in patients with incurable disease that has spread to distant organs or
whose co-morbidities prevent potentially curative treatment being given.

Adjuvant treatment
The presence of undetected micrometastases at the time of diagnosis means all breast cancer patients are at
risk of relapse following surgery. Prognostic information can predict the risk of recurrence for an individual
patient and the most commonly used scores in the United Kingdom are the Nottingham Prognostic Index
3
(NPI) and Adjuvant! Online. NPI is based on tumour size, grade, and number of positive lymph nodes and
Table 2.6.3.1 illustrates the variation of 10-year breast cancer mortality across subgroups and demonstrates
the complexity of adjuvant treatment options and decisions. The recommended treatment for each patient
is guided by their risk of relapse and other factors including hormone receptor and HER2 status are
important considerations in treatment selection. The increasing use of genetic tumour pro les (e.g.
oncotype DX) will continue to re ne these prognostic systems and may be able to tease out groups of
patients for whom current guidelines risk over-treatment as they are already at low risk of recurrence
4
following surgery.
Table 2.6.3.1 The North Trent Cancer Network adjuvant treatment guideline recommendations (2012)

ER strongly +ve ER weakly +ve ER –ve

Premenopausal

Tamoxifen
Excellent risk (NPI 3% 10-yr BCM 6% 10-yr BCM
< 2.4)
Tamoxifen No adjuvant treatment
5% patients

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Tamoxifen +/− OS
Very good risk 9% 10-yr MCM 14% 10-yr BCM
(NPI 2.4–3.39)
Tamoxifen +/− OS HER2 +ve FEC × 4, then
15% patients Herceptin

Good risk 15% 10-yr BCM Tamoxifen +/− Tamoxifen +/− OS 30% 10-yr BCM
OS
(NPI 3.4–4.39) FEC × 6 with trastuzumab in HER FEC × 6 with trastuzumab in HER
HER2 +ve FEC × 4, then 2 + ve 2 + ve
30% patients
Herceptin

Intermediate risk 33% 10-yr BCM
(NPI 4.4–5.39) Tamoxifen +/− OS
30% patients HER2 –ve. FEC × 6
HER2 +ve. Taxane-based chemo
× 6 + trastuzumab
Tamoxifen +/− OS 40% 10-yr BCM
HER2 –ve. FEC × 6 HER2 –ve. FEC × 6
HER2 +ve. Taxane-based chemo HER2 +ve. Taxane-based chemo
× 6 + trastuzumab × 6 + trastuzumab

Poor risk # 50% 10-yr BCM Tamoxifen +/− OS 60% 10-yr BCM
(NPI ≥ 5.4) Tamoxifen +/− OS HER2 –ve FEC or Taxane × 6 HER2 –ve. TAC × 6
20% patients HER2 –ve FEC or Taxane × 6 Taxane-based chemo × 6 + HER2 +ve. TAC × 6 + Herceptin
trastuzumab trastuzumab
HER2 +ve. Taxane-based chemo
× 6 + trastuzumab

Postmenopausal

Tamoxifen
Excellent risk (NPI 3% 10-yr BCM 6% 10-yr BCM
< 2.4)
Tamoxifen No adjuvant treatment
5% patients

Tamoxifen / AI switch
Very good risk 6% 10-yr BCM 10% 10-yr BCM
(NPI 2.4–3.39)
Tamoxifen / AI switch HER2 + ve FEC × 4, then
20% patients Herceptin
 Good risk 15% 10-yr BCM AI 30% 10-yr BCM
(NPI 3.4–4.39) AI FEC × 6 with trastuzumab in HER FEC × 6 with trastuzumab in HER
2 + ve 2 + ve
30% patients HER2 +ve FEC × 4, then
trastuzumab

Intermediate risk 30% 10-yr BCM AI 40% 10-yr BCM

(NPI 4.4–5.39) AI HER2 –ve. FEC × 6 HER2 –ve. FEC × 6
35% patients HER2 –ve. FEC × 6 HER2 +ve. FEC × 6 + trastuzumab HER2 +ve. Taxane-based chemo

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× 6 + trastuzumab
HER2 +ve. FEC × 6 + trastuzumab

Poor risk # 55% 10-yr BCM AI 60% 10-yr BCM

(NPI ≥ 5.4) AI HER2 –ve. FEC × 6 HER2 –ve FEC or Taxane × 6
10% patients HER2 –ve. FEC × 6 HER2 +ve. Taxane-based chemo HER2 +ve. FEC or Taxane × 6 +
× 6 + trastuzumab trastuzumab
HER2 +ve. Taxane-based chemo
× 6 + trastuzumab

Source: data from Referral and Management Guidelines for Breast Cancers within North Trent, North Trent Breast Cancer Group,
NHS, UK, Copyright © 2012, available from
http://www.yhscn.nhs.uk/media/PDFs/cancer/Breast%20docs/NEW%20NTBreast%20NSSG%20Guidelines%20revision%20Aug
%2012%20REC%20FINAL%20FINAL.pdf

10 yr BCM, 10-year breast cancer mortality rate; AI, aromatase inhibitor; NPI, Nottingham Prognostic Index; OS, ovarian
suppression.
Anthracycline-based chemotherapy: FEC (5FU, epirubicin, cyclophosphamide), TAC (docetaxel, epirubicin, cyclophosphamide).

Adjuvant hormone therapy

In the early 1970s, tamoxifen and other antioestrogen adjuvant therapy was shown to reduce overall
mortality from breast cancer in women with ER-positive disease. The Early Breast Cancer Trialists’
Collaborative Group (EBCTCG) showed that 5 years of tamoxifen therapy reduced annual recurrence rates by
5
almost half and breast cancer mortality by one-third. These trials established a standard of 5 years of
adjuvant tamoxifen therapy by showing this was superior to 2 years of treatment. The recently reported
ATLAS study (Adjuvant Tamoxifen, Longer Against Shorter) now suggests there may be bene t in
prolonging treatment further (8–10 years) in selected patients with 29% lower breast cancer mortality
6
compared with women who stopped tamoxifen after 5 years.

Tamoxifen is the mainstay of adjuvant treatment in ER-positive premenopausal women and in male breast
cancer. There is some evidence to suggest that combined hormonal treatments in premenopausal women by
the addition of ovarian suppression may be bene cial but this approach awaits the outcome of trials like the
SOFT study (ovarian suppression + tamoxifen or exemestane) before it can be considered a standard
7
approach.

In postmenopausal women, large-scale studies comparing tamoxifen with aromatase inhibitors found
signi cant improvements in disease-free survival and reduced toxicity from thromboembolic disease and
endometrial cancer. Typically an aromatase inhibitor prolongs disease-free survival and reduces distant
8
metastases by 14% but improvement in overall survival is yet to be documented. Aromatase inhibitors show
9
similar improvements when patients are ‘switched’ from tamoxifen halfway through the 5-year treatment
and when adjuvant treatment is extended by using an aromatase inhibitor for a further 3 years after the 5-
10
year adjuvant tamoxifen treatment nishes.

The role of adjuvant hormonal therapy following resection of ductal carcinoma in situ (DCIS) is less clear as
tamoxifen o ers a very small reduction in the risk of invasive breast cancers but no overall survival
11
bene t. Studies like the IBIS-II study which compares anastrozole and tamoxifen in postmenopausal
women with ER-positive DCIS will de ne the role of aromatase inhibitors in this form of the disease.

It should be remembered that side e ect pro les can in uence the decision about adjuvant hormonal
treatment. Menopausal symptoms are common to all and while tamoxifen protects against postmenopausal

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bone loss and lowers cholesterol it is associated with an increased risk of endometrial cancer and
thromboembolic events. The latter are less of a concern with aromatase inhibitors but there are e ects on
bone that require monitoring and often treatment to prevent osteoporosis.

Adjuvant chemotherapy
The EBCTCG/Oxford overview summarize the improvements in disease-free and overall survival seen with
12
adjuvant chemotherapy in breast cancer. The absolute gains from chemotherapy are in proportion to the
risk of recurrence and bene ts are greatest in women with poor prognosis disease as indicated by young age
(< 35 years), large tumour size, node positivity, high grade, hormone receptor negativity, and HER2
expression. The absolute bene t can be di cult to quantify and the use of prognostic scoring systems like
3
the NPI and Adjuvant! Online can be particularly helpful for individual patients with the latter system
delivering results in simple graphical formats that helps guide the decision-making process for many
women.

The general principles demonstrated in the Oxford overview are that single-agent adjuvant chemotherapy
is inferior to combination chemotherapy treatment and treatment over 3–6 months (four to eight cycles)
o ers the optimal balance between bene ts and side e ects. The bene t of adjuvant chemotherapy was rst
demonstrated with the CMF regimen (cyclophosphamide, methotrexate and 5- uorourcil) in node-positive
patients. Subsequently, trials demonstrated that the addition of an anthracycline gave further reduction in
12
breast cancer recurrence and mortality. Anthracycline-containing regimens are the current cornerstones
of adjuvant chemotherapy though more recent trials have demonstrated the addition of a taxane to be a
13
further improvement and the UK National Institute for Health and Care Excellence (NICE) recommends
14
the use of docetaxel in high-risk patients like those with lymph node-positive disease.

Adjuvant trastuzumab
The biggest change in adjuvant treatment over the past 10 years has been the introduction of trastuzumab
for patients with HER2-positive tumours. Studies showed it reduced the risk of relapse by 50% with
15
associated survival bene ts. Trastuzumab is generally well tolerated but does have cardiac toxicities and
cardiac monitoring is required during treatment and the drug should be used with caution in patients with
known left ventricular systolic dysfunction. The current focus for trials is the duration of adjuvant
trastuzumab and the role of newer drugs targeting the HER2 receptor pathway.
Adjuvant radiotherapy
Postoperative radiotherapy can be administered once the operative wound has healed and chemotherapy is
complete, taking into account the type of surgery, pathology, breast size, and the presence of a prosthesis,
and conventionally delivers 2 Gy fractions to doses of 50–60 Gy in 25–30 fractions over 5–6 weeks. It has
been recognized to reduce locoregional recurrence for over 40 years with a constant relative risk reduction
of approximately 50% for patients with invasive carcinoma or DCIS. However, the early radiotherapy
techniques gave signi cant doses to the heart and the improvements in breast cancer mortality were exactly
balanced by increases in cardiac mortality. Modi cations in the radiotherapy elds and improvements in
technology have reduced these toxicities and the EBCTCG meta-analysis of breast-conserving surgery

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followed by radiotherapy now shows a reduction in local recurrence, breast cancer deaths, and overall
16,17
mortality at 15 years.

The technological advances illustrated in Figures 2.6.3.2 and 2.6.3.3 contribute to the development of non-
conventional fractionation schedules. Results from the START trial have shown hypofractionation using
18
fewer, larger fractions to be as safe and e ective as the standard schedule. This has led to 40 Gy delivered
in 15 fractions over 3 weeks becoming standard practice in the United Kingdom with more accelerated
schedules that use a 5-fraction schedule to deliver treatment over 1 week being investigated in the FAST and
FAST Forward trials, with the former (30 Gy in ve once-weekly fractions) comparable to 50 Gy in 25
19
fractions in terms of adverse events. An alternative approach being explored is intraoperative radiotherapy
which has been investigated in the TARGIT study which assesses whether the use of partial breast
irradiation using intraoperative techniques is equivalent to whole-breast irradiation in women undergoing
conservation surgery without any adverse histopathological features.

Fig. 2.6.3.2

Postoperative radiotherapy to the right breast using IMRT, showing a five-field plan.
Fig. 2.6.3.3

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Same patient as Figure 2.6.3.2 illustrating dose distribution using a colourwash.

Indications for radiotherapy

Conservation surgery

All patients with invasive carcinoma should be considered for radiotherapy to the breast once clear
circumferential resection margins have been con rmed pathologically. There are relative contraindications
including poor performance status, signi cant respiratory or cardiovascular impairment, and local
anatomical factors such as poor shoulder movements or large pendulous breasts which may make the
practical administration of radiotherapy di cult.

Radiotherapy boost to the tumour bed

In patients with invasive breast cancer who have undergone breast conserving surgery and whole-breast
radiotherapy, the EORTC study showed 5-year local recurrence rates of 4.3% with boost radiotherapy versus
7.3% in no boost (reduction of 40%). Greatest bene t was seen in younger women (under the age of 40)
20
though breast cosmesis may be adversely a ected. Standard practice is to give the boost sequentially in a
5- or 8-fraction course of radiotherapy. However, new radiotherapy technologies (intensity modulated
radiotherapy (IMRT)) reduce the volume of normal tissue being treated and allow novel fractionations to
increase the biological tumour dose. An example where this is being tested are IMPORT trials which aim to
match the radiation dose to the di ering risks of recurrence across the breast and in e ect deliver the boost
dose concomitantly to the tumour bed during the standard 3-week treatment regimen.
Post mastectomy

Radiotherapy to the chest wall after mastectomy for invasive disease has been shown to improve local
21
control with improvements in overall survival in selected patients. These patients have been identi ed as
having T3/T4 primary tumours, four or more positive lymph nodes, or positive resection margins. There are
other factors recognized to increase the chance of local recurrence including vascular invasion, grade III
tumour, and one to three nodes positive, and the ongoing SUPREMO trial (Selective Use of Post-operative
22
Radiotherapy after Mastectomy) will determine the bene ts of radiotherapy in these patients.

Axilla

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This should be managed surgically and radiotherapy to the axilla after axillary node clearance is not
recommended due to the signi cant morbidity associated with lymphoedema of the arm. It can be
considered if the patient with invasive breast cancer refuses/is un t for axillary surgery or known residual
microscopic disease after surgery has been performed.

Supraclavicular fossa

Radiotherapy has been shown to reduce the risk of nodal recurrence in the supraclavicular fossa and
improve survival in patients with heavy (four or more) positive axillary nodes.

Ductal carcinoma in situ

DCIS comprises 15–20% of all screen-detected breast cancers and despite the lack of randomized trial
evidence it is widely recognized that mastectomy is over-treatment for many and breast conservation is
23,24 25
increasingly o ered. Evidence from prospective randomized trials and the EBCTCG indicates that
radiotherapy after breast-conserving surgery for DCIS approximately halved the local recurrence rate with
an absolute 10-year risk reduction of 15%, half due to a reduction in the recurrent DCIS and half invasive
breast cancer. With conservation surgery and radiotherapy becoming the standard of care in DCIS, the
challenge is now to identify a subgroup with small tumours and good surgical margins at low risk for
recurrence for whom adjuvant radiotherapy could be omitted. Retrospective studies by the National Surgical
Adjuvant Breast Project indicate nuclear grade, necrosis, size, and margin width are important in predicting
26
recurrence. Historical recurrence data have led to various predictive tools to aid patient selection for
adjuvant treatment, the Van Nuys Prognostic Index being the most widely recognized, but these tools have
not been prospectively validated. The results of the large prospective trials have so far failed to identify the
27,28
subgroups in whom radiotherapy is not needed and the speci c studies that have tried to address this
question have struggled to accrue and are unlikely to provide any de nitive answers.

Neoadjuvant treatment
Primary chemotherapy or hormone therapy is now commonly o ered in locally advanced, in ammatory, or
large operable breast cancer and allows the in vivo assessment of response to treatment and the opportunity
to change therapy early if no response is seen. Studies comparing this approach to adjuvant treatment have
29,30,31
shown equivalent survival which has allayed the perceived disadvantages of delaying de nitive local
surgery. The clear advantage to neoadjuvant systemic treatment is downstaging the primary tumour which
for some women allows breast-conserving surgery where mastectomy was otherwise required.

Pathological complete response rates have proved a good marker of prognosis in this situation and that is
seen in around 10% for anthracycline-based chemotherapy, 20% when a taxane is added, and in HER2-
positive patients the addition of trastuzumab which can signi cantly increase pathological complete
 32
response rates to approaching 50%. Clearly patients have to be monitored closely during treatment with
clinical assessment following each cycle and ultrasound assessment after two cycles with ultrasound-
guided insertion of marker clips for tumour bed localization. Post-treatment magnetic resonance imaging
is recommended in those patients being considered for breast-conserving surgery.

Primary endocrine therapy

When compared to chemotherapy, endocrine approaches are associated with a slower response to treatment
and lower complete response rate but for patients who are ER positive and un t for chemotherapy, an
aromatase inhibitor can downstage inoperable disease. Patients presenting with ER-positive operable

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disease but who are elderly and un t for surgical treatment should be considered for primary hormonal
therapy. Studies have shown complete and partial response rates of 12% and 35% respectively with clinical
33
bene t gained in 98% of patients on rst-line therapy. Response to rst-, second-, and third-line
hormonal therapies often last 24 months, 12 months, and approximately 9 months on average.

Metastatic breast cancer

About 15–20% of patients with breast cancer have metastatic disease at the time of diagnosis and with
advances in treatment of early invasive breast cancer women are surviving longer. They are then at
increasing risk of developing metastases even 10–20 years after surgery. Metastatic disease remains an
incurable disease and treatment is given with palliative intent aiming to control symptoms and improve
quality of life and prolong time to the progression of disease and death. The likelihood of metastasis is
strongly linked to the presence and quantity of positive axillary lymph nodes, and the grade and size of the
34
tumour. The role of preoperative screening remains debatable though most units will consider CT
scanning in the presence of histologically con rmed nodal involvement at diagnosis. When distant
metastases are found, prognostic factors including age, site of metastasis, and hormonal status are valuable
for predicting survival. While the overall median survival from the time of diagnosis of metastatic disease
has risen to around 24–30 months, certain groups like those with ER-positive disease and bone-only
metastasis will do signi cantly better.

Hormonal treatment is the preferred rst modality in patients with ER-positive disease because of the
better side e ect pro le in comparison to chemotherapy. In premenopausal women, tamoxifen or ovarian
suppression/ablation are used rst line whereas an aromatase inhibitor would be used in the
postmenopausal patient. Patients in whom the disease initially responds to endocrine therapy can be
o ered further lines of hormonal treatment with the expectation of a 25% response rate in the second line
and 10–15% third line.

Chemotherapy would be preferred in ER-negative disease, rapidly progressive or ER-positive disease that is
rapidly progressing, particularly when visceral metastases are present and it has a role for patients who are
failing to respond to hormones. Combination chemotherapy can o er higher response rates but at the cost
of extra toxicity in a palliative setting. The 2009 NICE guidelines on advanced breast cancer recommend
anthracyclines rst, followed by taxanes on progression, with single-agent vinorelbine or capecitabine in
35
the third-line setting.

HER2-directed treatment should be added in HER2-positive patients with trastuzumab the standard
treatment considered. However, this is a large-molecular-weight protein that does not cross the blood–
brain barrier and has a high rate of cerebral relapse. When relapse does occur, trials are reporting a number
of drugs are active and target di erent parts of the HER2 pathway. Examples that have activity con rmed in
36
phase III trials include pertuzumab (monoclonal antibody inhibiting receptor dimerization), mertansine
 37
DM1 (cytotoxic attachment delivered using the trastuzumab antibody, and lapatinib, a tyrosine kinase
38
inhibitor.

Radiotherapy is widely used in the palliative setting and can reduce symptoms at a range of metastatic
disease sites. It is most widely used as a treatment for bone metastasis when one fraction can improve pain
in 70–80%; other commonly used scenarios include the treatment of brain and spinal cord metastasis
where it is used to maintain function and reduce corticosteroid requirements. More fractionated treatment
(5–10 fractions) can be used to treat uncontrolled local disease and improve pain, bleeding, and other
symptoms.

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Over the past 10 years, the use of speci c bone-directed treatments has become standard in patients with
bone metastases and reduces skeletal-related events of fractures, cord compression, and prevention of
malignant hypercalcaemia. Bisphosphonates such as zoledronic acid are the current standard but recent
developments in metastatic bone research have identi ed the receptor activator of nuclear factor kappa-B
ligand (RANKL) as a primary mediator of osteoclast activity. Denosumab, a fully human monoclonal
antibody that reduces osteoclast-mediated bone destruction by inhibiting RANKL, has been shown to be
superior to zoledronate and has recently been approved by NICE for the prevention of skeletal-related
39
events. In addition, there is also some intriguing data suggesting that the addition of these treatments
may have a role in the adjuvant setting o ering a further treatment option that can reduce the risk of
40
recurrence following surgery.
References

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