Breast cancer

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10 Breast cancer

TV. Ajithkumar, HM. Hatcher

Introduction

Breast cancer is the most common female malignancy in the UK and USA. In the UK, 30,000 new cases and 15,000 deaths occur each year due to breast cancer. In the USA, there are 192,000 new cases and 43,300 breast cancer deaths every year. The life-time risk of developing breast cancer for a woman is 1 in 12 in the UK and 1 in 8 in the USA.

Aetiology

The reported risk factors include hormonal, genetic, dietetic and radiation. Table 10.1 shows these risk factors and protective factors for breast cancer. The effect of hormones, notably oestrogen, is the most significant aetiological factor in breast cancer. Genetic factors in breast cancers are dealt with in Chapter 5 (p. 47). BRCA1 mutation associated cancers tend to occur at an early age, are highly aggressive and are typically negative for oestrogen (ER), progesterone (PgR) and human epithelial growth factor receptor 2 (HER2/neu (’Triple negative’). BRCA2 mutations account for 1% of breast cancers which are often ER and PgR positive.

Table 10.1 Risk factors of breast cancer

	Relative risk
Early menarche (before 11 years)	3
Late menopause (after 54 years)	2
First pregnancy after 40 years	3
Nulliparity	3
HRT	1.7
Oral contraceptive	1.2
One maternal first degree relative	1.5–2
Two first degree relatives	3–5
First degree relative diagnosed before 40 years	3
Bilateral breast cancer	4
Alcohol	1.3
Protective factors
Artificial menopause before 35 years	0.5
Increased parity	0.5–0.8
Age at first pregnancy less than 30 years	0.6–0.8
Breast feeding	0.8

Other risk factors include:

• Previous breast cancer – increases the risk of a contralateral breast cancer (0.5–1% per year).

• Prior radiation – to the breast or part of breast increases the risk of cancer (RR 3) (e.g. Mantle radiotherapy for Hodgkin’s disease).

• Some benign conditions of the breast (e.g. atypical hyperplasia).

Pathogenesis and pathology

Breast cancer arises from the epithelial cells lining the terminal duct lobular unit. Development of invasive breast cancer is thought to be due to a multi-step process. WHO classification of breast cancer is shown in Box 10.1.

Precursor lesions

Lobular carcinoma-in-situ is considered as a precursor of invasive lobular cancer, but in most cases, it does not progress to the invasive stage. It is regarded as a marker for either lobular or ductal carcinoma.

Atypical ductal hyperplasia is characterized by intraductal epithelial proliferation with some of the features of DCIS. These increase the risk of invasive cancer 4–5 times.

In ductal carcinoma-in-situ (DCIS) malignant epithelial proliferation is confined to a duct with no stromal invasion. It accounts for 3–5% of palpable breast cancer and 15–20% of screen detected cancer. It is graded according to the appearance of cell nuclei. Low-grade micropapillary DCIS can occur as a multicentric tumour whereas high-grade comedo carcinoma DCIS can be associated with invasive tumour in the same quadrant.

Microinvasive carcinoma is focus of invasive cancer of <1 mm in maximum extent.

Malignant breast lesions

• Invasive ductal carcinoma: 70–80% of all invasive carcinomas are classified as invasive ductal carcinomas, which are thought to arise from DCIS. They occur most commonly as ‘ductal no special type’ (ductal NST). Ductal NST is a diagnosis of exclusion. Other special subtypes of ductal carcinomas include:

• Tubular carcinoma: 1–2% of breast cancer.

• Medullary carcinoma: 4–9% of breast cancer.

• Mucinous carcinoma: 2%.

• Papillary carcinoma: 1–2%.

• Invasive lobular carcinoma – constitutes 10–15% of invasive cancers. These tumours infiltrate diffusely leading to a discrepancy between imaging findings and histologic tumour size.

• Other cancers: include lymphoma, sarcoma, melanoma and metastasis.

The postoperative pathology report should include: number of tumours, maximum diameter of largest tumour, histologic type and grade, circumferential excision margin and minimal margin, vascular invasion, number of nodes retrieved, number of nodes involved and extent of involvement (e.g. micrometastasis or metastasis), presence of DCIS and immunohistochemical status of ER and PgR and HER2. Patients with an ambiguous HER2 (2+) status on immunohistochemistry, require fluorescent in situ hybridization (FISH) to look for gene amplification (Box 10.2).

Box 10.2
Grading and scoring systems in breast cancer

ER and PgR scoring systems

McCarty’s Semi quantitative H scoring (total score 0–300).

(Percentage of stained cells multiplied by a number, 0–3, reflecting the intensity of staining).

Negative	score ≤50 (−)
Weakly positive	51–100 (+)
Moderately positive	101–200 (++)
Strongly positive	201–300 (+++)

Her-2/neu scoring

Immunohistochemical scoring

Score 0–1+: Negative

2+: Borderline – needs further testing

3+: Positive

FISH score

<2.0, not amplified: Negative

>2.0, amplified: Positive

Molecular profiling has identified five subtypes of breast cancer: luminal A, luminal B, HER2+, normal breast-like and basal-like. The luminal tumours are ER+ whereas others are ER−. The outcome of these types is different. The role of molecular profiling in routine clinical practice is evolving but it is possible in the future that these subtypes will be treated differently.

Surgical anatomy of breast and lymphatics (Figure 10.1)

The adult breast extends from the second rib superiorly to the sixth rib inferiorly and from the lateral edge of the body of the sternum medially to mid-axillary line laterally. There are approximately 20–30 axillary lymph nodes which are surgically defined as:

• Level I – nodes inferior to pectoralis minor (12–14 in number).

• Level II – nodes posterior to pectoralis minor (6–8 in number).

• Level III – nodes superior to the pectoralis minor (2–4 in number).

Figure 10.1 Surgical anatomy of breast and lymphatic drainage.

Internal mammary nodes (3–5 nodes on either side) lie 2–3 cm from the sternal edge from the 3rd to 5th to intercostal space at a depth of 4–6 cm depending on the body habitus.

More than 75% of all lymphatic drainage passes through the axillary nodes and the remainder through the internal mammary nodes. There is a higher risk of internal mammary node involvement with medially located tumours and in those with extensive axillary nodes. Apical axillary node involvement leads to blockage of lymphatics and subsequent retrograde spread of cancer to supraclavicular nodes (see Figure 10.1).

Presentation

Example Box 10.1
Breast cancer: key points for a case presentation

All patients

• Age, menopausal status, performance status

• Previous breast disease, co-morbidities which affect treatments (cardiac/diabetes/systemic sclerosis), history of blood clots, other medications and allergies

• Family history (breast cancer, ovary, prostate, sarcoma)

New patient with local disease

• Size and location of tumour

• Nodal status

• Receptor status

• Patient anxieties about body image and thoughts about reconstruction if appropriate

• Planned surgery

New patient with metastatic disease

• Location and extent (bulk) of metastatic disease

• Receptor status

• Any signs of impending emergencies which affect treatment (e.g. SVCO, SCC)

• Any signs of life-threatening visceral involvement

Patient with local relapse

• Previous stage and date of original diagnosis

• Details of previous treatments and treatment related complications and time since completion of original treatment

• Receptor status

• Duration of current symptoms/signs hormone status

• Staging at time of local relapse (current staging)

Patient with metastatic relapse

• Previous stage and date of original diagnosis

• Details of previous treatments and treatment related complications and time since completion of original treatment

• Receptor status

• Duration of current symptoms/signs hormone status

• Current staging

• Any signs of impending emergencies which affect treatment (e.g. SVCO, SCC)

• Any signs of life-threatening visceral involvement

Many patients with early breast cancer are detected during screening by mammography.

The usual presentations are painless lump (65–75%), distortion of the breast (5%) and nipple discharge (2%). A small proportion of patients present with isolated axillary lymphadenopathy. Some patients present with metastatic manifestations such as bone pain, respiratory symptoms and features of liver metastases and brain disease.

Signs

Breast examination may reveal a non-tender, well or ill-defined lump with or without fixity to the skin or chest wall. The skin may be dimpled, invaded, reddened, indurated or with nodular irregularity.

Axillary and supraclavicular lymph nodes may be enlarged. Hepatomegaly, pleural effusion and spinal tenderness (usually thoracic and lumbar) can occur in metastatic disease.

Initial assessment

‘Triple’ assessment of patients with suspected breast cancer includes a combination of clinical examination, breast imaging (mammography and/or ultrasound) and pathologic evaluation (core biopsy). With this approach, a definite diagnosis of breast cancer can be made in 99% of cases.

Clinical examination

Clinical examination helps to elicit physical signs, accurately document the site of lesion, and contributes to tumour and nodal staging.

Breast imaging

Pathological diagnosis

Pathological diagnosis may be obtained by core biopsy or open surgical biopsy. Core biopsy can be obtained by conventional or vacuum assisted means such as Mammotome. Vacuum assisted core biopsy yields a larger sample and may in some cases allow complete removal of the target abnormality in the breast. Clinically impalpable lesions may necessitate image localization using mammography or ultrasound and hook wire replacement before open biopsy.

Investigations after triple assessment

Most patients with early stage disease without clinical evidence of metastatic disease will proceed to surgery after preoperative assessment. Patients who require neoadjuvant systemic treatment prior to definite surgical management need staging investigations including:

• Full blood count, liver function, renal function tests and serum alkaline phosphatase.

• Chest X-ray and CT scan of chest and abdomen – to rule out distant metastasis.

• Bone scan.

Postoperatively, patients with ≥4 positive lymph nodes and T4 disease also need the above investigations. In those with less than four positive nodes, normal biochemistry and no symptoms suggestive of metastasis, the incidence of metastasis is 2–4% and hence routine staging is not advised.

Staging

TNM staging of breast cancer is given in Box 10.3.

Box 10.3
Staging of breast cancer

Stage 0

• Tx – primary tumour cannot be assessed.

• T0 – no evidence of primary tumour.

• Tis – carcinoma-in-situ and Paget’s disease with no tumour

Stage I (T1N0M0)

• T1 – tumour 2 cm or less in its greatest dimension

• N0 – no regional lymph node metastasis

• M0 – no distant metastases

Stage II

IIA (TxN1M0, T1N1M0, T2N0M0)

• T2 – tumour larger than 2 cm but not larger than 5 cm

• N1 – ipsilateral non-fixed lymph node metastasis

IIB (T2N1M0, T3N0M0)

• T3 – tumour more than 5 cm

Stage IV (any T, any N, M1)

• M1 – distant metastasis

Management of carcinoma-in-situ

Ductal carcinoma-in-situ (DCIS)

Treatment is aimed at preventing local recurrence, particularly of invasive cancer. After biopsy alone, 40% will progress to invasive cancer. Surgical management of unicentric DCIS includes conservative surgery and simple mastectomy. These choices should be discussed with patients. Those who undergo mastectomy can be considered for immediate reconstruction. There is no recommended optimal margin for DCIS; a margin of >10 mm is adequate and <1 mm in inadequate (NICE recommends 2 mm). Patients with a persistent positive margin after repeat surgical excision, widespread DCIS (involving two or more quadrants), suspicious microcalcification throughout the breast and those likely to have an unacceptable cosmetic result with conservative surgery are considered for simple mastectomy. Axillary staging and dissection are unnecessary for patients with pure DCIS. Some series report up to 2% incidence of axillary node metastasis due to an unrecognized invasive cancer.

Randomized studies show that postoperative radiotherapy (45–50 Gy in 1.8–2 Gy per fraction) reduces breast recurrence (both in situ and invasive) with no effect on survival and irrespective of prognostic factors. However, in a subgroup with <10 mm, low/intermediate grade DCIS with adequate margin, radiotherapy may be safely omitted (<10% local recurrence at 10 years). Though there is no randomized study looking at the benefit of tumour bed boost radiotherapy, it may be considered if further excision to obtain a wider margin is likely to compromise cosmetic results.

Two studies evaluated the benefits of tamoxifen in DCIS. NSABP B-24 showed that tamoxifen reduced local recurrence of DCIS and invasive cancer (11% vs. 7.7%, p = 0.02) whereas UKCCCR trial showed that tamoxifen had no beneficial effect in reducing local recurrence when combined with whole breast radiotherapy (15 vs. 13%, p = 0.42). In the absence of radiotherapy tamoxifen reduced the risk of DCIS recurrence (10 vs. 6%, p = 0.03) but not invasive recurrence. There is no universally accepted recommendation for adjuvant hormones. Current studies evaluate various hormonal agents (e.g. IBIS II).

With mammographic follow-up, breast cancer disease free survival in DCIS approaches 100%.

Women with DCIS in one breast are at risk of a contralateral tumour occurring at a rate of 0.5–1% per annum.

Lobular carcinoma-in-situ (LCIS)

LCIS comprises 30–50% of carcinoma-in-situ, associated with invasive cancer in 10% and are frequently bilateral (35–60%). It is usually undetectable clinically and cannot be seen on mammogram due to the lack of central necrosis. One-third of people develop invasive cancer in the same or contralateral breast over 20 years. However, the issue of whether LCIS is a direct precursor of invasive lobular carcinoma has yet to be resolved.

Isolated LCIS following biopsy is managed with close observation. The rate of progression to cancer after biopsy alone is approximately 1% per annum. Mastectomy is generally reserved for patients with the highest risk of invasive recurrence such as young age, diffuse high-grade lesions and significant family history. Tamoxifen is being increasingly used as prophylactic treatment which has shown to reduce the invasive recurrence by 56%.

LCIS associated with DCIS or invasive cancer is managed according to the dominant malignant histology. There is no need for further surgery to obtain a clear margin for LCIS.

Management of early stage invasive cancer (Figure 10.5)

After triple assessment, initial treatment options for early stage (non-inflammatory T1–2N0–1M0) include:

• Conservative surgery with axillary surgery.

• Mastectomy with axillary surgery.

• Neoadjuvant chemotherapy followed by conservative surgery (when primary surgery is likely to result in unacceptable cosmesis).

Figure 10.5 Adjuvant systemic treatment in breast cancer (based on St. Galen International consensus 2007).

Surgery

Surgery is aimed at removal of the primary breast tumour and staging and/or treating the axilla. Primary breast surgery can be either conservative (wide local excision – WLE followed by radiotherapy) or mastectomy. Conservative surgery followed by postoperative radiotherapy offers a better cosmetic outcome than mastectomy. However, not all patients are suitable for breast conservation (Box 10.4).

Box 10.4
Contraindications to breast conservation surgery

• Prior radiotherapy to the breast or chest wall (can’t give more radiotherapy)

• Radiotherapy during pregnancy (risk of radiation to the foetus)

• Diffuse suspicious or malignant appearing microcalcification (difficult to obtain clear margin)

• Widespread disease that cannot be completely excised with satisfactory cosmesis through a single incision (result in negative margin and/or poor cosmesis)

• Persistent positive pathological margin (can’t obtain clear margin of >1 mm)

• Active connective tissue disease involving skin (scleroderma and lupus) (due to increased risk of radiation toxicity, if patient insists on conservation, radiotherapy is given at a reduced dose)

• Tumours of >5 cm (may result in poor cosmesis; however conservation can be attempted after neoadjuvant chemotherapy)

• Focally positive disease with extensive intraducal component (focally positive disease without extensive intraductal component can be treated with higher dose of radiotherapy)

• Women ≤35 years or premenopausal with BRCA1/2 mutation (higher risk of recurrence)

Breast surgery

WLE aims to remove the cancer with at least >1 mm circumferential microscopic disease free margin. The clinico-pathological factors that increase the risk of local recurrence after WLE include:

• Positive margin (<1 mm). The risk of recurrence is 16–21% with a positive margin compared with 2–5% with a negative margin and hence all patients need re-excision if technically feasible.

• Age ≤35 years (2–3 times increased risk of local recurrence).

• Extensive intraductal component (defined as an infiltrating ductal cancer where >25% of the tumour volume is DCIS and DCIS extends beyond the invasive cancer into the surrounding normal breast parenchyma).

• Lymphovascular invasion – increases the risk of recurrence by 1.5 times.

• Grade (grade I tumours have 1.5 times less risk of recurrence than grade II–III).

Mastectomy: involves complete removal of the breast from the pectoral fascia. Risk factors for chest wall recurrence after mastectomy include tumour of >5 cm, more than 4 nodes involved, margin <1 mm. Grade 3 and vascular invasion are not independent risk factors for recurrence.

Breast reconstruction after mastectomy

Reconstruction can be done at the same time as mastectomy (immediate) or at a later date (delayed). Immediate reconstruction can be offered to patients with diffuse DCIS and early breast cancer who may not require postoperative radiotherapy (radiotherapy to a reconstructed breast can result in poor cosmetic outcome). Delayed reconstruction is appropriate when postoperative radiotherapy is planned and there is concern about tumour clearance.

Methods of reconstruction include:

• Tissue expanders – initially the expander is placed in the pocket deep to pectoralis muscle, which is later replaced with a permanent implant containing silicone gel or saline after a few months. Complications include infections, failure of expansion and capsular contracture (particularly after radiotherapy).

• Autologous tissue – using either a pediculated flap (e.g. latissimus dorsi flap) or a free flap (free transverse rectus abdominis – TRAM flap).

Axillary surgery

Axillary surgery includes sentinel node biopsy (SNB) alone, SNB followed by axillary dissection or axillary dissection alone. SNB is not done in cases of high risk of axillary node involvement (e.g. palpable axillary node >3 cm or T3 or T4 tumours, multicentric tumours), previous history of surgery to breast or axilla, during pregnancy or lactation (contraindication of dye and radioisotope) and after neoadjuvant systemic treatment outside of clinical trials (role not defined), where dissection is the norm.

For SNB the sentinel node is localized by preoperative intradermal injection of technetium labelled colloid and lymphoscintiscan or by intraoperative injection of blue due or using both techniques. Sentinel node biopsy has >95% detection rate.

Patients who are sentinel node positive will undergo axillary clearance. A current study (ALMANAC) is evaluating the role of axillary radiotherapy in patients who are sentinel node positive.

Adjuvant radiotherapy (Boxes 10.5 and 10.6)

A meta-analysis suggests that adjuvant radiotherapy results in a reduction of local recurrence by two-thirds and improves 15-year survival by 5%. It also suggested that at 15 years one breast cancer death is avoided for every four local recurrences prevented.

Box 10.5
Radiotherapy in breast cancer

Position

• Supine with arm abducted (for CT plan)

• Supine with angled breast boards (conventional)

Localization

• Simulator or CT planning

• Target volume

Clinical target volume (CTV)

• Whole breast – entire breast tissue and subcutaneous tissue excluding muscles, rib cage and skin

• Chest wall – skin including scar extending up to deep fascia excluding muscles and rib cage

• Tumour bed – 1.5–2 cm around surgical cavity or haematoma

• SCF nodes – SCF node, infraclavicular nodes and apical nodes

Planning target volume

• 1 cm margin around CTV

After conservative surgery

Radiotherapy reduces the risk of local recurrence after breast conservation (5-year local recurrence of 7% with radiotherapy and 26% without radiotherapy) and is the current standard after WLE. However, one study showed that in patients over 70 years with good prognostic factors ( less than 2 cm tumour, grade 1 or 2, ER positive, node negative and no lymphovascular invasion) omission of radiotherapy may not compromise survival.

Addition of radiotherapy to the tumour bed (boost) after whole breast radiotherapy has shown to reduce local recurrence (10-year local recurrence rate of 6.2% with boost and 10.2% without boost p < 0.001). On multivariate analysis, age was the only significant predictor of local recurrence and the greatest benefit was seen in those aged <40 years. Boost radiotherapy did not improve 10-year overall survival. Many centres now follow a risk adapted policy for boost.

Postmastectomy radiotherapy (Boxes 10.5 and 10.6)

There is ongoing debate on the role of radiotherapy after mastectomy. Chest wall recurrence is thought to arise from tumour that has involved dermal lymphatics. Patients with a tumour of ≥5 cm size and ≥4 positive lymph nodes are at high risk of chest wall recurrence (20–30%) and routine postoperative chest wall radiotherapy is advised. This results in less local recurrence (6% vs. 23%) and improvement of 15-year survival by 5%. Postmastectomy radiotherapy may be considered in cases of T1 tumour with 1–3 positive nodes or T2 tumours with features of biological aggressiveness (ER−, HER2+, grade 3 and high proliferative index).

Patients with ≥4 involved nodes after axillary dissection are at risk of supraclavicular recurrence (>15%) and hence supraclavicular radiotherapy is advised. Axillary radiotherapy is not recommended after axillary dissection as there is 30–40% risk of significant lymphoedema and the risk of isolated axillary recurrence without radiotherapy is only 1–4%. However, it may be considered in rare instances of residual macroscopic disease in the axilla or positive dissection margin.

Adjuvant systemic treatment

Adjuvant systemic therapy is aimed at preventing recurrences by eradicating micro metastatic disease which is presumed to be present at the time of diagnosis. Adjuvant systemic treatment is recommended when there is a significant reduction in calculated risk of recurrence with an acceptable level of treatment related toxicity. However, the optimal strategy for advising systemic treatment has not yet been determined.

Hormone receptor status and HER2 status are the most important determinants in the choice of systemic treatment. Patients with ER+ tumours may receive hormones alone or a combination of endocrine treatment and chemotherapy. Patients with ER− tumours are considered for adjuvant chemotherapy alone. However, there are no clear guidelines on the threshold of benefit above which adjuvant chemotherapy is advised. Some experts justify adjuvant chemotherapy for patients with <90% 10-year survival and others use an absolute survival benefit of at least 3–5% at 10 years with chemotherapy. Several decision making tools (e.g. adjuvant online – https://www.adjuvantonline.com and Nottingham prognostic index) have been developed to help to make adjuvant treatment decisions. According to the 2007 St. Gallen Consensus adjuvant chemotherapy is generally recommended for intermediate and high-risk patients (Figure 10.5). Patients with HER2+ tumours of >1 cm and/or nodal involvement are considered for adjuvant trastuzumab (see later, p. 128).

Adjuvant chemotherapy

A meta-analysis suggest that 6 months of anthracycline based combination chemotherapy reduces yearly death from breast cancer by about 38% in women younger than 50 years and by 20% for women aged 50–69 years (absolute risk reduction at 5 years of approximately 3% for DFS and OS). A recent meta-analysis showed that addition of a taxane to anthracycline-based chemotherapy results in an absolute risk reduction at 5 years of 5% for DFS (17% relative reduction in relapse) and 3% for OS (15% relative reduction in death) for high risk early breast cancer. Subgroup analysis showed that the DFS benefit was present irrespective of ER status, number of lymph nodes involved, age, menopausal status and HER-2 status. However, it is uncertain whether all subgroups, particularly those with node-negative disease, derive such benefit from adjuvant taxanes.

A practical approach is to use anthracycline based chemotherapy (e.g. FEC or Epi-CMF) for patients without high-risk early breast cancer and taxane-anthracycline chemotherapy for high risk patients needing chemotherapy (Figure 10.5). In the UK, anthracyclines-taxane combination is licensed to use in patients with node positive breast cancer. Box 10.7 shows the commonly used chemotherapy regimes in breast cancer

Box 10.7
Chemotherapy regimes in breast cancer

Adjuvant/neoadjuvant

CMF

• Cyclophosphamide 100 mg/m² po days 1–14

• Methotrexate 40 mg/m² IV days 1 and 8

• 5 FU 600 mg/m² IV days 1 and 8

• Folinic Acid Rescue 15 mg 6-hourly × 6 doses po days 2 and 9. Start 24 hours post MTX

28-day cycle × 4–6 cycles

Epi-CMF (efficacy based on preliminary results from the NEAT study, ASCO 2003)

• Epirubicin 100 mg/m² IV bolus 21-day cycle for 4 cycles

• CMF as below for 4 cycles for 4 cycles

FEC

• 5 FU 600 mg/m² IV day 1

• Epirubicin 60–75 mg/m² IV day 1

• Cyclophosphamide 600 mg/m² IV day 1

21-day cycle. For 6 cycles

FEC100

• Epirubicin 100 mg/m² IV day 1

• 5 FU 500 mg/m² IV day 1

• Cyclophosphamide 500 mg/m² IV day 1

21-day cycle. For 6 cycles

FEC-D

FEC given 3 weekly for 3 cycles (as above) followed by docetaxel 100 mg/m² IV on D1 every 21 days for 3 cycles.

TAC

• Docetaxel 75 mg/m² IV day 1

• Adriamycin 50 mg/m² IV day 1

• Cyclophosphamide 500 mg/m² IV day 1

21-day cycle for 6 cycles

EC-T (EC given 3 weekly for 4 cycles followed by T given 3 weekly for 4 cycles)

• Epirubicin 90 mg/m² IV day 1 once in 3 weeks

• Cyclophosphamide 600 mg/m² IV day 1 once in 3 weeks

• Docetaxel 100 mg/m² IV day 1 once in 3 weeks

Docetaxel

• Docetaxel 100 mg/m² IV day 1

21-day cycle for 6 cycles

• Doxorubicin 60 mg/m² IV day 1

• Cyclophosphamide 600 mg/m² IV day 1

21-day cycle for 4–6 cycles (there is controversy regarding optimum duration)

Palliative

• Capecitabine 1250 mg/m² PO twice daily 1-14 given 3 weekly until progression, intolerable toxicity or patient/clinician choice to stop

And many others including the previous regimes!

Adjuvant endocrine therapy (Figure 10.5)

The Early Breast Cancer Trialists’ Group overview of adjuvant tamoxifen has shown that tamoxifen for 5 years results in a 41% proportional reduction in recurrence and 34% proportional reduction in mortality in oestrogen receptor positive breast cancer patients irrespective of age, menopausal status, and administration of chemotherapy. There is also a proportional reduction of contralateral breast cancer by 47%.

In premenopausal women tamoxifen (20 mg daily for 5 years) or tamoxifen combined with ovarian function ablation achieved either by bilateral oophorectomy or gonadotropin releasing hormone agonists (GnRH) for at least 2 years are standard recommendations. Aromatase inhibitors (AIs) are not indicated for premenopausal women (see below). A study of GnRH agonist, goserelin for 2 years (ZIPP) showed that in women who weren’t given tamoxifen, goserelin resulted in 14% less cancer related events and prevented 8.5 deaths whereas when given with tamoxifen, goserelin results in 2.8% fewer events and 2.6% less death compared with patients received only tamoxifen.

In postmenopausal women the adjuvant hormone options are:

• Tamoxifen for 5 years.

• Tamoxifen for 2–3 years with early switch to AIs exemestane or letrozole (total 5 years).

• AI for 5-years – letrozole or anastrazole (for large tumours, node positivity or HER2+ disease).

• Tamoxifen for 5 years followed by AI (letrozole) for another 2–3 years (for node positive disease).

The optimal duration of tamoxifen currently appears to be 5 years. Early results of the two randomized studies of extended tamoxifen (aTTom and ATLAS) did not show any significant benefit but an increased risk of endometrial cancer and venous thrombosis with 10 years of tamoxifen.

Early switch to AI, initial AI and extended use of hormones have all shown improvement in DFS with a decrease in distant metastasis, breast recurrence and contralateral tumours.

Mechanisms of action of hormonal agents

Oestrogen stimulates the growth of breast cancer. In premenopausal women 90% of total oestrogen is produced by the ovary which is stimulated by FSH and LH. The remaining oestrogen is produced by peripheral conversion of circulating androgen by the enzyme aromatase which is seen in extraovarian tissues such as subcutaneous fat, liver, muscle, breast and breast cancer cells. In postmenopausal women, ovarian production of oestrogen ceases and extraovarian production from secondary sources continues. Aromatase activity also increases with age.

Hormonal treatment is aimed at decreasing oestrogenic stimulation of breast cancer cells. This is achieved by either preventing the binding of oestrogen to cancer cells (e.g. tamoxifen), or by inhibiting ovarian and extraovarian production of oestrogens (e.g. oophorectomy, GnRH agonists and aromatase inhibitors).

Hormonal agents

Tamoxifen is a non-steroidal antioestrogen which has antagonist activity against breast cancer cells and agonist effect on bone, endometrium and serum lipids. Tamoxifen causes competitive inhibition with oestrogen for oestrogen receptors which results in a G1 block leading to decreased tumour growth. Other mechanisms include induction of apoptosis, and increasing NK cell activity.

The side effects of tamoxifen include hot flushes (50%), vaginal discharge and irregular menses. Tamoxifen increases the risk of endometrial cancer, especially in those above 50 years of age (80 excess cases per 10,000 tamoxifen treated women at 10 years). Other side effects include endometrial polyp and hyperplasia, thromboembolism (1–2%) and retinopathy. The beneficial effects of tamoxifen include increase in bone mineral density and decreased circulating cholesterol and LDL.

Aromatase inhibitors reduce oestrogen levels in postmenopausal women by inhibiting the aromatase enzyme in extraovarian tissue. However these are ineffective in premenopausal women as they increase gonadotropin secretion which leads to reduced feedback of oestrogen on the hypothalamic–pituitary axis, thereby causing increased aromatase activity. There are two groups of AIs:

• Type 1 inhibitor (steroidal analogue–enzyme inactivator) – irreversibly bind to aromatase, e.g. exemestane.

• Type 2 inhibitor – non-steroidal analogue–enzyme inhibitor – reversibly bind to the enzyme, e.g. anastrazole and letrozole.

The usual side effects of AIs are hot flushes, joint pain and muscular stiffness. The long-term risk of osteoporosis is a concern (see p. 61, late effects). All patients need bone mineral density assessment by DEXA scan prior to starting AI. Patients with osteopenia need vitamin D and calcium supplement whereas those with a T-score less than −2.5 SD (osteoporosis) need bisphosphonates. All patients on AI need a 2-yearly DEXA scan.

Adjuvant trastuzumab

In patients with HER2+ disease (immunohistochemical score of 3+ or FISH score >2.0) one year of adjuvant trastuzumab is recommended. Trastuzumab (Herceptin) is a humanized monoclonal antibody again the extracellular domain of HER2. All the six randomized studies have shown improved DFS with addition of trastuzumab to chemotherapy while 4 of the 6 trials showed an overall survival benefit with adjuvant trastuzumab, e.g. HERA study which compared chemotherapy vs. chemotherapy with trastuzumab showed a better 3-year DFS (81% vs. 74%) and OS (92% vs. 90%).

Adjuvant trastuzumab is indicated in patients with >1 cm and/or node positive tumour and who received adjuvant chemotherapy. The role of trastuzumab in <1 cm and node negative disease as well as a single modality is not studied.

A loading dose of 8 mg/kg followed by 17 maintenance doses of 6 mg/kg every three weeks is the recommended schedule. If there are more than 7 days delay treatment needs to be restarted with a loading dose.

Common side effects include hypersensitivity and flu-like symptoms. Cardiotoxicity is a concern (<4% symptomatic or severe cardiac failure). Hence it is not given if the left ventricular ejection fraction is <50%. It is not given concurrently with anthracyclines, but can be given concurrently with taxanes. Cardiac monitoring during treatment is mandatory. A recent study reported no increase in adverse cardiac events in patients receiving trastuzumab with adjuvant radiotherapy.

Locally advanced disease (T3 N1, T1–3 N2–3, T4 N0–3) (Figure 10.6)

Patients with locally advanced breast cancer are usually treated with neoadjuvant systemic therapy which is aimed at down staging the primary tumour which may facilitate surgery or even avoid the need for mastectomy. Full staging workup is needed in this group of patients.

Figure 10.6 Management of locally advanced and metastatic breast cancer.

In older women with receptor positive tumours, initial hormonal treatment can be used. Although studies show that all the AIs result in a higher response than tamoxifen, letrozole is the only licensed drug for neoadjuvant use. Two randomized studies, separately comparing letrozole and anastrazole with tamoxifen, showed that aromatase inhibitors induce a higher rate of regression allowing breast conservation. In the comparative study of 4 months of tamoxifen with letrozole, letrozole has a higher response rate (55%) than tamoxifen (36%). This study also showed that those patients with HER-1 or HER-2+ tumours had a higher response to letrozole (88% vs. 21%). In the second study anastrazole achieved significantly higher breast-conservation rate than tamoxifen (47% vs. 22%, p = 0.03).

Neoadjuvant chemotherapy is the standard treatment for patients with large primary tumours aiming for conservation and for inflammatory breast cancer (see p. 132). Chemotherapy results in a 70–90% response with a 20% pathological complete response. NSABP B-27 showed that an initial anthracycline regime followed by docetaxel results in a better response rate (90.7% vs. 85.5%, p < 0.001) and pathological complete response (64% vs. 40%, p < 0.001). In patients with HER2 positive tumours addition of trastuzumab results in improved pathological response (65% vs. 26%, p = 0.016) and it is advisable to incorporate trastuzumab with the neoadjuvant non-anthracycline chemotherapy. One such approach is to give initial 3–4 courses of anthracycline chemotherapy followed by taxanes with trastuzumab. In breast cancer, type and degree of response to primary systemic treatment predicts disease-free as well as overall survival.

After neoadjuvant chemotherapy, inflammatory breast cancer patients undergo total mastectomy whereas non-inflammatory breast cancer patients undergo mastectomy or conservation if appropriate. If patients had negative SNB pre-chemotherapy, no axillary surgery is needed. If axillary nodal status is unknown or positive SNB, axillary clearance is needed.

All patients need postoperative radiotherapy to chest wall or breast (Figure 10.6). Adjuvant systemic treatment depends on hormone receptor and HER2 status.

Metastatic disease (any T, any N, M1) (Figure 10.6)

Approximately 6% patients present with distant metastasis at diagnosis and 40% of patients with early stage disease will eventually develop metastases. The survival of patients with metastatic disease varies from months to years. Bone metastases have the best outcome, followed by lung, liver and brain metastases.

Evaluation includes complete history and examination, blood tests including the tumour marker CA15-3 if available, CT scan chest, abdomen and pelvis, bone scan and receptor status. Imaging of the brain is indicated only if symptomatic.

The aims of treatment are symptom control, improving quality of life and survival. Treatment options include hormones, chemotherapy and biological agents.

Patients with hormone receptor positive disease without life-threatening visceral involvement are treated with hormonal treatment. In premenopausal women who have not previously had tamoxifen or discontinued for >12 months, the standard option is tamoxifen and ovarian ablation or suppression. Otherwise, an AI with ovarian ablation may be considered.

In postmenopausal women studies show that AI have superior results compared with tamoxifen so should be the drug of choice, if not received previously. In one study, letrozole resulted in a significantly longer time to progression (41 vs. 26 weeks, p = 0.0001) and higher response rate (30% vs. 20%, p = 0.0006) compared with tamoxifen in advanced breast cancer. Since data are in more favour of letrozole, it is the agent of choice. There is no definite recommendation for second-line, but the options include tamoxifen, anastrazole, letrozole, exemestane, fulvestrant and megesterol acetate. Unless there is an indication for chemotherapy, various hormonal agents are used as a cascade of treatment until all options are exhausted.

Chemotherapy is used in patients with receptor negative tumours, hormone resistant tumours, and life-threatening progressive disease. Chemotherapy results in a 50% response rate usually lasting less than one year. Based on meta-analysis, anthracyclines result in a greater clinical benefit than a CMF regime and should be considered as first-line treatment if the patient has not previously received an anthracycline. Taxanes are the options after anthracycline failure. Both docetaxel and paclitaxel have proven activity. Other agents used in breast cancer include capecitabine, vinorelbine, gemcitabine, carboplatin, etc. (Box 10.6).

Patients with HER2 positive disease are treated with trastuzumab with or without chemotherapy. In patients who progress on trastuzumab, retrospective data support a change of chemotherapy with continuation of trastuzumab; however, NICE recommends discontinuation if it is systemic progression. Patients with HER2 positive disease have a high risk of brain metastasis. Trastuzumab need not be discontinued on isolated progression/relapse in the brain.

In patients after trastuzumab failure, lapatinib is a treatment option, though currently not yet approved in the UK. It is an inhibitor of HER2 and as well as EGFR (ErbB1) receptor. A randomized study in patients who had been previously treated with trastuzumab showed a significant improvement in time to progression with capecitabine combined with lapatinib compared with capecitabine alone (6.2 months vs. 4.3 months, p = 0.00013).

A very small subset of patients present with bone marrow failure subsequent to extensive bone disease. Modified chemotherapy with low-dose weekly anthracycline or taxanes is the option in these patients (Box 10.6).

In patients with metastatic disease, response to treatment should be evaluated after 3 months of endocrine treatment and after 2–3 cycles of chemotherapy.

Recurrent disease

2–20% patients after conservative surgery and <10% patients after radical surgery will present with loco-regional recurrence within 10 years. 10–70% patients present with metastatic recurrence within 10 years.

Patients presenting with isolated loco-regional recurrence need complete staging prior to potentially curative treatment and ‘secondary’ adjuvant treatment. Patients with systemic recurrence are treated similarly to those with metastatic disease.

Palliative care

• Bone metastases – treated with pain management as per WHO analgesic ladder (p. 66) and local radiotherapy studies show that 8–10 Gy as a single fraction has similar efficacy to that of prolonged. Women with bone metastases should be given bisphosphonates which help to control pain as well as prevent fractures, need for radiotherapy or orthopaedic surgery and epidoses of hypercalcaemia. Pamidronate, ibandronate, clodronate and zoledronic acid have all been shown to be effective.

• Brain metastasis – management of brain metastases are dealt with in Chapter 16 (p. 278). Patients with HER2+ disease have a high risk of brain metastasis, particularly to the posterior fossa.

• Management of oncological emergencies such as spinal cord compression and hypercalcaemia are discussed in Chapter 23 (p. 328).