5.7 Medical management of breast cancer 505

5.7 Medical management of breast cancer 505

ESSENTIALS Early breast cancer Most patients with breast cancer are offered surgery, the main op- tions being modified radical mastectomy, with or without immediate or delayed breast reconstruction, or breast-​conserving surgery. All patients treated surgically for early breast cancer should be con- sidered for risk-​reducing neoadjuvant (before surgery) or adjuvant (after surgery) treatments. Adjuvant radiotherapy should be considered for all patients who have undergone breast-​conserving surgery. Adjuvant med- ical therapies include (1)  endocrine therapy—​should be given to all oestrogen-​receptor positive patients (premenopausal—​ tamoxifen; postmenopausal—​aromatase inhibitors); (2) anti-​HER2 targeted therapy (e.g. trastuzumab) in cancers that overexpress the HER2 oncogene; (3)  chemotherapy—​selection is informed by clinic-​pathological parameters and increasingly by molecular genetic platforms such as Oncotype DX; patients with oestrogen-​ receptor negative, node-​positive disease should receive regimens containing sequential anthracyclines and taxanes. Regimens for neoadjuvant treatment are similar to those used in the adjuvant setting. Metastatic breast cancer Although local treatment of symptomatic lesions with radiotherapy or (in selected cases) with palliative surgery can be considered, the mainstay of treatment for metastatic disease is systemic therapy. Unless contraindicated, rebiopsy should be performed to confirm diagnosis and establish updated receptor immunophenotype. In oestrogen-​receptor positive cases, first-​line systemic therapy should be with endocrine agents, unless there is impending visceral or bone marrow crisis and/​or rapid clinical response is required. Choice of chemotherapy regimen should take into account treat- ment given in the adjuvant setting and single agents are usually preferred to combination regimens. In HER2-​positive disease, dual anti-​HER2 blockade with trastuzumab and pertuzumab combined with a taxane is standard of care. Options for triple negative breast cancer may include platinum-​based regimens and anti-​PD-​1 dir- ected immunotherapy. Patients should always be considered for participation in clinical trials. Pharmacogenomics to individualize systemic therapy is certain to become an integral part of the treatment decision-​making process in the near future. Introduction More than one million women worldwide are diagnosed with breast cancer each year, with about 400 000 dying of the disease. Familial breast cancer, most commonly related to BRCA1 and BRCA2, accounts for only 5% of all cases. Many of the known risk factors are not modifiable because they are inherent or would require un- realistic lifestyle changes, but moderating alcohol consumption, avoiding obesity, and increasing physical activity are all possibly useful interventions. See Chapter 5.1 for further discussion of the epidemiology of breast cancer. Screening for breast cancer is an effective means of achieving earlier diagnosis and provides the opportunity for reducing mor- tality: X-​ray mammography screening alone can be expected to re- duce mortality by 30% in women aged 40–​70 years who participate. Diagnostic assessment of symptomatic breast problems and screen-​detected abnormalities is best carried out by multidiscip- linary teams following the principles of triple assessment, which in- volves (1) detailed history and clinical examination of both breasts, axillae, and supraclavicular regions; (2) imaging; and (where indi- cated) (3) cytology/​core biopsy. The primary imaging techniques are X-​ray mammography and ultrasonography, with MRI when there is diagnostic uncertainty. Ultrasound-​guided core needle biopsy is the preferred method for sampling abnormalities. Once the diagnosis has been made, further imaging is used to assess the extent of cancer in the breast and detect the spread of disease to the axilla. The most significant clinico-​pathological predictors of prognosis are lymph node stage, histological grade, and histological assess- ment of tumour size, but evaluation of tumour type and the absence or presence of lymphovascular invasion provide additional informa- tion. Tumour oestrogen receptor (ER) status and human epidermal growth factor receptor 2 (HER2) status have been used to guide se- lection of therapy for many years, and clinical practice is increasingly 5.7 Medical management of breast cancer Tim Crook, Su Li, and Peter Harper

506 SECTION 5  Principles of clinical oncology informed by analysis of expression of other genes (e.g. Ki67, which encodes a nuclear protein associated with cellular proliferation). In terms of management, most patients with breast cancer are offered surgery. The main options are modified radical mastec- tomy, with or without immediate or delayed breast reconstruction, or breast-​conserving surgery. Metastatic involvement of axillary nodes is the best predictor of risk of recurrence and death, hence accurate assessment of axillary node status is important for sta- ging, prognosis, and guiding adjuvant treatment selection, and many regard sentinel lymph node biopsy as the best technique for establishing this. In this context, medical management of breast cancer has made remarkable progress since the first demonstration in 1975 that adju- vant chemotherapy in the form of cyclophosphamide, methotrexate, and fluorouracil (CMF) improved outcomes in node-​positive breast cancer. In day-​to-​day clinical practice, systemic therapy of breast cancer continues to rely on a set of proven agents and regimens containing cytotoxic drugs, endocrine modulators, and targeted therapies. However, we are now entering a phase of rapid change in which these well-​established approaches are increasingly being added to, and in some case replaced by, a more personalized ap- proach. Interesting and active drugs with novel mechanisms of action are emerging, which will change therapeutic algorithms. Moreover, as genomics allows molecular subclassification of breast cancer, it is certain that this will lead to more individualized treat- ment. Novel approaches (including immunotherapy) in specific patient subsets are starting to impact on potential management of metastatic breast cancer. Adjuvant therapy Although many patients with early breast cancer are undoubtedly cured by surgery alone, a significant proportion will ultimately re- lapse with metastatic disease, at which time they have incurable dis- ease. The term adjuvant therapy is used to describe treatment given after surgery. Adjuvant radiotherapy Adjuvant radiotherapy is indicated for all patients who have under- gone breast-​conserving surgery. Chest wall radiotherapy is recom- mended for patients treated with mastectomy for larger cancers (>50 mm) or with four or more involved axillary lymph nodes. Over and above radiotherapy, the task of the oncologist in early breast cancer is to assess the risk of relapse/​death for an individual patient and to initiate appropriate (adjuvant) systemic therapy to reduce this risk. Endocrine therapy, chemotherapy, and targeted therapy all have important places in the adjuvant treatment of early breast cancer and are considered individually. Adjuvant endocrine therapy Strategies to block the effect of oestrogen are fundamental to the ad- juvant therapy of ER-​positive early breast cancer. In the premeno- pausal patient, tamoxifen remains the most commonly used agent, and the large ATLAS and aTTom trials support the use of tamoxifen for 10 rather than the previous standard of 5 years. In postmenopausal ER positive patients, the aromatase inhibitors are the drugs of choice. These agents inhibit the enzyme aromatase, which catalyses the conversion of androgens into oestrogen in the peripheral fat. Many large clinical trials show superior efficacy of aromatase inhibitors over tamoxifen in the postmenopausal patient population, and recent studies suggest that extending adjuvant use of aromatase inhibitors up to 10 years is superior to 5 years, pre- dominantly as a result of prevention of contralateral breast cancer. Patients who have completed 5  years of adjuvant aromatase in- hibitors should therefore be considered for extended use, taking into account patient factors such as bone health and tolerability. Treatment with bisphosphonates or denosumab not only promotes maintenance of bone mineral density but also improves outcomes in postmenopausal patients taking aromatase inhibitors. Adjuvant therapy for HER2-​positive breast cancer About 20% of primary invasive breast cancers overexpress the HER2 oncogene. If this is demonstrated, either by histochemical staining or fluorescent in situ hybridization (FISH) analysis, an adjuvant regimen containing trastuzumab should be offered to all women with node-​positive disease, and to women with node-​negative disease who have larger tumours. Trastuzumab improves survival outcomes for HER2 positive patients with breast cancer (number needed to treat is eight for patients with high risk), but with a chance of 2–​20% of inducing congestive heart failure (depending on prior risk of that condition), hence routine cardiac monitoring is recommended. Adjuvant chemotherapy Adjuvant chemotherapy is given with the aim of reducing future disease recurrence by eliminating subclinical micro-​foci of meta- static cancer cells which are present but not detectable at diagnosis. Traditionally, patients being considered for adjuvant chemotherapy were risk-​stratified using clinically based systems such as the St Gallen criteria and the Nottingham Prognostic Index (NPI), which incorporates the size of the tumour, the number of involved lymph nodes, and the tumour grade to generate a value predictive of 5-​ year survival. Subsequently, multiparameter models have become available. The first of these was Adjuvant! on Line (https://​www. adjuvantonline.com), and this has been joined recently by the NHS Predict model (http://​www.predict.nhs.uk). Unlike previous sys- tems, NHS Predict incorporates HER2 and Ki67 status and is useful in the decision-​making process for adjuvant therapy. Notwithstanding the utility of these systems in facilitating patient selection for adjuvant chemotherapy, a major evolving theme in recent years has been the drive to personalize treatment decision-​ making using molecular genetic rather than clinico-​pathological parameters. Several platforms are available, of which Oncotype DX is the most well-​known (and the sole product currently avail- able in the National Health Service wherein its used is restricted to ER positive, node-​negative patients). Other testing systems include Endopredict, which incorporates the traditional prognostic factors of tumour size and lymph node status with analysis of an eight gene panel to derive a measure of risk of future relapse and how this can be offset by chemotherapy. Drugs used in the adjuvant setting are those previously shown to have efficacy in treating metastases, and adjuvant chemotherapy for breast cancer continues to rely on established agents such as the anthracyclines (doxorubicin [Adriamycin], Epirubicin), taxanes (docetaxel and paclitaxel), and the bifunctional alkylating agent cyclophosphamide.

5.7  Medical management of breast cancer 507 Several pivotal trials have provided guidance on which regimens are appropriate for specific subsets of patients. The prognostic sig- nificance of lymph node status is well-​recognized, and it is now widely held that patients with node-​positive disease should re- ceive both taxanes and anthracyclines, particularly if they have ER-​ negative cancers. In addition to lymph node status, specific subsets of patients have a higher probability of relapse and accordingly have a lower threshold for the use of adjuvant chemotherapy. For ex- ample, in patients with triple negative breast cancer there are (by definition) no endocrine or anti-​HER2 treatment options, and adju- vant chemotherapy is indicated for most patients. Of note, in triple negative breast cancer there is now good evidence that adjuvant paclitaxel given in the dose-​dense (accelerated) or (even better) on a weekly regimen is superior to docetaxel. Similarly, cases positive for HER2 should usually be offered adjuvant chemotherapy together with trastuzumab, even if small, ER positive and node negative. Neoadjuvant systemic therapy The term neoadjuvant therapy is used to describe treatment given before surgery with the intention of ‘down staging’ the tumour and allowing surgery to take place more easily and with less mor- bidity. Neoadjuvant treatment of breast cancer is now established as a (frequently) effective strategy for early breast cancer, particularly in larger cancers, in locally advanced cases, and in many patients with HER2-​positive disease. There are several factors which make neoadjuvant therapy an attractive option for selected patients: • Cancers can often be downsized to facilitate more cosmetic- ally acceptable completion surgery and, in some cases, breast conservation. • Use of systemic therapy ‘upfront’ provides a rapid indication of the sensitivity of individual cancers to chemotherapy and may there- fore guide adjuvant treatment options. • Achievement of a pathological complete response is a useful prog- nostic parameter and may, at least in part, inform the decision to offer additional (postoperative) chemotherapy. Regimens for neoadjuvant treatment are often identical to those used in the adjuvant setting. However, in HER2-​positive disease, dual blockade with the combination of trastuzumab and pertuzumab (initially given together with taxanes) achieves a significantly higher rate of pathological complete response than trastuzumab alone. Metastatic breast cancer Approximately 6% of patients with metastatic breast cancer present with de novo disease and metastatic relapse will ultimately occur in 10–​40% of patients treated (apparently successfully) for early breast cancer. Although local treatment of symptomatic lesions with radio- therapy or (in selected cases) with palliative surgery can be con- sidered, the mainstay of treatment is systemic therapy. As in the adjuvant setting, there are three modes of systemic treat- ment for metastatic disease, namely endocrine therapy, chemo- therapy, and anti-​HER2. There are, however, several important differences in the way these agents are deployed in the metastatic set- ting. Oncological orthodoxy has long considered metastatic breast cancer to be an incurable disorder, the goal of management being extension of life with control of symptoms, and selection of regimens must reflect these different therapeutic objectives and be adaptable to widely differing patient factors, including performance status. Rebiopsy of a metastatic lesion should be performed wherever possible, not only to confirm the diagnosis of breast cancer, but also to obtain an up-​to-​date picture of the expression of ER and HER2. It is now well-​recognized that expression of ER not infrequently changes with tumour evolution, and inappropriate and ineffective endocrine therapy could be given if ER status is assumed from the primary cancer. Furthermore, HER2 status flips from negative to positive in a few cases, affording new anti-​HER2 treatment options. Endocrine therapy In cancers shown to be ER positive, first-​line therapy is with endo- crine agents unless there is visceral crisis (bone marrow failure, lymphangitis carcinomatosis, or impending liver failure), evidence of rapidly progressing disease, or progression through multiple lines of endocrine therapy. Selection of drugs for endocrine therapy will depend on menopausal status and previous/​ongoing therapy. Those who have received tamoxifen in the adjuvant setting can be retreated with this agent if there is a long interval since completion of adjuvant therapy. Otherwise, initial endocrine therapy of meta- static breast cancer in premenopausal patients is with ovarian sup- pression together with an aromatase inhibitor. In postmenopausal patients, aromatase inhibitors are superior to tamoxifen and pre- ferred as first-​line therapy. Patients who received aromatase inhibitors in the adjuvant setting can be rechallenged if there is a disease-​free interval of at least one year. An alternative approach is the use of fulvestrant (Faslodex), whose mechanism of action is to promote degradation of the ER. The 500 mg dose of fulvestrant is clearly more active than the 250 mg previously used, and recent data reveal its superiority to aromatase inhibitors in the first-​line setting in metastatic breast cancer. Resistance to endocrine therapy is a major problem. Up to 50% of ER positive metastatic breast cancers exhibit de novo resistance to endocrine therapy, and acquired resistance is almost certain in patients whose disease is initially responsive. In patients progressing on first-​line non​steroidal aromatase inhibitors, the combination of exemestane and everolimus improves progression-​free survival and is currently recommended in routine clinical practice. Chemotherapy When chemotherapy is required, most treatment guidelines propose the use of single agent rather than combination regimens, because although the response rate may be higher with combination chemo- therapy there is increased toxicity without a significant survival benefit. There remains an absence of biomarkers to inform first-​line chemotherapy. This situation will undoubtedly change to a more genomically informed approach in the future, but at present, choice of agent continues to be tailored to the patient rather than to the mo- lecular genetic parameters of the cancer. In the ER-​positive, HER2-​negative metastatic breast cancer pa- tient population, many agents can be given in the metastatic setting, including the taxanes, capecitabine, vinorelbine, doxorubicin, and the microtubule growth inhibitor eribulin (the latter after at least two previous lines of chemotherapy). Selection and sequencing of agents is in part influenced by drugs given in the adjuvant setting.

508 SECTION 5  Principles of clinical oncology For example, patients given docetaxel in the adjuvant setting are suitable for consideration for weekly paclitaxel, and anthracyclines should be considered in naïve patients. As with adjuvant therapy, special considerations are applicable for HER2 positive and triple negative breast cancer. In HER-​2 posi- tive metastatic breast cancer, first-​line therapy with double HER2 blockade via trastuzumab and pertuzumab (combined initially with a taxane) has produced unprecedented improvements in out- comes as shown by data from the Cleopatra trial, and this is now standard of care. Trastuzumab emtansine (T-​DM1, Kadcyla) is now established as optimal second-​line treatment, relegating the com- bination of lapatinib and capecitabine to third-​line use. In triple negative breast cancer there is evidence that a platinum doublet may have efficacy, particularly in patients with germ-​line mutations in BRCA1 and BRAC2. Eribulin also shows increased efficacy in the triple negative breast cancer patient population compared to ER positive cases. Patients with bone metastases should receive bisphosphonates or denosumab. Future developments Management of metastatic breast cancer is rapidly progressing and several new agents show considerable promise. In ER-​positive disease progressing despite adjuvant aromatase inhibition, palbociclib (the first in class CDK4/​CDK6 inhibitor) given as first line with letrozole or fulvestrant shows a significant improvement in progression-​free survival and is sure to find a place in the man- agement of this patient population. Novel treatment approaches are emerging in triple negative breast cancer. For example, several anti-​ PD-​1 immunotherapeutic antibodies show promise. These include pembrolizumab, atezolizumab (in combination with Abraxane), and the bifunctional anti-​PD-​1 avelumab, all of which have activity in PD-​L1 positive triple negative breast cancer (see Chapter  5.4 for further discussion). There is also evidence that anti-​androgens may benefit some patients with triple negative breast cancer, both bicalutamide and enzalutamide having efficacy. FURTHER READING Cardoso F, et  al. (2017). 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC3). Ann Oncol, 28, 16–​33. Santa-​Maria CA, Gradishar WJ (2015). Changing treatment para- digms in metastatic breast cancer:  lessons learned. JAMA Oncol, 1(4), 528–​34. Sparano JA, et al. (2015). Prospective validation of a 21-​gene expres- sion assay in breast cancer. N Engl J Med, 373(21), 2005–​14.

SECTION 6 Old age medicine Section editor: Finbarr C. Martin 6.1 Ageing and clinical medicine   511 Claire Steves and Neil Pendleton 6.2 Frailty and sarcopenia   521 Andrew Clegg and Harnish Patel 6.3 Optimizing well-​being into old age   532 Steve Iliffe 6.4 Older people and urgent care   539 Simon Conroy and Jay Banerjee 6.5 Older people in hospital   548 Graham Ellis, Alasdair MacLullich, and Rowan Harwood 6.6 Supporting older peoples’ care in surgical
and oncological services   563 Jugdeep Dhesi and Judith Partridge 6.7 Drugs and prescribing in the older
patient   571 Miles Witham, Jacob George, and Denis O’Mahony 6.8 Falls, faints, and fragility fractures   579 Fiona Kearney and Tahir Masud 6.9 Bladder and bowels   589 Susie Orme and Danielle Harari 6.10 Neurodegenerative disorders in older people   601 John Hindle 6.11 Promotion of dignity in the life and death
of older patients   612 Eileen Burns and Claire Scampion