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Metastatic breast cancer

Breast cancer is the most common life-threatening cancer among women in Ireland, with an annual incidence of 123/100,000 of the population and a median age at diagnosis of 59 years. At the time of diagnosis, approximately 7 per cent of patients will have metastatic disease but it is estimated that between 20-to-30 per cent of those with localised disease will develop metastatic disease in their lifetime. While metastatic disease is ultimately fatal for the majority of patients, significant advances in the management of the disease have improved quality and duration of life for many patients.

Hormone receptor-positive breast cancer

Just over 80 per cent of all breast cancers diagnosed in Ireland between 2011 and 2013 were oestrogen-receptor (ER)-positive, with a progesterone-receptor (PR)-positivity rate of 51 per cent. In the adjuvant setting, such patients receive anti-oestrogen therapy in the form of selective oestrogen-receptor- modulators (SERMs) (ie, tamoxifen) or aromatase inhibitors (AI) (eg, anastrozole or letrozole), depending upon menopausal status.

In the metastatic setting, those patients not requiring urgent cytotoxic therapy (eg, in the absence of a visceral crisis), will typically receive endocrine therapy if their tumours express hormone receptors. In those patients still on adjuvant treatment, this can include a switch from SERM to AI, a switch between AIs or alternatively, a drug such as fulvestrant (an oestrogen receptor-down-regulator). In those with de novo metastatic disease or metastatic disease following completion of adjuvant therapy, treatment with the above agents can be considered. However, it is recognised that resistance to hormonal therapy represents a significant challenge in the treatment of such patients, with several mechanisms of resistance seen in pre-clinical and translational studies. Among these are loss of the oestrogen receptor (which is rare); alterations of the oestrogen-receptor through the oestrogen-receptor gene (ESR mutations); activation of other growth factors; alteration of the tumour microenvironment; and alteration in cell-signalling-molecules.

Alteration of cell-signalling molecules causes an overexpression of MYC and cyclins D1 and E1. Cyclin-dependent kinases (CDK) are subsequently recruited, bypassing the negative inhibitory effects of endocrine blockade. Inhibitors of CDK have thus been investigated as a therapeutic strategy, with recent approvals for palbociclib. Other CDK inhibitors, eg, ribociclib, are currently in various stages of development.

Palbociclib is an orally-available CDK4/6 inhibitor, which potently inhibits cell proliferation. It has been studied in the PALOMA trials, in both first and later lines of treatment, in which it demonstrated a five-to-10-month progression-free survival benefit over the comparator arm. It is given on a daily basis for 21 days of a 28-day cycle. The associated toxicity profile is modest and includes a risk of myelosuppression, with 65 per cent of patients developing grade 3 or 4 neutropaenia on the PALOMA-3 trial. However, overall it is a well-tolerated drug with only 4 per cent of patients discontinuing treatment due to toxicity. It is licensed and available on a named-patient basis in Ireland. Adjuvant trials are currently accruing. Ribociclib is another CDK-inhibitor, recently approved by the Food and Drug Administration in the US for first-line treatment based upon an interim analysis of a large phase 3 study, where it demonstrated an increase in progression-free survival. Other agents in development include dinaciclib and alvocidib.

Her2-positive breast cancer

Approximately 15 per cent of breast cancers diagnosed in Ireland between 2011 and 2013 were Her2-positive. Her2 is a receptor-tyrosine-protein kinase, a member of the epidermal growth-factor-receptor family. It is normally present on the cell membrane but in patients with Her2-positive disease, the gene is amplified and the protein is, therefore, over-expressed. Prior to the development of targeted treatment, Her2-positive breast cancer was associated with increased disease recurrence and poor prognosis. However, with the development of trastuzumab, a monoclonal antibody, in the late 1990s, an improvement in both these factors was seen. As with hormone receptor-positive disease, progression on targeted therapy or resistance to treatment exists or develops over time.

Several new Her2-targeting medications have been developed over the past decade. Lapatinib is an oral  small molecular-dual-kinase inhibitor, licensed for use in patients with Her2-positive breast cancer in combination with capecitabine, a cytotoxic oral chemotherapy. Its license is based on use in patients with Her2-positive disease who have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab. It was the first Her2-targeting medication to be available for clinical use since the introduction of trastuzumab. Associated toxicities include diarrhoea and rash.

Pertuzumab is a monoclonal antibody targeting the heterodimerisation of the  receptor. It is licensed in two different settings: In the neoadjuvant setting for patients with Her2-positive disease; and as first-line treatment in those patients with metastatic, Her2-positive disease. It is usually given in combination with trastuzumab and docetaxel, based upon the CLEOPATRA study. In this study, it demonstrated a 15.7 month overall survival benefit when compared to docetaxel and trastuzumab alone in those patients with metastatic Her2-positive disease.

Trastuzumab emtansine (TDM1) is the newest available agent. It is an antibody drug conjugate of the monoclonal antibody trastuzumab linked to the cytotoxic agent emtansine (DM1). Trastuzumab halts the growth of the Her2-positive cancer cells when it binds to the  receptor. The DM1 component enters the cells, causing cell death by binding to tubulin. As the drug is targeted, the DM1 is only delivered to the cancer cells, thus allowing the use of an effective cytotoxic treatment that would otherwise cause significant toxicity. Based upon the positive phase 3 trials EMILIA and TH3RESA, it is licensed for use in patients with HER2-positive metastatic disease. In these studies, TDM1 demonstrated a five-month overall survival benefit in one (EMILIA) and a trend towards improved overall survival in the other. It has demonstrated good tolerability, with most grade 3 or 4 toxicities in clinical trials being laboratory abnormalities (elevated transaminases and thrombocytopaenia).

Triple-negative breast cancer

Triple-negative breast cancer (TNBC) is defined by a lack of oestrogen and progesterone-receptor expression, in conjunction with an absence of  overexpression and/or amplification. It represents approximately 20 per cent worldwide of all breast cancers, with regional variations being less prevalent in Ireland (15 per cent) but more common in West Africa. The absence of such hormone receptors, or  expression, precludes endocrine treatment or treatment with Her2-targeting agents, meaning that cytotoxic chemotherapy had been the only systemic treatment option in metastatic disease. Responses to cytotoxic therapy occur but relapse is frequent, and so further investigation into novel agents is required.

Immunotherapy is a burgeoning area in oncology, with approvals in many advanced malignancies for drugs targeting CTLA4 (cytotoxic T-lymphocyte-associated antigen 4) or the PD-1/PD-L1 (programmed cell death protein-1 and its ligand) interaction. These pathways play a critical role in regulating the immune response to tumours. Tumour cells express PD-L1, which acts to limit tumour cell recognition (and thus activation of the immune system to target the tumour). PD-L1 is known to be expressed in TNBC and there is some evidence that PD-L1 expression may correlate with treatment response. Hence, immunotherapy offers a promising potential treatment option in TNBC.

Pembrolizumab is one such immunotherapy. It is a humanised anti PD-1 antibody, already approved in other malignancies (ie, melanoma, non-small cell lung cancer). Several trials are currently in progress evaluating its role in combination with traditional cytotoxic chemotherapy, radiation and other novel agents. To date, the KEYNOTE-012 study is the only published trial of pembrolizumab in this patient population. Expression of PD-L1 greater than 1 per cent in tumour cells or stroma was an entry requirement. In total, 32 patients were treated with pembrolizumab, with an overall response rate of 18.5 per cent and an as-yet-not-reached median duration of response (15.0 to ≥47.3 weeks). While the data are incomplete, they provide encouraging evidence for further investigation of immunotherapy in TNBC and we await results from several ongoing trials. The I-SPY 2 study, presented recently at the American Society of Clinical Oncology Annual Meeting 2017, combined pembrolizumab with standard chemotherapy. It demonstrated an increase in pathologic complete response rate at time of surgical resection in patients with TNBC by at least 40 per cent. This encouraging data offers the potential for a specific treatment for TNBC.

Conclusion

Traditionally thought of as a homogenous, single disease entity, the landscape of breast cancer research and care has developed into a complex area, with significant subtleties emerging. While hormone receptor status has long been assessed, the incorporation of other histological markers, such as the Ki67 score, has allowed more specific classification. Treatment options, however, remain broadly grouped into hormone receptor-positive cancers, Her2-positive cancers and triple- negative cancers.

For most patients diagnosed with breast cancer, surgery in combination with adjuvant therapies is sufficient to prevent disease relapse. However, in the proportion of patients who develop metastatic disease, or indeed, those who present with advanced disease, further advances are necessary. The advent of therapies to resensitise the tumour cell to endocrine therapy has added another line of treatment for these patients. This treatment is delivered in the outpatient setting, allowing maximum time with loved ones and augmenting quality-of-life.

Treatment of patients with HER2-positive disease was revolutionised with the introduction of trastuzumab in the late ’90s/early 2000s. However, until the introduction of lapatinib, no other targeted therapies existed. Since then, several novel agents have been developed, offering disease-control options for these patients.

TNBC remains an underserved subgroup of breast cancers in current treatment paradigms. The era of immuno-oncology may yet provide the long-awaited improvements with a well-tolerated treatment for these patients.

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