The role of the selective oestrogen receptor modulator, tamoxifen, is well established in the treatment of hormone sensitive breast cancer. The metabolism of tamoxifen to its active metabolites is however complex. Despite much research, a conclusive stance on the clinical implications of CYP2D6, active metabolites including endoxifen in efficacy and toxicity, is yet to be reached. Herein we examine the literature to clarify the connections between tamoxifen, CYP2D6 and endoxifen with resultant clinical recommendations.
In postmenopausal women, and premenopausal women treated concomitantly with ovarian suppression, aromatase inhibitors are a standard of care in the adjuvant treatment of hormone sensitive breast cancer. Dosed daily for up to 10 years, these drugs are not without significant toxicity. Given such protracted duration of treatment and that the majority of women treated in this setting have very favourable disease free and overall survival from their early stage breast cancer, long-term toxicity is a particular concern. The most concerning long-term toxicity is the deleterious effect of aromatase inhibitors on bone density. Accelerated bone loss due to aromatase inhibitors confers increased fracture risk and thereby significant morbidity. Therefore it is important to investigate and monitor bone health prior to commencement of and during aromatase inihibitor treatment, and ensure appropriate measures to optimize bone health are instituted. Recommendations from the summary of the literature to date, relevant to the Australian setting are outlined in this paper.
For many years, tamoxifen and aromatase inhibitors have been the mainstay of treatment for ER positive breast cancer, although it has been apparent that resistance to these drugs is a limiting factor. We are now at the beginning of a new era, as drugs that block the development of endocrine resistance are becoming available. Pre-clinical research has given us an understanding of some of the molecular mechanisms of endocrine resistance, identifying new targets for drug development. Chief among these are the PI3 kinase/AKT pathway and the cell cycle control mechanism governed by cyclins and cyclin dependent kinases (CDKs). We are now in the process of integrating mTOR inhibitors, PI3kinas inhibitors and CDK 4/6 inhibitors into clinical practice on the back of clinical trial results that show they can prolong the effects of endocrine agents.
Triple negative breast cancer (TNBC) is a heterogeneous disease. While simply defined by immunohistochemical parameters, TNBC actually encompasses a raft of tumour subtypes with variable prognoses and treatment sensitivities. Systemic treatment decisions for patients with TNBC are becoming increasingly complex. In many cases, decision-making remains hampered by the current lack of predictive and prognostic biomarkers, and as such, chemotherapy remains the mainstay of systemic treatment options. Sequential anthracycline and taxane regimens, delivered as either neoadjuvant or adjuvant therapy, are widely accepted as the ‘standard of care’ in early stage disease. TNBC in BRCA1 and BRCA2 mutation carriers are more likely to be sensitive to platinum-based chemotherapy and PARP inhibitors. The role for these approaches is currently under investigation in large clinical trails for this population. As with certain other solid tumours, harnessing the immune system to tackle this challenging breast cancer subtype is showing some promise and the role of immunotherapy in TNBC is currently being investigated in large clinical trials. Data on safety and efficacy are eagerly awaited but will need to take into account the heterogeneous nature of this disease.
Thanks to careful, persistent research, the outlook for women diagnosed with early HER2 positive breast cancer has improved markedly over the last two decades. The evolution of HER2-targeted treatments has been a game changer, and the pathology report that reads “HER2 amplified” is not as dreaded as it once was. Clinical trials have proven the safety and effectiveness of adjuvant trastuzumab, and longer term follow-up has been reassuring. However, now is a good time to reflect on these achievements and ask ourselves two questions: how can we do better, and can some patients get by with less treatment?
For women with metastatic HER2 positive breast cancer, the introduction of trastuzumab into routine practice was transformative. More recently, the addition of pertuzumab has further improved the outlook. However in almost all cases, the disease unfortunately progresses. Much research has gone into what to do next. We now have evidence to support a number of strategies, with the underlying understanding that HER2 blockade should be continued for as long as possible. Historically, lapatinib was the first anti-HER2 agent to show activity after relapse on trastuzumab. Subsequently the effectiveness of T-DM1 (Kadcyla) has been demonstrated, as has the use of alternating chemotherapy agents with trastuzumab. Research is now focused on understanding and combating the mechanisms of resistance to anti-HER2 agents that inevitably develop. Promising data suggest that mTOR inhibitors, PI3 kinase inhibitors and immune-activating therapies may be helpful.
In the past, brain metastases were essentially all treated in the same way, and heralded a poor prognosis. Improvements in ways of delivering radiotherapy as well as in anaesthetic and neurosurgical techniques and in imaging mean that much more can be achieved. A knowledge of what subtype of breast cancer is being treated is now critical to take into account, especially in HER2 positive disease, where an expanding array of anti-HER2 drugs means that extra-cranial disease may be controlled for many years. Ideally, brain metastases should be managed in a multidisciplinary setting, so that imaging, radiation oncology and neurosurgery input can be combined.
Great hopes have been accorded to the potential of immunotherapy to exploit host anti-tumour immunity and deliver improved survival outcomes. Impressive results in cancers known to be immunogenic have led to a plethora of immunotherapy trials in several cancer types, including breast cancer. Descriptions of tumour-infiltrating lymphocytes in early breast cancer have unravelled the landscape of immunogenicity across the breast cancer subtypes, and provide rationale for investigation into immunotherapeutic approaches. Subsequently, numerous clinical trials have been launched, predominantly with checkpoint blockade. While triple negative and HER2-positive breast cancers appear to be more immunogenic than ER-positive/HER-2 negative breast cancers, responses to checkpoint blockade are still seen in this subtype, suggesting that subtype alone may not be a sufficient predictor of response to immunotherapies. Moreover, tumour-intrinsic contributors towards immunogenicity and immune-evasion are increasingly being explored, as is the ability of conventional therapies to modulate the immune microenvironment. Reports from early phase trials in breast cancer show that while immunotherapeutic approaches may not be suitable for all breast cancer patients, there are promising signs for a potential role of immunotherapy in the treatment of selected breast cancers.