Crown Princess Mary Cancer Centre, Westmead Hospital, University of Sydney, New South Wales, Australia.
As cancer medicine moved into the 21st century, the long relationship between molecular biology and clinical care was finally consummated with the aid of biomathematics, and the era of the cancer subtype was born.1 The intuitive understanding that clinicians had – that not all breast cancers behaved the same – was given a molecular basis, and has subsequently informed our care and produced new tools with which to contain this disease.
In this edition of Cancer Forum, we aim to give a broad view of how our understanding of breast cancer as a disease of subtypes has changed the day-to-day management of our patients and shaped the new questions to be asked of future researchers.
We start by revisiting old favourites with new knowledge. Clara Lee and Howard Gurney take us through what has been a confusing journey in understanding tamoxifen metabolism.2 It was found quite late that tamoxifen is in fact a prodrug, with most of its activity due to the metabolite endoxifen, produced in part by an enzyme called CYP2D6. The efficiency with which individuals metabolise tamoxifen was subsequently shown to vary, partly due to genetic factors.
This variation initially led to calls in the US for genotyping to be carried out for those patients treated with tamoxifen, although this advice has since been withdrawn. Lee and Gurney show why CYP2D6 genotyping only partially explains variations in endoxifen level, the likely reason being that studies examining whether CYP2D6 genotypes have prognostic implications for women on tamoxifen have produced such divergent conclusions.
Next, Clara Lee assesses the clinical implications of aromatase inhibitor use as adjuvant treatment, focussing on the important issue of bone health.3 As our treatments improve, women with breast cancer are living longer and longer. In addition, accumulating evidence suggests that at least for some women with ER positive early breast cancer, being on endocrine therapy for as long as 10 or 15 years may be beneficial. Thus a focus on long term side-effects is appropriate and increasingly important. Although aromatase inhibitors can have an adverse effect on bone density, we now have the knowledge and technology to monitor and treat this problem, as outlined in this article.
Finally, I review what I have labelled ‘the enablers’ – new classes of drug that can impede the development of resistance to endocrine therapies.4 Again, as our knowledge of the molecular basis of pathological events increases, so too do the opportunities to intervene in these processes for the benefit of our patients. It has long been clear in the laboratory and in our clinics that ER positive cancers eventually become resistant to endocrine therapy. We now have drugs – mTOR inhibitors, PI3 kinase inhibitors and cyclin dependent kinase inhibitors – that have proven clinical benefits.
Bergin et al provide a comprehensive review of this most challenging of breast cancer subtypes.5 Drawing on knowledge from the laboratories of the Walter and Eliza Hall Institute and extending this to the results of recent clinical trials, the authors explain the heterogeneity of this subtype and the limitations as well as the successes in our attempts to understand and treat this disease.
The rationale behind the potential benefits of platin therapy is explained, as well as the benefits and limitations of the PARP inhibitors and the possibility that immunotherapies may become clinically relevant treatments for a subgroup of ‘triple negative’ cancers. This last suggestion is expanded upon in our final chapter.
Great strides have been made in our management of HER2 positive disease. Our understanding of the disease and the development of new drugs have meant that it has become almost a separate disease identity. Most of what we have learnt about treating breast cancer in the past has been done without knowledge of HER2 biology or the HER2 status of our patients.
Luckily trastuzumab, our first exemplar of targeted therapy after tamoxifen, has proved to be a spectacular success both in the adjuvant and metastatic setting. Clearly much more has to be learned, but already we have moved beyond trastuzumab as being the only drug that is effective for this breast cancer subtype.
First we discuss early HER2 positive breast cancer and ask whether adding new anti-HER2 drugs may improve outcomes. We then contemplate the question of whether in fact for some women with HER2 positive early breast cancer, we may be able to scale back some of the therapy to avoid toxicity while maintaining efficacy.6
Finally, Arlene Chan reviews the data from clinical trials that help us treat women with metastatic disease for whom trastuzumab is no longer effective.7 While we do have new and exciting drugs and have managed to extend survival for this group of women, Chan explains how we now need to explore ways of combating resistance to anti-HER2 therapies by targeting different molecules.
Brain metastases have always been a feared outcome for any cancer. However, as Claire Phillips explains, much has changed in the breast cancer world and the approach to the treatment of brain metastases needs to be adapted to disease subtype.8 The standard approach of treating everyone the same way is now inappropriate, and improvements in technology have seen great improvements in management.
Phillips argues that women with brain metastases are best managed with the help of a multidisciplinary approach, involving imaging, radiation oncology and neurosurgery input in order to individualise treatment.
And so perhaps to the least understood horizon. New immune checkpoint inhibitors have revolutionised the treatment of melanoma, and promising results are being obtained in non-small cell lung cancer, kidney cancer and other cancers. Will the same principles apply in breast cancer? Stephen Luen and Sherene Loi give us a comprehensive overview of the relevant data, much of it generated by Loi herself.9
Again, breast cancer subtype is important, although as Luen and Loi explain, responses to immunotherapies may be seen in all subtypes. The most promising data so far have been in triple negative disease and HER2 positive disease. While this is a very exciting development, early results are clearly not as dramatic as those seen in melanoma, and much is to be learned about the relationship between the immune system and breast cancer.
This issue of Cancer Forum aims to put into clinical context the understanding that breast cancer is in effect a collection of diseases requiring different approaches. Much has been learned in the first 15 years of this millennium and patient outcomes have improved, but our appetite for further knowledge and better treatments remains.