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Professor Mitch Dowsett, Endocrinology team

 

Translational Breast Cancer Research

The interests of the team are focused almost entirely on translational breast cancer research with an emphasis on endocrine aspects and biomarker analyses.

Our main goal is to identify the mechanisms by which oestrogens enhance the progression of oestrogen receptor positive breast cancer and to use that information for improved targeted therapy. We comprehensively characterise using established molecular techniques breast cancer biopsies from the presurgical setting both in the short-term “window of opportunity setting” and the therapeutic neoadjuvant setting. The techniques include whole genome expression arrays, arrayCGH, rtPCR, SNP assays and immunohistochemistry. While our focus has been on the profound effects of endocrine therapy on proliferation we are extending analyses to apoptosis, hypoxia, angiogenesis and other hallmarks of cancer. Our most important clinical resource is the 4,000 patient POETIC (PeriOperative Endocrine Therapy for Individualised Care) trial with all biological material from this study being analysed by our labs. Our cell signaling group is orientated towards mechanistic studies of candidate aberrations from these clinical studies and also conducts mechanistic studies of models of endocrine resistance that can then be studied further in our clinical materials.

We also conduct work to enhance the clinical use of biomarkers to predict benefit from treatment and long-term clinical outcome. As such we have established a 4 marker panel (oestrogen receptor, progesterone receptor, HER2, Ki67: IHC4) that predicts outcome as well as the far more expensive Oncotype Dx 21-gene panel. The work makes use of clinical trial material whenever possible because of the better quality of the tissue and clinical information than from ad hoc collections. The major sources of material come from the key ATAC and HERA registration trials for the aromatase inhibitor, anastrozole, and trastuzumab (Herceptin), respectively. We have extended our work in these studies to several pharmacogenetic projects that relate genetic polymorphisms to both toxicity and disease outcome.

Our endocrine expertise is an important asset for several collaborations with groups involved in the epidemiology of breast cancer, most notably now with the Breakthrough Generations study. Our highly sensitive oestrogen assays have also been applied for many years in the development of new endocrine agents (e.g. aromatase inhibitors). They continue to be a very important tool in such studies including currently for extending the use of the 17,20-lyase inhibitor abiraterone into breast cancer and also for studies of pharmacogenetics.

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