By: Mitch Dowsett
Quest post by Mitch Dowsett, Ph.D., F. Med. Sci., Head of the Academic Department of Biochemistry at the Royal Marsden Hospital, Professor of Biochemical Endocrinology, and Head of the Center for Molecular Pathology at the Royal Marsden Hospital and Institute of Cancer Research in London, England
As a teenager, I was fascinated by the genetic code, and I still find it astonishing that the immense complexity of living things is derived through a chemical code based on just four small molecules. Learning about the genetic code in my mid-teens established my interest in pursuing a career in life sciences. As a result of this interest. I earned a Bachelor of Science degree in Zoology (Imperial College, London), taking as many biochemical and genetic courses as possible, and went on to undertake a Ph.D. in health research.
I’ve always wanted there to be a direct clinical connection to my research, hoping that it will have an impact on patient care. As time has gone on I have tried to focus increasingly on issues that are rated by clinicians as having particularly high importance for the management of their patients.
I began studying breast cancer during my postgraduate fellowship at the Institute of Cancer Research (ICR), where I studied the very debilitating bone breakdown caused by breast cancer metastases. It was here, nearly 40 years ago, that I started a clinical research collaboration with Professor Trevor Powles and colleagues at the Royal Marsden Hospital.
In 1979, after three years’ training in clinical biochemistry, I won a Senior Biochemist post to undertake steroid hormone analyses at Chelsea Hospital for Women (CHW). This career-defining piece of good fortune allowed me to begin working with an extraordinary team of medical oncologists: Adrian Harris, Charles Coombes, Trevor Powles (again) and Ian Smith, the last of these being my very close collaborator since that time. Years later, Powles and Smith became the UK’s only other Brinker Award winners.
We set up steroid assays at CHW to study the activity of a complex drug called aminoglutethimide which was known to be effective in breast cancer We demonstrated that this effectiveness was because it inhibited aromatase, an enzyme responsible for a key step in synthesizing estrogens, thus validating this enzyme as a therapeutic target. Our CHW steroid assays were critical for the clinical development of the first specific aromatase inhibitor (AI) used in breast cancer, 4-hydroxyandrostenedione, undertaken with my colleagues Charles Coombes and Angela Brodie, and later anastrozole and letrozole, third-generation AIs.
In 1988, upon moving to the Royal Marsden Hospital, Per Eystein Lonning and I developed an assay to measure whole-body aromatization that became a benchmark for pharmacological comparisons.
In the 1990s, good fortune featured again when Professor Michael Baum joined the Royal Marsden. Together we initiated the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial that established aromatase inhibition as more effective adjuvant endocrine treatment for postmenopausal women than tamoxifen.
I have been privileged to lead the AI Overview Group, a global collaboration that has shown that AIs lead to improvements in survival from breast cancer beyond the substantial gains achieved with tamoxifen.
More recently, in collaboration with Jack Cuzick and many others, we studied tumor samples from ATAC to identify markers that could help identify patients with ER-positive primary breast cancer who could avoid chemotherapy, and in doing so created a simple but effective new index, IHC4, that can help guide decisions about breast cancer treatment.
It astonished me that the ATAC trial needed to recruit >9,000 women with breast cancer to find if an AI was better than tamoxifen. I was therefore very keen to collaborate with Ian Smith on presurgical studies which validated that early changes in the proliferation marker Ki67 could be used to compare the relative efficacy of endocrine agents, a finding which has allowed for more rapid evaluation of new drugs.
We also found that Ki67 levels in the tumor during AI treatment might help predict the likelihood of a patient’s breast cancer recurring. Based on this finding, we created the POETIC (PeriOperative Endocrine Treatment for Individualised Care) trial which enrolled nearly 4,500 patients at over 120 UK hospitals. I believe the trial provides the best opportunity to understand the extraordinarily complex issue of resistance to endocrine treatment and how to select treatments to reverse that resistance, and ultimately could improve the personalized management of ER-positive breast cancer.
Mine is a story of a patient-focused scientific curiosity, good fortune and great collaborations. So many others have contributed to my career and my receiving the 2014 Brinker Award for Clinical Research that this blog could easily have been exhausted by simply listing them. I am grateful for the support of many funders over the years, and would also like to thank the countless patients who have trusted and joined with us in helping to reduce the toll from breast cancer.
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