Mitch Dowsett, PhD, BSc

Over the last few years a group of hormone-blocking agents, the aromatase inhibitors (AIs: Anastrozole, Letrozole and Exemestane), have increasingly replaced Tamoxifen as first line hormone treatment of choice for postmenopausal women with early breast cancer. The overall aim of the work of Drs. Dowsett and Smith is to enable clinicians to identify more accurately which patients are most likely to benefit from, or conversely to be resistant to, AIs and to better understand the biology that underpins this behaviour.

Estradiol (E2) is the most important estrogen, and overall the most important stimulant of breast cancer but there has been a major controversy over the most significant source of its production. The researchers’ data strongly suggest that the E2 in tumors is derived predominantly by uptake from the plasma or surrounding tissues with enzymes in the tumor playing an important role in maintaining it. Their separate observation that one of these enzymes (HSD17B7) correlates with time-to-treatment failure on an aromatase inhibitor in advanced breast cancer indicates the probable clinical significance of these results.

The majority of breast carcinomas are estrogen receptor positive (ER+). Virtually all patients with ER+ tumors receive some form of treatment designed to either suppress or block the growth stimulation of these tumors by estrogens. It is known that not all such tumors respond to this treatment but the means of predicting this are poorly developed. In postmenopausal women Drs. Dowsett and Smith have developed and are testing a strategy in which recently diagnosed patients receive an aromatase inhibitor to stop estrogen stimulation for two weeks before surgery and they then measure the effect of this on markers of tumor cell proliferation and of other estrogen-dependent processes. In that way the researchers expect to be able to identify more accurately those patients who will or will not benefit from long-term treatment.

In premenopausal women the scientists believe, and aim to test in this project, that the changes in hormone levels during the menstrual cycle may influence proliferation and other estrogen-regulated activity in those tumors that would respond to hormonal treatment but not those that would not respond. To determine this they will collect and analyze small samples of tumor tissue from premenopausal breast cancer patients at diagnosis and then at surgery which in the UK generally occurs about two weeks later. They will also ask the patients details about their menstrual cycle and collect blood samples to measure the hormonal levels that may influence the tumor. They will assess the tumor levels of many thousands of genes and will determine which of these provide the most accurate guide to response. If this work is successful it could have a substantial impact on the selection of patients for treatment while requiring little or no change to clinical practice at diagnosis.

Bio:
Professor Mitchell Dowsett is Professor of Biochemical Endocrinology, Head of the Academic Department of Biochemistry and Head of Breast Cancer Translational Research at the Royal Marsden Hospital and the Institute of Cancer Research.

His research interests are predominantly in endocrine aspects of breast cancer and in biomarker evaluation and application. He has a laboratory research team of approximately 25, all of whom are focused on translational aspects of breast cancer research.

Professor Dowsett is the founding chairman of the UK National Cancer Research Institute Translational Clinical Study Group, which aims to enhance Translational Research across the countries clinical trial portfolio in cancer. He is a member of the Steering and Executive Committees of several prominent international breast cancer trials including ATAC and HERA for which he is chairman of the translational research committees. Membership of a number of peer-review committees includes the Scientific Committees of Cancer Research Ireland and the Danish Cancer Society.

He is the author of over 430 professional papers.