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. Over the same period, molecular markers based on patterns of gene expression in individual tumors have been explored to predict the likelihood of response to tamoxifen. The growing importance of AIs has prompted the researchers to do the same for AIs. The aim of their work is to enable clinicians to identify more accurately which patients are most likely to benefit from, or conversely to be resistant to, AIs.

Dr. Dowsett and his co-investigator Dr. Ian Smith are using a large tissue bank of frozen tumor and standard paraffin embedded tumor specimens obtained from patients with both early and advanced breast cancer to do this. Data on treatment response is available for 136 patients with frozen tumors, 58 of whom had not received medical treatment before surgery and form the focus of their initial studies. The researchers have now assessed the expression of about 20,000 genes in these samples as RNA and have identified two candidate molecular pathways of interest that they will now evaluate in other sample sets.

They have created tissue microarrays (TMAs) from 200 of a total of 400 samples of fixed tissue from AI-treated patients. This involves taking very small cores of tissue from each tumor and placing these in a single block that can then be cut into thin sections for studying the activity of the candidate molecular pathways. In addition the scientists are investigating these same pathways in patients who have been treated with an AI prior to surgery.

Mid-Year Progress Report:
Drs. Dowsett and Smith report that they have now assessed the expression of about 20,000 genes in a series of patients treated with an AI in the advanced breast cancer setting, and results were obtained on 58 tumours. 183 genes and 11 biological pathways were expressed differently between responders and non-responders. Of particular interest, the androgen-estrogen metabolism pathway was the most different and this difference was explained largely by the different expression of a gene that converts the low-activity estrogen, estrone to the high-activity estrogen, estradiol. The researchers are now determining whether this observation can be confirmed in a larger series of fixed samples prior to assessing whether this may form a viable target for treatment with or without AI.

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.