Ian E. Smith, MD, FRCP, FRCPE

2009-2010 BCRF Project:
(made possible with generous support from The Housewares Charity Foundation)
Co-Investigator: Mitch Dowsett, PhD, BSc, Royal Marsden Hospital and Institute of Cancer Research, London

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. Smith and Dowsett 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. Smith and Dowsett 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.

Mid-Year Progress Report:
Two activities are funded by the grant for 2009/10. Firstly, Drs. Smith and Dowsett are bringing together breast cancer tissue samples from the Royal Marsden Hospital pathology archives on 180 premenopausal patients that had menstrual cycle status recorded at the time of surgery. The researchers wish to establish whether there are systematic changes in the biology of the tumors in response to the changing hormones through the cycle. If this is the case those changes are likely to only occur in tumors that are dependent on those hormones for their growth. This should allow the development of a test that could select patients most likely to respond to treatment. Secondly, in preliminary studies the scientists have identified a variant gene that appears to be strongly related to the benefit derived from tamoxifen in the Royal Marsden Hospital Tamoxifen Prevention Trial. They are part way through analysis of two further sets of samples to confirm both its importance and the likely biological basis for the relationship.

Bio:
Ian Smith is Professor of Cancer Medicine at The Royal Marsden Hospital and Institute of Cancer Research, London, UK He is also Head of the Breast Unit at The Royal Marsden and was Medical Director there from 2000 to 2003

His initial medical training was in Edinburgh and then he came to the Royal Marsden, London for specialist training in cancer medicine. He also spent some time in Boston at the Dana Farber Cancer Institute and Harvard University. Over the years his principal clinical research interests have been in breast cancer, lung cancer and in new drug development. He has been involved in the early clinical development of several anti-cancer drugs which have subsequently proved effective in the clinic, including carboplatin, letrozole, mitozantrone and more recently Herceptin. In the last decade he has become increasingly involved in neoadjuvant therapies and translational research. He is currently UK Principal Investigator for several international multicentre trials including HERA (Herceptin), BIG1-98 (Letrozole) and ALTTO (Lapatinib), and he is international co-chair of the FACE trial (letrozole v anastrozole)

Professor Smith is Chairman of the newly formed UK Breast Trials Intergroup and Chairman of the British Breast Group. He has been past Chairman of several national professional bodies including the Association of Cancer Physicians, the Royal College of Physicians Specialist Advisory Committee for Medical Oncology, and the NCRI Lung Cancer Clinical Studies Group. He is currently a member of the NCRI Breast Cancer Study Group and is a member of numerous international cancer societies and pharmaceutical advisory boards. He is currently on the Scientific Review Committee for the San Antonio Breast Cancer Symposium and has published around 300 peer reviewed scientific papers, and lectures widely around the world.