Professor of Cancer Medicine
Head of the Breast Unit
The Royal Marsden Hospital
Institute of Cancer Research
London, United Kingdom
Co-Investigator: Mitch Dowsett, PhD, BSc, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom
Drs. Smith and Dowsett demonstrated in a retrospective study that there are significant differences in the expression of four estrogen-regulated genes (ERG) during the menstrual cycle. This could affect the interpretation of molecular profiling tests in premenopausal women and have the potential to be used as a test of endocrine responsiveness. This team recently extended their gene expression assays on a larger set of ERGs using the nCounter Analysis System (Nanostring) in the same retrospective samples to determine whether (1) other ERGs and/or proliferation genes showed more dynamic differences across the menstrual cycle and (2) if these gene expression differences occurred at a different periodicity. Preliminary analysis of this data from this new technology has confirmed the team’s previous findings. Detailed statistical analyses are underway to determine the relevance of the other genes and to refine the timing of this team’s pre-defined “windows” of the menstrual cycle. Drs. Dowsett and Smith will test the validity their findings from the retrospective study in both samples being collected from their own UK-based prospective study (MenCER) and in samples received from their collaboration with the study led by fellow BCRF grantee Dr. Richard Love on a Vietnamese study of the impact of oophorectomy (removal of the ovaries) prior to surgery for breast cancer. In a secondary project, Drs. Dowsett and Smith will examine the potential use of RNA extracts from lymph nodes for assessing ER and/or HER2 status where no invasive primary tissue is available; collection of samples for this study is now complete and gene expression analyses are commencing.
Previously Drs. Dowsett and Smith noted substantial differences in the expression of estrogen-regulated genes (ERGs) and proliferation genes in ER+ breast cancer through the menstrual cycle. This variability may affect the interpretation of gene expression profiles incorporating ERGs and potentially be useful as a test of endocrine responsiveness. Further analysis of their data has shown that the expression of a key progesterone effector, RANKL, also differs during the menstrual cycle and is negatively correlated to the expression of the proliferation-associated genes. In order to validate the above work prospectively the researchers are collecting paired tumor tissue and blood samples in premenopausal patients at different points of the menstrual cycle in two studies (i) their own UK-based study (now extended to 10 centres) and (ii) a trial performed in collaboration with North American and Vietnamese colleagues. Both of these studies are now close to completion (the former in April, the latter in February 2014). Analysis of these prospectively collected samples will enable the researchers to confirm (or not) the possibility of using changes in gene expression through the menstrual cycle as a test of endocrine responsiveness.
In a secondary project, they have demonstrated that it is possible to measure gene expression levels of ESR1 and HER2 in the residual lymph node homogenates that remain after sentinel lymph node analysis and show that these could be used to predict HER2 positivity of the primary tumor.
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 multi-center 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.