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Ian E. Smith, MD, FRCP, FRCPE
Professor of Cancer Medicine,
The Royal Marsden Hospital and Institute of Cancer Research
Head of the Breast Unit, The Royal Marsden Hospital
London, United Kingdom
Goal: Reducing recurrence of estrogen receptor (ER)-positive breast cancer by developing new strategies to prevent resistance to anti-estrogen drugs.
Impact: Drs. Smith and Dowsett have been studying the molecular makeup of tumors that do or do not respond to a class of anti-estrogen medications called aromatase inhibitors (AIs). By understanding what makes some tumors become resistant to these therapies, they can develop new treatment strategies to prevent or overcome resistance.
What’s next: The team will investigate whether the mutations observed following treatment with AIs are also are present in certain tumors at the time of diagnosis. In addition, Drs. Dowsett and Smith plan to study why some tumor cells continue to grow in some patients who have received AIs and undergone surgery.
ER-positive breast cancers, which require estrogen to grow, are the most commonly diagnosed type of breast cancer. Patients with ER-positive breast cancer typically respond well to anti-estrogen drugs, but some become resistant to them, which is often the cause of cancer recurrence and breast cancer deaths. Drs. Smith and Dowsett are pursuing ways to help predict which patients are most vulnerable to resistance so early action can be taken to prevent it.
Full Research Summary
Research area: Studying the underlying causes of endocrine resistance in order to reduce recurrence of estrogen receptor (ER)-positive breast cancer.
Impact: Breast cancers that require estrogen to grow respond well to endocrine therapy, which blocks the growth-promoting effects of estrogen. Unfortunately, some patients develop resistance to endocrine therapy, and the reasons why this occurs are unclear. Drs. Dowsett and Smith are analyzing early breast cancers from patients treated with aromatase inhibitors (AIs), a class of endocrine drugs, to identify treatment-induced changes in the tumor genome that lead to drug resistance. Their work could identify preventive strategies to overcome resistance, which could further reduce breast cancer mortality.
Current investigation: Drs. Smith and Dowsett are characterizing the molecular makeup of tumors that do and do not develop mutations in the estrogen receptor, called ESR1, when treated with aromatase inhibitors (AIs).
What they’ve learned so far: The doctors made a surprising discovery in women taking AIs for prevention of recurrence. In contrast to those who take an AI for treatment where ESR1 mutations commonly occur, women diagnosed with breast cancer while on an AI for prevention are less likely to have a breast cancer that harbor ESR1 mutations. This information is helping them to understand how and why such mutations develop.
The team has also discovered that mutations in ESR1 may be responsible for tumor cell growth during AI therapy. They hope this knowledge will enable them to develop new treatment combinations to avoid resistance to an AI long before this resistance emerges clinically.
What’s next: Drs. Smith and Dowsett will embark on two investigations they hope will identify which tumors are more likely to develop resistance to endocrine therapies, when the patient is diagnosed.
In one study, they will have patients take an AI for two weeks before their surgery—an approach that, in most cases, leads to profound or complete suppression of tumor growth. However, some tumors have cells that continue to despite this treatment. Drs. Dowsett and Smith isolate the cells that continue to grow and identify how they differ from the cells did not.
Their second study relates to the finding that mutations in ESR1 develop in 25-35 percent of patients with advanced breast cancer during their treatment with an AI. Drs. Smith and Dowsett suspect this is most likely to occur in tumors that are most dependent on estrogen for their growth at diagnosis and will test their theory using collected pairs of biopsies taken at diagnosis and at resistance to an AI.
Ian E. Smith, MD, FRCP, FRCPE, is Professor of Cancer Medicine at The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom. He is also Head of the Breast Unit at The Royal Marsden Hospital.
His initial medical training was in Edinburgh and he came to the Royal Marsden, London, for specialist training in cancer medicine. He spent some time in Boston at the Dana-Farber Cancer Institute, Harvard. His principal clinical research interests have been in breast cancer, lung cancer, and in new drug development. He was involved in the early clinical development of several anticancer drugs that have subsequently proved effective in the clinic, including carboplatin and letrozole. In the last decade he has become increasingly involved in neoadjuvant therapies as a research approach towards individualizing treatment for breast cancer. He is currently Chief Investigator or UK Principal Investigator for several international multicenter breast cancer trials involving in particular targeted therapies and aromatase inhibitors. He publishes and lectures extensively. He was awarded the Susan G Komen for the Cure Brinker Award for Scientific Distinction at the 2009 San Antonio International Breast Cancer Conference.
Professor Smith is Co –Chairman of the ASCO Clinical Guidelines Group for Chemotherapy in Metastatic Breast Cancer, and has just been appointed the first Chair of the newly formed UK Breast Cancer Clinical Reference Group. He is a patron of Breast Cancer Care, the largest UK breast charity for patient support.