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Mitch Dowsett, FMedSci, PhD
Head, Department of Biochemistry and Centre for Molecular Pathology
Professor of Biochemical Endocrinology,
Breakthrough Research Centre
Professor of Translational Research
The Royal Marsden Hospital
Institute of Cancer Research
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. Dowsett and Smith 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 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. Dowsett and Smith 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. Dowsett and Smith are characterizing the molecular makeup of tumors that do and do not develop mutations in the estrogen receptor gene, called ESR1, when treated with aromatase inhibitors.
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. Dowsett and Smith will embark on two investigations they hope will identify which tumors are more likely to develop resistance to endocrine therapies at the time 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 suppression of tumor growth. Based on their earlier finding, the know that some tumor cells will continue to grow despite this treatment. They will isolate the cells that continue to grow and identify how they differ from the cells do 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. Dowsett and Smith 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 when AI resistance occurs.
Professor Mitch Dowsett, FMedSci, PhD, is Head of the Academic Department of Biochemistry and Head of the Centre for Molecular Pathology at the Royal Marsden Hospital; Professor of Biochemical Endocrinology at the Institute of Cancer Research; and Professor of Translational Research in the Breakthrough Breast Cancer Centre, London.
Professor Dowsett’s research focuses almost exclusively on breast cancer and predominantly on hormonal aspects of the disease and biomarkers of response with a research team of about 24 investigators. He was closely involved with the clinical development of aromatase inhibitors and in the creation of national and international standards for steroid receptor and HER2 analysis (ASCO/CAP Guidelines Steering Committees). He co-chairs the International Working Party for Ki67 in Breast Cancer. He was the founding chairman of the UK NCRI Translational Research (subsequently Biomarker and Imaging) Clinical Study Group. In 2004 he founded and continues to chair the Aromatase Inhibitor Overview Group.
He has authored nearly 600 published papers related to breast cancer, and given numerous named lectures including the 2007 William L McGuire Memorial Lecture. He recently rotated off the Executive Board of the Breast International Group (BIG) after seven years, and sits on the Executive/Steering Committees of several clinical trials. He has been a NCRI Senior Clinical Investigator since 2009. In 2013 he was appointed as a Fellow of the Academy of Medical Sciences.