Beth Israel Deaconess Medical Center Boston, Massachusetts
Director, Cancer Risk and Prevention Program Beth Israel Deaconess Medical Center Professor of Medicine, Harvard Medical School
Understanding the molecular nature of treatment response and resistance in breast cancer.
The BRCA1 and BRCA2 genes are the most affected genes in hereditary breast and ovarian cancers. Normally, BRCA1 and BRCA2 function to ensure the proper repair of DNA damage, but mutations in these genes lead to rapid accumulation of DNA errors, which leads to cancer. However, this defect also makes BRCA-mutated cells vulnerable to treatments that cause DNA damage. Cisplatin, a platinum-containing chemotherapy agent not typically used to treat breast cancer, has demonstrated good activity in BRCA mutation carriers with breast cancer and in some women with triple-negative breast cancer (TNBC). Recently, Drs. Tung and Schnitt completed the INFORM trial, which showed that while cisplatin is an active agent in BRCA mutation carriers with breast cancer, it was not more effective than the standard chemotherapy regimen. Drs. Tung and Schnitt are evaluating why some breast cancers respond to chemotherapy, including platinum chemotherapy, and other breast cancers do not.
Using tumor samples from the INFORM trial, the research team applied artificial intelligence to analyze tumor characteristics before treatment. They have found that among tumors with low levels of immune cell activity, those with more uniform immune cells responded significantly better to chemotherapy. In fact, these tumors responded as well as those with high levels of immune activity, offering a new way to identify patients who may benefit from treatment even when traditional indicators suggest otherwise. In parallel, the team analyzed genetic material from the tumors and blood samples. Tumors that had acquired more mutations were found to be more resistant to chemotherapy, while two blood-based markers were associated with improved response to the chemotherapy drug cisplatin.
In the upcoming year, Drs. Tung and Schnitt will further compare tumor tissue before and after chemotherapy to identify changes that allow some cancer cells to survive. This is especially important for women with inherited BRCA1 or BRCA2 mutations, since these mutations usually make tumors more sensitive to chemotherapy. However, sometimes the tumor can acquire additional genetic changes that restore the function of the BRCA gene, essentially masking the inherited mutation in the cancer cells. This makes it more challenging to treat, since it may become resistant to PARP inhibitors, a type of drug often used in patients with BRCA mutations. Learning how tumors develop this type of resistance could guide better treatment decisions in the future.
Nadine Tung, MD is the Director of the Cancer Genetics and Prevention Program at Beth Israel Deaconess Medical Center (BIDMC), which she established in 1997 to evaluate patients and families with hereditary cancer syndromes. She is also a breast medical oncologist and a member of the Dana-Farber Harvard Cancer Center as well as Professor of Medicine at Harvard Medical School. She graduated from Princeton University in 1980 and Harvard Medical School in 1984. Dr. Tung’s research focuses on hereditary causes of breast cancer as well as effective strategies for breast cancer prevention and treatment. Much of her research has focused on women with BRCA1 and BRCA2 mutations, studying the genetic and environmental factors that influence cancer development as well as the biology and prognosis of the breast cancers they develop. Dr. Tung was recently elected as a Fellow of the American Society of Clinical Oncology (ASCO).
2007
The Hale Family Award
Dana-Farber Cancer Institute/Brigham and Women’s Cancer Center Boston, Massachusetts
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