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James M. Rae, PhD
Associate Professor of Internal Medicine and Pharmacology
Thomas H. Simpson Collegiate Professorship in Cancer Research
University of Michigan
Ann Arbor, Michigan
- Seeking to understand how a patient’s unique genetic makeup can influence her ability to benefit from specific breast cancer therapies.
- Rigorous analyses of DNA from tumor tissue and patient blood samples are conducted to identify genetic predictors of drug response.
- Correlating the genetic makeup of breast cancer patients with response to therapies will lead to more personalized treatments in breast cancer.
Most breast cancers require estrogen to grow and are treatable with anti-estrogen therapies such as tamoxifen or aromatase inhibitors. Not all patients, however, respond the same to these therapies, some may experience severe side effects or not respond to the drugs. Prospective clinical trials provide a rich resource of information on patient outcomes that can help guide treatment for future patients. Drs. Rae and Hayes are utilizing patient samples from large clinical trials to understand how inherited genetic factors can affect tolerance of or response to specific therapies.
Full Research Summary
Anti-estrogen therapies such as tamoxifen and aromatase inhibitors (AIs) have dramatically improved outcomes in breast cancers that express the estrogen receptor (ER). Not all women with ER-positive tumors, however, will respond to these therapies, and some may experience a cancer recurrence after treatment.
The work of Drs. Rae and Hayes is focused on identifying inherited genetic markers that will be able to predict whether an individual patient will respond to and tolerate specific anti-estrogen breast cancer therapies.
To this end, they have been analyzing archived DNA from three of the largest clinical trials that tested the efficacy and safety of tamoxifen and AIs: the "Intergroup Exemestane Study" (IES), the "Arimidex, Tamoxifen, Alone or in Combination" Trial (ATAC), and Breast International Group (BIG) 1-98 study. They have now included two additional patient cohorts: the Exemestane and Letrozole Pharmacogenetic Study (ELPh) and the NCI-funded, SWOG cooperative group S0226 trial, which compared anastrozole to anastrozole plus fulvestrant in postmenopausal women with metastatic disease.
They recently discovered that some women have variants in liver enzymes that lead to lower blood levels of AIs, which would make these drugs less effective. They are now testing to see if these women would benefit from switching to a different form of therapy. They have also identified a number of gene variants that, if successfully validated, could lead to a genetic test to predict drug activity.
These findings could lead to more precise selection of the optimal type of endocrine therapy by identifying preferable activity in individual patients, or improved adherence and persistence to these lifesaving medicines by identifying individual susceptibilities to toxicities.
Dr. Rae received a BS in biology from the University of Pittsburgh and PhD in pharmacology from Georgetown University. In graduate school he combined his interest in breast cancer research with cutting-edge aspects of pharmacology including personalized medicine which uses a patient’s unique genetic makeup to guide treatment decisions. He moved to the University of Michigan in 2001 where he rose to the rank of Associate Professor (with tenure) in the Department of Internal Medicine and holds a joint appointment in the Department of Pharmacology. Dr. Rae’s principal expertise is in the area of cancer drug metabolism, pharmacogenetics/genomics, translational oncology, biomarker identification and characterization, and estrogen receptor signaling, particularly as these may apply to the prediction of breast cancer treatment response. His current research focuses on identifying the subset of estrogen receptor positive breast cancer patients who will respond to endocrine therapy. His work involves two major lines of investigation; one attempts to predict patient response to therapy using a pharmacogenetics approach, while the other seeks to identify and characterize the role of steroid hormone signaling in the growth regulation of breast cancer and the molecular and cellular biology of malignant progression. His work in pharmacogenetics, the study of genetic variability in the way patients respond to medications, involves studies with tamoxifen and aromatase inhibitors and the use of genetic testing to identify patients likely to respond to therapy.