James M. Rae, PhD
Associate Professor of Internal Medicine and Pharmacology
University of Michigan
Ann Arbor, Michigan
2013-2014 BCRF Project(s):
Co-Investigator: Daniel F. Hayes, MD, University of Michigan, Ann Arbor, MI
The primary goal of Drs. Hayes and Rae's research is to identify genetic markers that can be used to predict whether an individual patient will respond to and tolerate specific anti-estrogen breast cancer therapies. To this end, they have been genotyping patients from two of the largest clinical trials that tested the efficacy and safety of tamoxifen and aromatase inhibitors (AIs), the “Intergroup Exemestane Study” (IES) and the “Arimidex, Tamoxifen, Alone or in Combination” Trial (ATAC). Drs. Hayes and Rae recently published their results showing that CYP2D6 genotype does not predict response to tamoxifen therapy in patients enrolled in ATAC. They have also completed analysis of an independent validation set using patients enrolled in IES. They have now genotyped nearly 1,200 patients for CYP2D6 alleles, and completed their statistical analyses testing for possible associations between CYP2D6 genotype and response to tamoxifen and exemestane (as a control group). The researchers failed to detect an association between CYP2D6 genotype and response in this patient population. The results from IES reconfirm their findings from ATAC. Both studies did not support the hypothesis that CYP2D6 genotype predicts clinical benefit from adjuvant tamoxifen treatment among postmenopausal breast cancer patients, and Drs. Hayes and Rae conclude that CYP2D6 genotype should not be used clinically to determine the use of tamoxifen. Having successfully completed their analyses of CYP2D6, this group has begun a series of studies examining additional gene variants for their possible association with response to anti-estrogen therapy in both the ATAC and IES trials.
Drs. Rae and Hayes are now conducting a large series of genetic analyses in these patient populations in order to test the clinical utility of additional proposed genetic markers of anti-estrogen response and side effects. They anticipate that successful completion of their studies will lead to personalized endocrine therapy based on the patient’s unique genetic makeup.
Dr. Rae received a BS in biology from the University of Pittsburgh and PhD in pharmacology from Georgetown University. Prior to his graduate work, Dr. Rae received several years of training from Marc E. Lippman, then Director of Georgetown's Lombardi Cancer Center. This experience led to Dr. Rae's intense interest and commitment to breast cancer research. In graduate school, Dr. Rae combined his experience with 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 holds joint appointments in the Departments of Internal Medicine and Pharmacology.
Dr. Rae's principal expertise is in the area of pharmacogenetics/ pharmacogenomics, biomarker identification and characterization, 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 using a pharmacogenetics approach, while the other seeks to identify and characterize genes that are critically involved in hormone induced breast cancer growth.
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 unable to respond to therapy. Dr. Rae is part of the NIH-funded COnsortium on BReast cAncer pharmacogenomics (COBRA). COBRA was organized in the early 2000s to study the pharmacogenomics of endocrine therapy of breast cancer and includes a multi-disciplinary team of laboratory, clinical, and statistical investigators from the University of Michigan, Indiana University, and Johns Hopkins. The consortium recently identified an active metabolite of tamoxifen that is made by a liver enzyme (CYP2D6) which is absent in approximately 10% of Caucasians due to genetic variation. Dr. Rae's group then went on to demonstrate that patients with specific CYP2D6 mutations have worse clinical outcomes than normal patients when treated with tamoxifen.
Dr. Rae's other main focus is the identification and characterization of genes uniquely responsible for estrogen stimulated breast cancer growth.
His continued collaborations with Dr. Lippman's group have led to the identification of several genes believed to be critically involved in the estrogen stimulated growth of breast cancer and detailed characterization of the genes suggests that they may play a role normal mammary gland development, are clinical markers for endocrine response, and represent new potential therapeutic targets in breast cancer.