James M. Rae, PhD

2012-2013 BCRF Project(s):
Co-Investigator: Daniel F. Hayes, MD, University of Michigan, Ann Arbor, MI
(made possible by generous support from FIAT)

The group led by Drs. Hayes and Rae has been studying how a patient's unique genetic make-up can influence his or her ability to respond to and tolerate specific anti-estrogen breast cancer therapies. To this end, they have genotyped patients from three large clinical trials that tested the efficacy and safety of tamoxifen and/or aromatase inhibitors (AIs), the "Intergroup Exemestane Study" (IES), the "Arimidex, Tamoxifen, Alone or in Combination" trial (ATAC), and the Femara versus Anastrozole Clinical Evaluation (FACE) trial. Using samples from these trials, Drs. Hayes and Rae have been evaluating a number of gene variants to determine if they can be used to predict drug response and side effects. In addition to these pharmacogenetic studies, they have been conducting a number of preclinical studies to identify anti-estrogen drug mechanisms of actions and potential pathways of drug resistance. These studies led to the identification of key regulatory genes whose variants can be studied within the setting of the three clinical trials. Drs. Hayes and Rae believe that their studies will facilitate important pharmacogenetic discoveries and result in better treatment strategies based on a patient's genetic profile.

Mid-year Progress: Drs. Hayes and Rae recently published their results in the Journal of the National Cancer Institute showing that CYP2D6 genotype does not predict response to tamoxifen therapy in patients enrolled in the ATAC trial. Since the fall, they have completed analysis of an independent validation set using patients enrolled in the IES study. They have genotyped 1,197 patient samples for the six most common CYP2D6 alleles and conducted statistical analyses testing for associations between CYP2D6 genotype and clinical outcomes in both tamoxifen and exemestane (as a control group) treated patients. Drs. Hayes and Rae have not detected any statistically significant associations between CYP2D6 genotype and disease-free survival in tamoxifen-treated patients. Furthermore, no associations were observed between CYP2D6 genotypes and disease-free or overall survival in exemestane-treated patients. The results from IES reconfirm the team's findings from ATAC. Neither study supports the hypothesis that CYP2D6 genotype predicts clinical benefit from adjuvant tamoxifen treatment among postmenopausal breast cancer patients, and Drs. Hayes and Rae have concluded that CYP2D6 genotype should not be used clinically to determine the use of tamoxifen.

Bio:
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.