James M. Rae, PhD

2009-2010 BCRF Project:
Co-investigator: Daniel F. Hayes, MD, University of Michigan, Ann Arbor, MI

Approximately 70% of all newly diagnosed breast cancers are ER-positive, and of these, approximately 60% will respond to anti-estrogen therapy. There are clear differences between anti-estrogens and aromatase inhibitors (AIs) with respect to overall response and side effects. However, it is not currently possible to identify which patients will benefit the most from a particular form of therapy. The laboratories of Drs. Rae and Hayes have been developing the means to identify patients who will respond to the anti-estrogen tamoxifen and to AIs by studying how inherited genetic variants affect they way patients alter and eliminate these drugs. Tamoxifen is considered a pro drug which means that it must activated by the body after it is ingested. The investigators have discovered that a specific liver enzyme is responsible for converting the tamoxifen into its potent active form called "endoxifen." Furthermore, they have shown that approximately 10% of Caucasian patients are unable to "activate" tamoxifen due to inherited genetic mutations.

Support provided by BCRF has enabled Drs. Rae and Hayes to conduct important clinical translational research studies to test how a patient's unique genetic makeup influences their ability to tolerate and benefit from breast cancer endocrine therapy. They believe that a genetic approach can identify the specific subsets of patients for whom a particular endocrine therapy will serve them best. In addition, their approach may predict the subset of women for whom a particular endocrine therapy will not be effective, thus avoiding delays in receiving alternative therapies and avoiding unnecessary toxicity.

Mid-Year Progress Report:
Over the past four decades, a number of studies have shown that a person's unique genetic makeup is a major determinant of drug response and adverse drug reactions. This field of study, designated pharmacogenetics, is defined as the study of inherited germline variants in genes that code for proteins responsible for drug disposition and/or drug targets. Pharmacogenetics is shaping the future of personalized medicine, and may enable tailoring of the type and dose of therapy based on a patient's genotype. This approach promises to have a significant impact in the field of breast cancer. Approximately 70% of all newly diagnosed breast cancers are estrogen receptor(ER)-positive, and of these, approximately 60% will respond to some form of endocrine therapy (primarily the selective anti-estrogen modulator (SERM) tamoxifen or the aromatase inhibitor (AIs) class of drugs). There are clear differences between anti-estrogens and AIs with respect to overall response and side effects. However, it is not currently possible to identify which patients will benefit the most from a particular form of therapy.

The Hayes and Rae laboratories have been developing the means to identify patients who are more likely to respond to anti-estrogens by studying how inherited genetic variants affect they way patients alter and eliminate these drugs. They have shown that genetic variants in the liver enzyme called cytochrome P450 2D6 (CYP2D6) correlate with decreased plasma concentrations of an important active metabolite of tamoxifen, designated "endoxifen" and that this may correlate with response to tamoxifen therapy. Currently, the clinical consequences of administering tamoxifen to ER-positive breast cancer patients with CYP2D6 genetic mutations are not known. Similarly, they and others have found that genetic variants of ER (tamoxifen’s drug target) and aromatase (AI's drug target) are associated with drug-induced side effects and possibly response to treatment.

The goal of this proposal is to translate important pharmacogenetic findings into clinical practice. Funding provided by BCRF has enabled the researchers to genotype patients enrolled in two of the seminal large prospective randomized clinical trials that tested the efficacy and safety of tamoxifen and AIs. The scientists believe that interrogating existing clinical trials for correlations between genotype and phenotype (in the form of response and / or toxicity) relationships will facilitate important pharmacogenetic discoveries and lead to better treatment strategies based on a patient's genetic profile. They believe that a genetic approach can identify the specific subsets of patients who are best suited to a particular type of endocrine therapy. Results from their studies correlating the genotype of patients treated for breast cancer with tamoxifen and/or AIs with outcomes and side effects have the potential to lead to more personalized treatment decision-making in breast cancer, including clinical pharmacogenetic testing for adjuvant anti-estrogen therapy.

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.