Daniel F. Hayes, MD

1) On behalf of The Breast Cancer Intergroup of North America
The Breast Cancer Intergroup (TBCI) of North America conducts fundamentally important prospective randomized clinical trials that have changed practice patterns for patients with breast cancer, especially in the adjuvant setting. Therapy for patients with breast cancer can be individualized by judicious use of tumor markers, such as using ER to decide if a patient should get anti-estrogen therapy and HER-2 to decide if a patient should get trastuzumab (Herceptin™).

Since the early 1990s, TBCI has prospectively collected and stored breast cancer tissue from patients who participated in our clinical trials. These samples are available for studies of new or promising tumor markers. A Correlative Science Committee (CSC), established by TBCI, rigorously reviews submitted concepts to decide which should go forward using these precious samples. However, no funding mechanism has been linked to TBCI CSC reviews. Therefore investigators with approved projects must then fund the studies themselves, or be subjected to a second set of peer review from outside funding sources (such as the NIH or DOD). This cumbersome and redundant process results in delays of efficient conduct of these studies.

BCRF has supplied support for ongoing activities of the Correlative Science Committee. These include: 1. Research grants to individual laboratory investigators to conduct correlative science studies; 2. Infrastructure grants to the Pathology Coordinating Offices of the individual cooperative groups to support conduct of routine but important tasks, such as construction of tissue microarrays, harvesting of DNA and RNA, and staining of tissue sections for standard markers, such as estrogen receptor and HER2; and 3. Support of a "Summit" meeting between investigators in TBCI and investigators in the NIH-funded Pharmacogenetics Research Network to facilitate research in the relatively new field of pharmacogenomics. This meeting, which was by all measures a total success, was held in Bethesda in March, 2008. These projects will continue over the coming year.

Mid-year Progress Report:
Funds from BCRF this year are being used in part for support of a "workshop" meeting among investigators in The Breast Cancer Intergroup to address issues related to tumor marker study design and conduct. Planning for this meeting has been ongoing for several months and it will occur in February 2009 in Bethesda.

2) Co-investigator: James M. Rae, PhD, 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. Hayes and Rae 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. Furthermore, they have shown that approximately 10% of Caucasian patients are unable to "activate" tamoxifen due to inherited genetic mutations.

In this proposal, the researchers will determine the extent to which a patient’s unique genetic makeup influences her ability to respond to endocrine therapy. They believe that a genetic approach can identify the specific subsets of patients for whom a particular hormonal therapy will serve them best. Perhaps more importantly, this approach may predict the subset of women for whom tamoxifen will not be effective, thus avoiding delays in receiving alternative therapies and avoiding unnecessary toxicity.

Mid-year Progress Report:
The Hayes and Rae laboratories 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 the way patients alter and eliminate these drugs. Tamoxifen itself has weak anti-estrogenic activity and undergoes metabolic conversion to more potent anti-estrogenic forms. They have discovered that a specific liver enzyme called cytochrome P450 2D6 (CYP2D6) 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 in CYP2D6. However, the clinical consequences of administering tamoxifen to ER-positive breast cancer patients with CYP2D6 genetic mutations are not known.

The scientists hypothesize that patients who are homozygous for variant (non-functional) CYP2D6 alleles will not convert tamoxifen to its most abundant anti-estrogenic metabolite, endoxifen. Therefore, these patients should do worse on tamoxifen versus those women who are wild-type for this gene. They have begun studies to test this hypothesis in a retrospective analysis of prospective clinical trial conducted by the International Exemestane Study Group. They believe that interrogating existing clinical trials for correlations between genotype and phenotype (in the form of response and / or toxicity) relationships will facilitate important pharmacogenomic 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 for whom a particular endocrine therapy will serve them best. Perhaps more importantly, this approach may predict the subset of women for whom tamoxifen will not be effective, thereby avoiding delays in receiving alternative therapies and avoiding unnecessary toxicity.

Bio:
Daniel Fleming Hayes, MD, is the Director of the Breast Oncology Program at the University of Michigan Cancer Center, where he is also a Professor of Medicine. The University of Michigan is a federally designated Comprehensive Cancer Center that has placed a particular emphasis on cancer research that translates exciting findings from the laboratory to the clinic.

Over nearly twenty years, Dr. Hayes professional training and career have been directed toward bridging the gap between laboratory and clinical research. He received a bachelor's degree (1974) in biology and a master's degree (1977) in biochemistry at Indiana University. He received his MD from the Indiana University School of Medicine in 1979, followed by a residency in internal medicine at the University of Texas Health Science Center at Dallas, Texas (Parkland Memorial and affiliated hospitals). He served a fellowship in medical oncology from 1982-1985 at Harvard’s Dana Farber Cancer Institute in Boston, where he subsequently distinguished himself on the faculty in regards to breast cancer research and care. In 1992, he assumed the role as the Medical Director of the Breast Evaluation Center at DFCI. He held that title until 1996, when he moved to Georgetown University and spent the succeeding five years establishing an enormously successful collaboration with Dr. Marc E. Lippman. In 2001, both Drs. Lippman and Hayes joined the already prestigious University of Michigan Cancer Center to continue their fruitful relationship in the context of the existing translational science.

Dr. Hayes has been influential in both clinical and laboratory studies of the diagnosis and treatment of breast cancer. With his long-time colleague, Dr. Donald Kufe, Dr. Hayes published the first reports concerning the development of the CA15-3 blood test, which is currently used world-wide to evaluate patients with breast cancer. He has become an internationally recognized leader in the use of this and other tumor markers, such as HER-2. More recently, he and his colleagues have reported ground breaking results regarding circulating tumor cells in metastatic breast cancer and regarding the pharmacogenomics of tamoxifen. He is widely considered to be an expert in the field of clinical research of breast cancer, especially in regards to new hormonal and chemotherapeutic treatments. He also lectures and publishes extensively regarding the management of patients with breast cancer.

Reflecting his expertise, Dr. Hayes has been Chair of the Solid Tumor Correlative Sciences Committee of the Cancer and Leukemia Group B (CALGB), one of the leading federally-funded multi-institutional cooperative groups that perform definitive clinical research in cancer care and he now hold similar positions in the Southwest Oncology Group and the U.S. Breast Cancer Intergroup. He co-chairs the Expert Panel for Tumor Marker Practice Guidelines for the American Society of Clinical Oncology, and he is on the editorial boards of several leading cancer journals.

Dr. Hayes lives in Ann Arbor with his wife, Jane.