Daniel F. Hayes, MD

2009-2010 BCRF Projects:

1) On behalf of The Breast Cancer Intergroup of North America
(made possible by generous support from Delta Air Lines, Inc.)
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 "Summit" meetings between investigators in TBCI and other investigators in related fields. Two such meetings have been held: a. Spring, 2008: between TBCI and the NIH-funded Pharmacogenetics Research Network to facilitate research in the relatively new field of pharmacogenomics. b. Spring 2009: between TBCI and various academic and commercial investigators performing high-throughput studies of genetics to determine if there is a joint interest in profiling the specimens held jointly by the respective groups. These projects will continue over the coming year.

Mid-Year Progress Report:
During this cycle, the Correlative Science Committee has provided an additional unrestricted grant to the International Breast Cancer Study Group (IBCSG) for personnel and supplies to support infrastructure preparation and processing of specimens from the "SOFT" trial. The SOFT trial has accrued patients from both Europe and North American, and addresses optimal hormone therapy in pre-menopausal women with ER positive breast cancer. These specimens will permit important studies of both germline and somatic differences that may predict outcomes after hormone therapy in general, or specific to treatment with tamoxifen alone, ovarian ablation and tamoxifen, or ovarian ablation and an aromatase inhibitor. During this cycle, funding has also been provided for analysis of specimens collected during the TailorRx trial, which is still accruing in North America. The TailorRx trial is addressing the relative worth of chemotherapy in women with ER positive, node negative breast cancer who have an intermediate Recurrence Score, as determined with the 21 gene assay correlative science concept has been approved by the NABCG CSC and has been funded.

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 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. Hayes and Rae 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:
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.