Daniel F. Hayes, MD

2012-2013 BCRF Projects:
1) (made possible by generous support from Eisai Oncology)
On behalf of North American Breast Cancer Group (NABCG)

The North American Breast Cancer Group (NABCG) conducts 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 estrogen receptor (ER) status to decide if a patient should get anti-estrogen therapy and HER2 status to decide if a patient should get Herceptin® (trastuzumab), a targeted therapy developed for breast cancer over-expressing HER2 proteins.

Since the early 1990s, NABCG has prospectively collected and stored breast cancer tissue from patients who participated in these trials. These samples are available for studies of new or promising tumor markers. A Correlative Science Committee (CSC), established by NABCG, rigorously reviews submitted concepts to decide which should go forward using these precious samples. However, no funding mechanism has been linked to NABCG 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 National Institutes of Health or Department of Defense). This cumbersome and redundant process results in delays of efficient conduct of these studies.

BCRF has supplied support for ongoing CSC activities. These include research grants to individual laboratory investigators to conduct correlative science studies, infrastructure grants to the Pathology Coordinating Offices of the individual cooperative groups to support construction of tissue microarrays (TMAs), harvesting of DNA and RNA, and staining of tissue sections for standard markers, such as estrogen receptor and HER2, and support of workshop meetings between investigators in NABCG and other investigators in related fields.

So far, CSC has provided funding to Dr. Torsten Nielsen to perform studies that will help standardize Ki67 analysis. These studies are a direct outgrowth of the NABCG/BIG Ki67 meeting held in London in March 2010, which was supported by BCRF. In addition to Dr. Nielsen’s study, a manuscript describing this meeting, designed to provide standardized methodology for this important marker, was published in the Journal of the National Cancer Institute in 2011 (Dowsett M, Nielsen TO, A’Her R, et al., in a paper entitled, Assessment of ki67 in breast cancer: recommendations from the international ki67 breast cancer working group.

The NABCG CSC also funded Dr. Bryan Schneider to perform germline, pharmacogenetic studies to determine if patients most likely to benefit or experience side effects from bevacizumab (Avastin®) can be identified. Dr. Christine Ambrosone has also received CSC support, and she will continue her studies of germline pharmacogenetics to determine if patients have different outcomes based on inherited genetic differences. In addition, CSC has provided funding to Dr. Monica Reinholz who is conducting research to determine if various markers might identify patients with HER2 positive breast cancer who did not benefit from adjuvant trastuzumab.

Furthermore, CSC has provided funding to support infrastructure projects that permit NABCG scientists to efficiently use the specimens they have collected. These grants have gone to Eastern Cooperative Oncology Group, and in an exciting new initiative, to the Breast International Group (BIG), so that they can construct a BIG website that will be linked to the NABCG website, thus standardizing the two groups. CSC has provided support to Dr. Giuseppe Viale to construct tissue microarrays from BIG clinical trials. Finally, this group has provided support to the Research Advocacy Network for patient focus groups regarding a new clinical trial being considered by SWOG/NABCG to address the issue of screening asymptomatic women after adjuvant therapy with tumor markers for occult recurrence.

Mid-year Progress: BCRF has supplied support for ongoing activities of the Correlative Science Committee. These include the following initiatives:
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 construction of tissue microarrays (TMAs), harvesting of DNA and RNA, and staining of tissue sections for standard markers, such as estrogen receptor and HER2
3. Support of workshop meetings between investigators in NABCG and other investigators in related fields
4. Support of various Breast International Group (BIG) activities including the development of a BIG correlative science website, which is linked to the NABCG CSC website; and the generation of TMAs from selected studies conducted by BIG and staining of these TMAs for standard markers;

Over the last half-decade, 13 papers have been published describing studies from the NABCG Correlative Science Committee.

BCRF funding has supported the incorporation of nearly all of the tissue specimens that NABCG has collected into tissue microarrays, and the NABCG and BIG websites now provide a transparent mechanism for the world's breast cancer translational scientists to determine what specimens are available, and how they relate to the clinical trials from which they were collected, and how to apply for them.

BCRF funding has supported an important initiative to standardize assessment of an important prognostic marker, Ki67. One of these studies culminated in a podium presentation by Dr. Torsten Nielsen at the 2012 San Antonio Breast Cancer Symposium, the world's largest annual meeting in breast cancer.

In the current funding period, NABCG will continue to provide support to investigators whose concepts are approved by the Correlative Science Committee, to the Pathology Coordinating Offices of the various cooperative groups to build new TMAs, perform routine marker analyses, and harvest nucleic acids, and to the Breast International Group to further organize their translational science committee in a fashion similar to that of the NABCG. The NABCG leadership is also making plans to establish a "translational fellowship" that will support a young investigator to coordinate the efforts of the Translational Science Committee of the Oxford Overview/Early Breast Cancer Trialists' Collaborative Group. The fellow, who will be chosen in a competitive fashion, will be charged with working closely with the Oxford Secretariat and the TransOx committee to identify, conduct, and complete various projects addressing biomarkers in breast cancer.

2) Co-Investigator: James M. Rae, PhD, University of Michigan, Ann Arbor, MI

In a separate project, the research group led by Dr. Hayes and James Rae, PhD (University of Michigan) 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:
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.