Hyman B. Muss, MD

2012-2013 BCRF Project:
(made possible by generous support from Play for P.I.N.K.)

Breast cancer is a disease of aging, and the majority of Americans who die from breast cancer are 65 years and older. Adjuvant ("post-operative") chemotherapy has been shown to improve survival in older women with breast cancer, but side effects can be substantial and may interfere with quality of life and daily function, making the risks of treatment exceed the benefits in some patients. As human cells age, p16INK4a (a protein coded by the p16 gene), which is known to have the ability to suppress the growth of tumors, increases. This increase is associated with cell senescence in almost all human tissues and organs. Chemotherapy and radiation are cancer therapies that increase p16 gene expression so tumor growth can be prevented or suppressed.

Dr. Muss's team has found that many women with early stage breast cancer treated with chemotherapy have a marked increase in the RNA expression of this gene. Their research is focusing on how this gene expression relates to the development of complications of treatment and whether expression of this gene can predict for treatment related toxicity. Being able to identify patients at greatest risk for treatment-related complications will allow for the use of interventions to minimize side effects.

In the coming year, Dr. Muss's team will complete the patient accrual and analysis of data from clinical trials determining if any specific chemotherapy regimen or clinical characteristics predict increases in p16INK4a. They will also expand collaboration with fellow BCRF grantee, Arti Hurria, MD (City of Hope) on a research project grant (RO1) from the National Institutes of Health on 500 older women with breast cancer. Dr. Muss's team will focus on the assessment of p16INK4a expression as part of this trial of 500 older women with breast cancer. They will also be comparing the p16INK4A results in these patients with the assessment metrics to determine if increasing p16INK4A is related to poorer outcomes including greater treatment related toxicity and shorter all cause and cancer-specific survival. They will also be comparing the p16INK4A results from the LCCC 0924 trial, which assess if increasing p16INK4A is related to poorer outcomes including greater treatment-related toxicity and shorter survival, both cancer-specific and from all causes, in older patients.

Dr. Muss's team also plans to start a new clinical trial to test exercise and other interventions in women with early breast cancer receiving chemotherapy to attenuate the rise in p16INK4a expression and with the goal of lowering the risk of short-, but more importantly, long-term toxicity. They will amend the LCCC 1027 clinical trial to add this exercise intervention. In patients without patients, they have previously shown that exercise was inversely related to p16INK4a status. Eligibility for this trial will include patients of all ages and will use a defined exercise strategy based on patient function.

Mid-year Progress: The p16 gene codes for a protein which causes human cells in all organs to age, resulting in the inability of cells to replicate. P16 expression is a major biomarker of aging and a measure of organ reserve. Cells with increased expression of the p16 protein are less capable of dividing than cells with low expression. Patients with high levels of p16 protein in their bone marrow stem cells and the cells lining the mouth, esophagus, and stomach prior to treatment or who have greater changes during treatment, could have greater toxicity with chemotherapy since after treatment these cells would take longer to replicate to normal levels as compared to patients with cells having lower p16 levels.

In addition to aging, which is associated with a ten-fold increase in p16 gene expression between the ages of 20 and 80 years, researchers led by Dr. Muss now have convincingly shown that common chemotherapy regimens used for the adjuvant treatment of breast cancer result in one to two fold rapid increase in p16 expression in circulating immune cells (T-lymphocytes) in the blood. In addition, this group's preliminary data suggests that patients with a higher median change in p16 during chemotherapy treatment are more likely to have more severe hematologic toxicity--confirming their hypothesis that p16 expression may prove to be an independent predictor of chemotherapy-related side effects.

Dr. Muss and colleagues are now close to completing patient entry into a trial to prospectively confirm these data in a large group of women receiving adjuvant chemotherapy. Their research findings have two major implications. First, patients who have high levels of p16 in their circulating T-lymphocytes cells prior to or during chemotherapy may have greater toxicity with treatment and might benefit from interventions such as the earlier use of white cell growth factors to minimize low white blood cell counts and the risk of infection. Second, and perhaps most importantly, the "aging" of the T-lymphocytes associated with chemotherapy administration may predispose women with breast cancer to increased risks of diseases associated with aging.

Bio:
Dr. Muss is currently Professor of Medicine at the University of North Carolina, Chapel Hill and Director of Geriatric Oncology at the Lineberger Comprehensive Cancer Center. His major research interests are breast cancer, with emphasis on the treatment of older women, issues related to treatment of all older cancer patients, and providing education in geriatrics to fellows in training. With his colleagues, Dr. Muss is trying to define to role molecular factors as well as geriatric assessment in optimizing treatments for older patients with cancer.

Dr. Muss is currently Co-Chair of the Cancer in the Elderly Committee for the Cancer and Leukemia Group B (CALGB), a National Cancer Institute sponsored cooperative group which endeavors to increase awareness and clinical trials opportunities for older patients. Partly through his efforts, the CALGB was awarded and completed major study on the use of adjuvant chemotherapy in older women with high risk/early stage breast cancer. Dr. Muss is a prior member of the Board of Directors of the American Society of Clinical Oncology (ASCO), the ASCO Foundation, and chairs their task force on Geriatric Oncology. He has previously served as Chair of the Medical Oncology Board for the American Board of Internal Medicine.