Hyman B. Muss, MD

2009-2010 BCRF Project:
Several projects begun with BCRF funding while Dr. Muss was at the University of Vermont continue there. Chemotherapy-related cognitive dysfunction, so-called "chemobrain," is a widely reported yet poorly defined complication of chemotherapy. Although much concern has been expressed about this potential toxicity, little is known about the central nervous system changes that may result from chemotherapy administration. This proposal is designed to study 50 women with early stage breast cancer receiving commonly used chemotherapy regimens used for adjuvant treatment. In addition to cognitive testing focusing on specific cognitive problems identified from prior studies, the trial will focus on neuroanatomical and neurofunctional changes defined by magnetic resonance imaging (MRI) including both functional MRI (fMRI) examining alterations in brain activity during cognitive operations such as memory tasks, and a technique that provides exquisite imaging of the white matter integrity of the brain (diffusion tensor imaging, DTI). The protocol opened for accrual in March 2009.

Another BCRF-supported study is evaluating the effects of a novel adjuvant biochemotherapy regimen on women who have residual disease after neoadjuvant chemotherapy for breast cancer. This study is now open and accruing patients at the University of Vermont. Samples are being collected for correlative studies to investigate how growth factors in the blood are affected by the study treatment. Dr. Muss and his colleagues will also test whether the APOE genotype, which has been related to cognitive impairment in aging and dementia, may be associated with the development of cognitive dysfunction with chemotherapy. Patients will have cognitive function testing, imaging and blood collection prior to chemotherapy treatment, after chemotherapy treatment, and at one year. The information obtained from this project will be used to define the risk and frequency of this complication and lead to further larger trials that will explore interventions.

Sunitinib is an oral anti-cancer agent that works by stopping the growth of blood vessels that supply tumors. Recent studies have shown that a combination of older chemotherapy agents (cyclophosphamide and methotrexate) has a similar effect when given in a low dose continuous schedule. In a project that began last year, Dr. Muss and his team propose to combine these two approaches in patients who have residual cancer after standard chemotherapy for early stage breast cancer. Their goals are to assess the percentage of patients who experience a relapse at two years and compare these results in patients given neoadjuvant therapy alone. The study is now open to enrollment and has accrued 4 patients to date.

In another previous BCRF-funded study, Dr. Muss and colleagues have found a differential impact of hormonal therapy on the angiogenic protein balance in women with breast cancer treated in the adjuvant setting. Their data demonstrate women treated with tamoxifen therapy have a significant increase in agonist induced platelet release of VEGF. Thus, women receiving tamoxifen therapy may derive particular benefit from the addition of an anti-platelet therapy that reduces VEGF release in the tumor micro-environment. This data is the first to suggest particular patient populations that may derive more benefit from platelet based anti-angiogenesis therapy. The researchers are elucidating the influence of the platelet antagonist, acetylsalicylic acid (Aspirin- taken for 45 days) on the release of angiogenic proteins from platelets in 30 patients with breast cancer who are currently treated with tamoxifen. The study began in August 2008 and has enrolled 9 patients to date; 8 have completed the study.

Vascular endothelial growth factor (VEGF) and endostatin (ES) are potent pro- and anti-angiogenic factors, respectively, found in the tumor, blood and in platelets. Platelets are small cells which circulate in the body and help to form blood clots as well as deliver proteins to sites of tumor growth and blood vessel injury. Platelet activation results in the release of VEGF and endostatin, which may influence angiogenesis. Since platelets contain over 30 different angiogenesis proteins (in addition to VEGF and ES), Dr. Muss and his colleagues were interested in studying the control of platelet protein release as a means of angiogenesis and breast cancer control. This approach has the potential advantage of simultaneously controlling many proteins involved in angiogenesis. They have demonstrated for the first time that anti-platelet therapy might affect the process of angiogenesis in women who are receiving endocrine therapy for treatment of their breast cancer. This observation suggests that already available anti-platelet agents that are in use for the treatment of heart disease may have a role in the treatment of breast cancer in combination with already used breast cancer therapy. The researchers report that they continue to accrue patients to this study towards a total goal of 60.

Finally, in another trial led by Dr. Muss and accruing patients, the researchers will build on the laboratory evidence that cholesterol lowering medications (statins) inhibit the growth of breast cancer cells. Clinical studies are controversial but some show that women taking statins are less likely to get breast cancer. This ongoing randomized trial compares one-year of atorvastatin (Lipitor™) or placebo for lowering mammography-defined breast density and other surrogate markers that increase breast cancer risk. Accrual is open but proceeding slowly; the researchers estimate that 33 women will have completed the study by December 2009.

A new project, based at the University of North Carolina, is focused on patients aged 65 and older. Breast cancer is a disease of aging and the majority of Americans who die from breast cancer are 65 years and older. Adjuvant 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. The Muss laboratory has shown that expression of the p16INK4a tumor suppressor gene in blood lymphocytes increases with age and is a dynamic biologic marker of aging (Liu et al, Aging Cell; in press for publication June 16, 2009). Moreover, preliminary data suggest that chemotherapy might also accelerate the aging process by increasing expression of the p16INK4a tumor suppressor gene. This suggests that the benefits of chemotherapy therapy may be partially offset by age-promoting effects and shortened survival. In this project, Dr. Muss and team will build on prior observations that increased expression of p16INK4a (measured on messenger RNA by RT-PCR) is related to aging and may also increase with the use of chemotherapy. In addition they will also measure p16INK4A expression in patients treated only with surgery (with or without radiation) and those treated with adjuvant endocrine therapy (tamoxifen or aromatase inhibitors). They will determine if the increased expression of p16INK4a seen in some older patients is associated with their susceptibility to the age-promoting effects and associated toxicities of chemotherapy.

Mid-Year Progress Report:
Dr. Marie Wood and colleagues at the University of Vermont report that the study to evaluate the effects of a novel adjuvant biochemotherapy regimen on women who have residual disease after neoadjuvant chemotherapy for breast cancer, is now open and accruing patients at the University of Vermont. Samples are being collected for correlative studies to investigate how growth factors in the blood are affected by the study treatment. As for the study on chemotherapy-related cognitive dysfunction, the University of Vermont researchers have enrolled seven women who were able to receive an MRI, and three women underwent cognitive testing without the MRI due to presence of MRI incompatible material. This recruitment represents approximately 25% of women approached to participate. Accrual has been slower than expected partially due to the time commitment required for study measures. The goal for recruitment is 20 women receiving chemotherapy and 10 women who do not receive chemotherapy.

With regard to the project on the effects of chemotherapy on older women with breast cancer, Dr. Muss and colleagues will also address a methodologic shortcoming of the assay. The current approach requires magnetic bead sorting of peripheral blood white cells within 24 hours of phlebotomy. This need for rapid sorting limits the use of this assay in the cooperative group setting and the community. In this work, the researchers will also test new assay methods which, if successful, will eliminate the need for rapid processing of blood samples and will enable them to assess the role of p16INK4A expression in large multi-center clinical trials.

Bio:
On May 1, 2009, Dr. Muss moved to the University of North Carolina, Chapel Hill, where he is Professor of Medicine and Director of Geriatric Oncology at the Lineberger Comprehensive Cancer Center.

For 13 years, he was Professor of Medicine at the University of Vermont College of Medicine. His major research interest is breast cancer, with emphasis on the treatment of breast cancer in older women. His research also focuses on adjuvant therapy and treatment of metastases. With his colleagues, he is trying to define molecular factors that predict which patients with early stage breast cancer will derive the greatest benefits from chemotherapy or hormone therapy, while minimizing toxicity.

Dr. Muss is currently co-chair of the Cancer in the Elderly Working Group 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 member of the Board of Directors of the American Society of Clinical Oncology 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.