Hyman B. Muss, MD

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).

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.

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.

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.

Bio:
Dr. Muss is currently Professor of Medicine at the University of Vermont College Of Medicine. His major research interest is breast cancer with a focus on the treatment of breast cancer in older women. He also has a major interest in adjuvant therapy and treatment of metastases. With his colleagues at the Vermont Cancer Center 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. The benefit of defining such markers will be of great importance to patients as some patients may be spared undo toxicity with treatments not likely to help them, while other patients can be reassured that their treatment is more likely to be beneficial.

In addition Dr. Muss served for ten years as Director of Hematology/Oncology for Fletcher Allen Health Care. He 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, and in this endeavor is trying to increase awareness and clinical trials opportunities for older patients with all types of cancer including breast cancer. Partly through his efforts the CALGB has been awarded a major grant to study the use of adjuvant chemotherapy in older women with high risk/early stage breast cancer.

Dr. Muss is currently a member of the Board of Directors of the American Society of Clinical Oncology and chairs their task force on Geriatric Oncology. He has also previously served as Chair of the Medical Oncology Board for the American Board of Internal Medicine (ABIM), and as a member of the ABIM Board of Directors.

Dr. Muss has served with honor and distinction as a major in the US Army in Vietnam. He was awarded a Bronze Star.