Hyman B. Muss, MD

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. Over the past year, 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 Muss team also has recently shown that hormonal therapy (tamoxifen or aromatase inhibitors) affects the release of proteins (specifically vascular endothelial growth factor – VEGF) that stimulate the growth of blood vessels necessary for breast cancer growth. Platelets, small cells in the blood that are needed for normal blood clotting, contain large amounts of VEGF. The scientists found that tamoxifen therapy increased VEGF release while aromatase inhibitors increased a VEGF blocking compound, endostatin. Thus, the benefits of tamoxifen therapy may be improved by the addition of an anti-platelet therapy that is widely used in patients with heart disease. They will test this in a pilot trial.

Women with early stage breast cancer who have large and/or aggressive tumors are often treated with chemotherapy prior to surgery (neoadjuvant chemotherapy). About 15-20% of these patients will have no residual tumor at the time of surgery. For the remainder, there is no additional chemotherapy that has been shown to be effective, although some patients may benefit from other therapies such as hormonal therapy, or trastuzumab therapy directed against the HER-2 receptor. Even with these additional treatments, patients who have residual disease at the time of surgery have a higher risk of experiencing a relapse.

More effective treatment for this group of patients is clearly needed. Sunitinib is a new 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 new project, 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. In addition, they will assess the safety of the combination during radiotherapy, measure markers of tumor activity and assess the levels of cytokines involved in blood vessel formation and growth, if this treatment is effective.

Mid-Year Progress Report:
Dr. Muss reports that his statin study was opened in 2005 and has accrued 33 women. For the anti-angiogenesis trial, he and his team have shown for the first time that tamoxifen and aromatase inhibitor therapy impacted intra-platelet, blood (plasma) and platelet mediated VEGF and ES levels differently. This suggests that these two drugs may have different effects on the process of angiogenesis. On balance, treatment with tamoxifen was pro-angiogenic as compared to aromatase inhibitor therapy. The impact of aspirin therapy on the angiogenic balance suggests anti-platelet and/or anti-angiogenic therapy may be particularly useful and improve outcomes for women receiving tamoxifen therapy. 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.

The researchers propose to elucidate the influence of the clinically available platelet antagonist, clopidogrel (PLAVIX), on the release of angiogenic proteins from platelets in 30 patients with breast cancer. Angiogenic proteins will be assessed prior to, 30 days following and 90 days following drug initiation. Results from this study using surrogate biomarker endpoints will allow assessment of the impact of the drug on angiogenesis and may lead to larger clinical trials of anti-platelet agents in the treatment and prevention of breast cancer. The researchers’ initial efforts have focused on the establishment of laboratory processing protocols which will allow appropriate processing and storage of patient samples; they are currently awaiting IRB approval.

The protocol for the proposed Sunitinib trial has been approved by the IRB of the University of Vermont and is currently being reviewed at the Dana Farber Cancer Center who will partner in this trial. Dr. Muss’ team is finalizing negotiations with Pfizer who will supply the drug for this trial free of charge.

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.