Kathy D. Miller, MD

2008-2010 BCRF Project:
(made possible by generous support from Ann Taylor Stores Corporation)

Put simply - cancer cells have discovered a fountain of youth and don't get old. Each time a normal cell divides, the end of each chromosome (the telomere) gets slightly shorter. Over time, the telomeres reach a 'critical' length that triggers cell death. Cancers avoid this normal aging process by reactivating an enzyme called telomerase. Telomerase builds up the ends of the chromosomes and prevents them from ever reaching the 'critical' length that triggers cell death.

A new drug that inhibits telomerase (called GRN163L) inhibits growth and metastasis of breast cancers in animal models and increases the effect of chemotherapy. Dr. Miller and colleagues are conducting the first trial of this agent in patients with breast cancer. The early results are encouraging with the fifth group of patients to start therapy soon. A correlative study supported by BCRF evaluated the impact of this therapy in circulating tumor cells in hopes of allowing the researchers to monitor treatment without repeated biopsies. As patients enrolled in this trial had few detectable circulating tumor cells (better for the patients), the scientists were unable to accurately measure telomerase activity. They are now investigating the potential to measure telomerase activity in hair follicles as an alternative for future trials.

Lymphedema is a significant long-term complication of primary therapy for breast cancer, causing decreased arm function, chronic pain, cosmetic deformity, recurrent infections or secondary malignancies. Little is known regarding the development of lymphedema outside of its relation to the number of lymph nodes removed. Dr. Miller and colleagues suggest the following model: Mechanical disruption of normal lymphatic drainage leads to increased back pressure on the lymphatic vessels. This increased pressure triggers local production of growth factors such as the Vascular Endothelial Growth Factor (VEGF) to stimulate compensatory growth of new blood and/or lymphatic vessels. Unfortunately VEGF also makes vessels more permeable (leaky), increasing the amount of lymph fluid that leaks into the tissues of the arm. This excess fluid must be transported by the damaged lymphatic system. In essence, the body's compensatory mechanism may make the lymphedema worse.

If Dr. Miller's model is correct, inhibition of VEGF could improve lymphedema. She has proposed a pilot study examine the effect of VEGF blockade on lymphedema in breast cancer survivors without overt metastatic disease using several measures of lymphedema and the impact of lymphedema on quality of life. Fifteen breast cancer survivors with significant unilateral lymphedema will be enrolled, with the unaffected arm acting as an internal control. Patients with objective or subjective improvement after the first 6 weeks will continue treatment for up to six months to investigate the longer-term affect of bevacizumab on lymphedema. If successful, observations from this pilot study will establish VEGF as a viable therapeutic target for patients with lymphedema and lead to a larger, definitive proof-of-concept trial, with the potential to significantly decrease morbidity in breast cancer survivors with lymphedema.

Bio:
Dr Kathy Miller is Associate Professor and Sheila D. Ward Scholar at the Indiana University School of Medicine, Division of Hematology/Oncology. She is an active member of the American Society of Clinical Oncology, the Eastern Cooperative Oncology Group and the Hoosier Oncology Group.

She received her B.S. in biology Magna Cum Laude from the University of Miami, Coral Gables, Florida, and her M.D. from Johns Hopkins School of Medicine in Baltimore, Maryland. She completed her internship as well as her residency at Johns Hopkins School of Medicine followed by a Hematology/Oncology fellowship at Indiana University.

Her research interests focus on the role of angiogenesis in breast cancer. This interests spans departmental boundaries and has taken several forms: laboratory evaluation of the modalities that measure tumor-associated vasculature, and clinical trials of anti-angiogenic agents.