Carol J. Fabian, MD

Hormones, in the forms of excess endogenous insulin and inflammatory factors, are involved in the promotion of breast cancer in overweight and obese women. Weight loss is recommended for breast cancer risk reduction, plus other health benefits. Dr. Fabian believes that it is possible to augment the effects of weight loss on breast cancer risk biomarkers in obese women with high dose omega-3 fatty acids. Omega-3 fatty acids have been shown to decrease breast cancer risk and breast cancer metastases in studies with laboratory models. The mechanism of action is unclear but is likely in part due to their ability to reduce pro-inflammatory cell (macrophage) infiltration into adipose tissue and fat-laden organs such as the breast, with decreased fat cell secretion of pro-inflammatory cytokines and favorable effects on neighboring breast duct cells. These favorable effects include reduction in growth and survival of abnormal cells.

Dr. Fabian’s project in 2012-2013 will build on successful outcomes of an energy balance/weight loss intervention on blood and tissue risk biomarkers in post-menopausal women (supported by the National Cancer Institute and BCRF) plus ongoing pilot studies (supported by BCRF) with high dose omega-3 ethyl esters in pre- and post-menopausal women at increased risk for breast cancer. In the energy balance pilot trial, a median 11% weight loss over six months was associated with reduction in serum insulin and bioavailable hormones, and improvement in serum and tissue adipokines and cytokines. Preliminary results of ongoing six-month pilot studies with high dose omega-3 fatty acids in average weight women indicate improvement in the proportion of women with atypical breast cell appearance and reduced cell growth in benign breast tissue sampled by random periareolar fine needle aspiration (RPFNA). Results of other blood and breast tissue risk biomarkers associated with gene and protein expression involved in cancer development and metastases are pending completion of the clinical trial. However, based on favorable results to date, Dr. Fabian’s team will undertake a pilot study of the combination of calorie restriction and high dose omega-3 fatty acids in obese women to determine tolerance of the combination and the magnitude of effect on risk and mechanism of action biomarkers. The clinical trial by virtue of scope and length can only examine effect on biomarkers but will be paired with preclinical investigations in an obese laboratory model of estrogen receptor positive (ER+) breast cancer performed at the University of Kansas and an obese transgenic laboratory model of estrogen receptor negative (ER-) breast cancer in a collaborative study with Dr. Stephen Hursting at the University of Texas at Austin. Together, the investigators will examine changes in mammary gland cancer incidence as well as risk biomarkers.

Mid-year Progress: The overall goal of Dr. Fabian's project is to augment the effects of weight loss by supplementation with high dose omega-3 fatty acids. A successful weight loss program developed by this team utilized reduced caloric intake via packaged meals, moderate exercise, and weekly behavioral guidance in groups setting. There is tremendous interest in omega-3 fatty acids as potential prevention agents for breast cancer which would complement their known effects on general health. The high dose omega-3 fatty acid intervention was developed as part of a phase II chemoprevention pilot trial funded by BCRF. Dr. Fabian's clinical trial model for both interventions involves women at high risk for development of breast cancer, with benign breast tissue acquired by random periareolar fine needle aspiration. Blood and breast epithelial cells are evaluated for a variety traditional risk biomarkers including hormones, cytomorphology, adiponectin, inflammatory cytokines and gene and protein expression in pathways important for development of breast cancer. Currently, the research team is adding microRNAs to our biomarker panel. They have observed favorable modulation of biomarkers for both interventions, strengthening the rationale for combining the two.

In preparation for the combined intervention clinical trial, Dr. Fabian's team is conducting studies in obese laboratory models of breast cancer. In this setting, they can examine the effects of caloric restriction for weight loss in addition to omega-3 fatty acid supplementation. Dr. Stephen Hursting, another BCRF grantee, is also collaborating on this study and is looking at the effect of omega-3 fatty acids in mouse models that allow the assessment of the effects of high fat diets and obesity on the development of cancer. He will be assessing the effects of omega-3 fatty acids in combination with weight loss. Biomarkers identified in the laboratory studies as promising for predicting response will be used in the clinical trial, in addition to those already targeted.

Bio:
Carol Fabian received her MD, internal medicine and oncology training from the University of Kansas School of Medicine in Kansas City, Kansas. Dr. Fabian joined the faculty at the University of Kansas Medical Center in 1977 and currently holds the rank of Professor. She serves as the Director of the Breast Cancer Prevention and Survivorship Centers. These Centers are heavily involved in translational research in addition to providing clinical services. She leads the Cancer Prevention Research Program within the University of Kansas Cancer Center and holds the Kansas Masonic Cancer Research Chair.

Dr. Fabian pioneered the use of random periareolar fine needle aspiration to acquire breast epithelial cells for refinement of breast cancer risk assessment and for evaluation of biomarkers as a means of monitoring response in early phase breast cancer prevention clinical trials. Subsequently she has trained investigators at multiple institutions in the use of this technique for research purposes. She is currently the principal investigator of three National Cancer Institute funded grants assessing the effects on breast cancer risk biomarkers of potential prevention strategies: 1) weight loss; 2) a flaxseed derivative; and 3) an aromatase inhibitor in postmenopausal women taking hormone replacement. The translational nature of her work and long-term relationships with her basic science colleagues in cancer biology (Bruce F. Kimler, PhD) and reproductive endocrinology veterinary medicine (Brian K. Petroff, DVM, PhD) have facilitated the development of this BRCF project.