Carol J. Fabian, MD

Although large primary prevention trials have confirmed that the incidence of breast cancer can be reduced by certain drugs (tamoxifen, raloxifene), future generations of promising interventions will be initially tested by small trials that use tissue-based assessments to demonstrate potential effectiveness. A well-accepted technique known as random periareolar fine needle aspiration (RPFNA) can be used to acquire benign breast cells that can be assessed for features associated with the risk of developing breast cancer, and modulation of these features or biomarkers after an intervention. Successful trials demonstrating modulation of "response biomarkers" often associated with cell growth have been conducted with pre-menopausal women and postmenopausal women taking hormones. Although risk for breast cancer increases with age, post-menopausal women not on hormones typically yield few benign epithelial cells by RPFNA; and so it has been difficult to conduct clinical prevention trials targeted at this cohort.

Dr. Fabian and her colleagues will address this problem by employing ultra-sensitive techniques to measure low levels of hormones in small amounts of breast tissue acquired by RPFNA. They will assess expression of critical genes using qRT-PCR which allows assessment even on very small numbers of cells. By developing effective biomarkers for assessment of response, they will facilitate the conduct of tissue-based prevention trials for the majority of postmenopausal women and allow the testing of not only novel drugs and natural products, but also lifestyle modifications such as diet and exercise.

The overall goal of Dr. Fabian's work is to identify reversible risk biomarkers in benign breast tissue suitable for response endpoints in proof of principle Phase II prevention trials. Her goal is to develop alternatives to Ki-67, the traditionally used response biomarker, in the form of tissue estrogen levels and a gene expression panel reflective of hormone, survival and growth factor signaling in addition to proliferation. With the help of collaborators, the Fabian team has been able to measure estrogen in the tiny amounts of tissue obtained from fine needle aspiration with a highly sensitive and specific form of mass spectroscopy and have also developed qRTPCR techniques to allow the researchers to quantify multiple genes important in the development of pre- cancer and which should be affected by prevention interventions which are likely to be tested over the next five years.

Mid-Year Progress Report:
The goal of Dr. Fabian's team is to develop alternatives to Ki-67, the traditionally used response biomarker, in the form of protein levels and gene expression reflective of hormone, survival and growth factor signaling in addition to proliferation. The focus has been on measurements in small amounts of benign breast epithelial cells that are acquired by random periareolar fine needle aspiration (RPFNA) and then immediately frozen, in contrast to the long established methods of standard fixation.

With the help of collaborators, the researchers have been able to make substantial progress in three areas: 1) measurement of omega-3 fatty acid levels in frozen FNA specimens; measurement of 11 different cytokines, adipokines, or hormones in frozen FNA specimens; and 3) assessment of change in levels of the risk biomarkers adiponectin and leptin in paired serum specimens collected pre-study and after a 12 month intervention with a natural product lignan (e.g., a compound in flaxseed).

These results have facilitated the development of new intervention trials that previously would have been difficult to design because of a lack of assessments of markers for the development of pre- cancer which might be affected by the planned prevention interventions.

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 PI of three NCI 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.