Breast Cancer Center of Excellence

Benign Breast Disease: Toward Molecular Prediction of Breast Cancer Risk

A Department of Defense (DOD), Congressionally Directed Medical Research Program
Award: 2002 - $5.8 million
Principal Investigator: Lynn Hartmann, M.D.

Breast cancer accounts for more than 30 percent of all new cancer diagnoses in women. It claims the lives of more than 40,000 women each year in the United States, and is diagnosed in nearly a quarter million women each year. Women who have had a breast biopsy with benign findings, so-called benign breast disease, have an increased risk of a later breast cancer. This Mayo effort is working to identify better risk predictors, at a clinical and tissue level, in benign breast tissue.

With the goal of one day eradicating breast cancer, the DOD Breast Cancer Research Program provides awards for unique breast cancer research projects. The Program uses a rigorous two-tier review process to ensure selection of the most promising research, and consists of a multidisciplinary research portfolio encompassing the full spectrum of breast cancer research, from prevention and detection to diagnosis and treatment.

Funded in 2002, Mayo Clinic Cancer Center's Breast Cancer Center of Excellence exists to bring molecular risk prediction for breast cancer into the clinical arena. To this end, a number of specific aims have been established:

1. To establish a large tissue repository from a retrospective cohort of women with benign breast disease, in order to identify the features of those who developed breast cancer and those who did not;
2. To test potential biomarkers of risk in this archival tissue set; and
3. To discover new, potentially relevant biomarkers of risk in samples of benign breast disease.

Mayo's cohort consists of 9,376 women with benign breast biopsies obtained between 1967 and 1991 at Mayo Clinic.

The researchers select markers to test based on the hypothesis that the process of breast carcinogenesis depends upon the acquisition of multiple genetic changes in key regulatory genes. They assumed that multiple changes could occur because of widespread genetic instability, and that such instability occurs early and is detectable in benign breast disease. The selected markers assess various measures of genomic instability. The researchers also seek to measure proliferation, cell death and estrogen receptor status.

Because the genes and markers that are currently known may not be adequate to describe the key phenomena causing breast carcinogenesis, a major goal of Mayo's Center of Excellence is discovery. The investigators' work includes in vitro culturing of select benign breast specimens to extend current understanding of the changes that occur in human mammary epithelial cells that precede the development of malignant transformation. These specimens are obtained from women who need a breast biopsy because of a clinical concern, but who have benign findings on the biopsy (and there is sufficient material available from the biopsy that can be used for research purposes). The team also is working to perform high throughput expression profiling of select samples of benign breast disease to help build the overall knowledge base and to identify and further study better risk markers.

Since receiving the Center of Excellence award in 2002, Mayo Clinic Cancer Center investigators and collaborating researchers have published a number of papers on their findings.

These include:

• Stratification of breast cancer risk in women with atypia: A Mayo cohort study
• Age-related lobular involution and risk of breast cancer
• An analysis of breast cancer risk in women with single, multiple, and atypical papilloma
• Benign breast disease and the risk of breast cancer

With improved identification of women at significantly increased risk, clinicians can better target surveillance and risk reduction strategies for individual women. Additionally, the new biomarkers being identified in benign breast disease may help to identify causative pathways in breast carcinogenesis that could then be targeted for specific prevention strategies.