Finding multiple mutations instead of just one primary mutation that can be targeted for therapy sheds more light on the challenges of treating triple-negative breast cancer.

The study, led by Justin Balko, Pharm.D., Ph.D., and research faculty in the laboratory of Carlos Arteaga, M.D., director of the Breast Cancer Program at VICC, was presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 4-8.

Approximately 15 percent of breast cancer patients in the U.S. have triple-negative cancer -- a form of the disease that disproportionately affects young African-American women. Triple-negative breast cancer has traditionally been more difficult to treat than other forms of the disease.

"The standard of care for many patients with triple-negative breast cancer is to administer chemotherapy before surgery to shrink the tumor," Balko said. "Unfortunately, about 70 percent of patients still have some residual disease at the time of surgery, despite treatment."

Balko and colleagues profiled residual tumor tissue from 114 patients with triple-negative breast cancer who had received chemotherapy prior to surgery. Triple-negative breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of the HER2/neu protein.

The investigators were able to evaluate DNA from 81 tumors and used deep sequencing to examine 182 oncogenes and tumor suppressors that are known to be altered in human cancers. Instead of finding similar genes affected among the patients, they found a diverse set of genes were altered.

"We already knew that triple-negative breast cancer is driven by a diverse group of genetic alterations," Balko said. "So, in one way, we fell further down this rabbit hole, but we also found some things that could be promising therapeutically, such as frequent MYC, MCL1 and JAK2 amplifications as well as mutations in the PI3K pathway."

The additional genetic alterations found in the study may provide targets for new therapies.

Balko said the next step is to confirm the findings in a larger patient group, and if the findings are replicated, broad molecular approaches will be needed to help develop personalized therapies for triple-negative breast cancer. It also will be necessary to explore the therapeutic sensitivity of breast cancers harboring these lesions in the laboratory to know how to treat patients who have these alterations.

This research was a collaboration of the Breast Cancer Research Program at Vanderbilt, the Instituto Nacional de Enfermedades Neoplásicas (Lima, Perú) and Foundation Medicine (Cambridge, Mass.). It was funded by the Susan G. Komen for the Cure Foundation, the National Cancer Institute -- a division of the National Institutes of Health (Vanderbilt Breast SPORE Grant P50 CA98131) and the Lee Jeans/Entertainment Industry Foundation Translational Breast Cancer Research Program.

The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium.