Researchers at Vanderbilt University Medical Center are reporting another advance in the understanding and treatment of triple-negative breast cancer, which is particularly aggressive and difficult to treat.
Their findings, detailed in the journal Clinical Cancer Research, offer new hope for identifying patients most likely to respond to the latest treatments.
“This study exemplifies a signature strength of Vanderbilt-Ingram Cancer Center (VICC) — our ability to translate basic science discoveries to the clinic for the benefit of our patients, and partner with other cancer centers to quickly advance clinical trials,” said Jennifer Pietenpol, PhD, VICC director and Executive Vice President for Research at VUMC.
Pietenpol, the Benjamin F. Byrd Jr. Professor of Oncology, co-authored the report with first authors Vandana Abramson, MD, associate professor of Medicine, and Brian Lehmann, PhD, research assistant professor of Medicine.
Triple-negative breast cancers test negative for estrogen receptors, progesterone receptors and amplification of the human epidermal growth factor receptor 2 (HER2) protein. They therefore do not respond to therapy that blocks the hormone estrogen or progesterone, or to drugs that target HER2.
A subset of triple-negative breast cancers express receptors that bind androgens, so-called “male hormones” which are also present in women but at much lower levels. Androgen receptor-positive (AR+) tumors tend to have cancer-linked mutations in PIK3CA, the gene that encodes the PIK3 protein.
Taking this information into account, the researchers tested the effect of treating patients who had AR+ metastatic triple-negative breast cancer with a combination of drugs that blocked the androgen receptor and inhibited PIK3.
Sixteen weeks after treatment was begun, nearly 36% of patients who received both drugs showed a clinical benefit rate — a complete response, partial response or stable disease — compared to none of the patients who received only the AR blocker.
AR+ patients, whose tumors had a luminal AR (LAR) “gene signature” and PIK3CA mutations, had an even greater response — 75% compared to 12.5% of patients who did not have this signature, and they also had longer progression-free survival.
The major side effects of the treatment were hyperglycemia (high blood glucose) and a significant skin rash that may have been caused by the PIK3 inhibitor, taselisib. “Future studies could explore combinations with other PI3K inhibitors that have more tolerable side effect profiles,” the researchers noted.
Given the lack of treatment options for metastatic triple-negative breast cancer, exploring subsets of these tumors that may respond to novel therapies, including new drug combinations in AR+ patients, “is of utmost importance,” they concluded.
The study was conducted in collaboration with the Translational Breast Cancer Research Consortium (TBCRC 032), composed of 19 clinical sites nationwide including VICC. Other VUMC co-authors were Melinda Sanders, MD, Paula Gonzalez Ericsson, MD, Violeta Sanchez, MS, Kimberly Johnson, Richard Abramson, MD, Sheau-Chiann Chen, PhD, and Yu Shyr, PhD.
The research was supported by National Cancer Institute grants CA098131 (Breast SPORE) and CA068485 and by the Susan G. Komen organization, a major funder of metastatic breast cancer research.
