“Triple-negative breast cancer (TNBC)”, is one of the most life threatening forms of breast cancer. It is aggressive, least responsive to standard therapy and accounts for 10 to 20 percent of all breast cancers. In a recent breakthrough six distinct subtypes of this cancer have been recognized by scientists from the Vanderbilt-Ingram Cancer Center.

Molecular features of these six distinct subtypes have been described by the Director of the Cancer Center Jennifer Pietenpol, Ph.D., and colleagues in the July issue of the Journal of Clinical Investigation. As reported in the article, the response of all six cancer subtypes to chemotherapies was assessed both in culture cells as well as animal models. The authors further stated that the ability to determine the specific subtype of TNBC would enable the physicians to prescribe targeted chemotherapy to patients suffering from this disease. It would also pave the way for discovery and development of new drugs to cure this difficult-to-treat form of breast cancer.

Dr. J. Pietenpol writes:

“It’s a pretty significant health problem from the standpoint that 11 percent of Caucasians, 17 percent of Hispanics, and 25 percent of African-Americans have this type of breast cancer.”

Standard chemotherapy works well for some patients for an initial period of treatment, but eventually the tumors recur. Recurrence is followed by poor prognosis (due to lack of targeted therapy), and statistics reveal that more than 70% of patients with metastatic TNBC survive for less than 5 years.

The term “triple-negative breast cancer,” said Dr. Pietenpol, “is just a definition of what (the cancer) isn’t.”

Approximately 60% of breast cancers are driven by estrogen receptors (ER) and progesterone receptors (PR), and another 20-30% by the HER2 receptors. All three of these receptors are absent in patients with TNBC, thus the name ‘triple-negative’. The absence of these receptors means that the tumors are less likely to respond to hormone therapies like tamoxifen and to therapies targeted to HER2 like trastuzumab (Herceptin).

587 cases of TNBC among 21 publicly-available breast cancer data sets were identified by Postdoctoral fellows Brian Lehmann, Ph.D., and Joshua Bauer, Ph.D., along with biostatistician Xi (Steven) Chen, Ph.D. Upon analysis of the genomic data, unique gene expression profiles (sets of genes that are either turned “up” or “down” in the tumors) were revealed.

The six distinct subtypes identified by the researchers were – two “mesenchymal” types (M and MSL) controlled by genes associated with cell differentiation and growth factor pathways; two “basal-like” types (BL1 and BL2) linked with cell cycle and DNA damage response genes; an “immunomodulatory” (IM) group, controlled by the genes of the immune system; and a “luminal” subgroup (LAR) driven by the “male” sex hormone (androgen) signaling.

Cell lines that represented each one of the six distinct subtypes were determined and a number of available chemotherapies were tested in them by the researchers. Animal models of these distinct tumor subtypes were also generated by implanting the identified cells into mice.

Scientists found that the mesenchymal-like subtypes (M and MSL) responded to dasatinib and experimental drug NVP-BEZ235; basal-like subtypes (BL1 and BL2) responded to cisplatin; and the LAR subtypes were sensitive to bicalutamide.

The results of this study have outlined an approach to identify molecular differences within this form of breast cancer and also informs about various molecular targets for each subtype. This study can help to significantly advance drug discovery and development efforts for TNBC.

Dr. Pietenpol said:

“In our opinion, the big breakthrough is just being able to say ‘this isn’t one disease.’ Being able to distinguish distinct biological subtypes of TNBC could help guide the design of select clinical trials for subtypes of breast cancer, point toward new biomarkers for patient selection for a given therapy, and identify new targets for drug discovery. This really is the first step in translating genomic information into personalizing therapy for women with a very difficult-to-treat breast cancer.”

“Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies”
Brian D. Lehmann, Joshua A. Bauer, Xi Chen, Melinda E. Sanders, A. Bapsi Chakravarthy, Yu Shyr and Jennifer A. Pietenpol
J Clin Invest. doi:10.1172/JCI45014.

Written by Barry Windsor