A new study has reported that triple negative breast cancer can be divided into subtypes which respond to treatments tailored to them. Triple negative refers to breast cancer that is estrogen receptor negative (ER-), progesterone receptor negative (PR-), and does not overexpress human epidermal growth factor receptor 2 (HER2). However, triple negative breast cancer has been shown to be a highly diverse group of cancers, and subtyping is needed to better identify effective treatments.
To conduct the study, the authors analyzed gene expression profiles in 21 public breast cancer data sets, identifying 587 triple negative breast cancer cases. Six triple negative breast cancer subtypes displaying unique gene expression and characteristics were found, including two subtypes (BL1 and BL2) involving cell cycle and DNA damage response genes, a subtype (IM) driven by immune system genes, two subtypes (M and MSL) with genes active in cell differentiation and growth, and an androgen receptor subtype (LAR) driven by male sex hormone signaling.
Gene expression analysis also enabled the authors to identify triple negative breast cancer cell lines representative of these subtypes. In addition, the authors implanted these cells into mice to generate animal models of the tumor subtypes. Predicted “driver” signaling pathways were targeted by drugs in these subtype models to demonstrate that analysis of distinct gene expression signatures can inform treatment selection. The BL1 and BL2 subtypes. with their relatively high expression of cell cycle and DNA damage response genes, preferentially responded to treatment with cisplatin. The M and MSL subtypes, with enriched gene expression for epithelial-mesenchymal transition and growth factor pathways, responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype included patients with unfavorable relapse-free survival rates and was characterized by androgen receptor signaling; LAR cell lines were uniquely sensitive to bicalutamide (an androgen receptor antagonist). The authors comment that the study results may be useful in biomarker selection, drug discovery, and clinical trial design to enable triple negative breast cancer patients obtain appropriate targeted treatments.