Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications

We evaluated 6341 consecutive breast cancer samples across multiple platforms to identify biomarkers of potential drug response. Subgroups of triple-negative breast cancers were identified, with different gene mutations, protein expression levels, and patterns in co-incidence, which might inform individualized treatment options. Background: Triple-negative breast cancer (TNBC) is an aggressive disease without established targeted treatment options for patients with metastatic disease. This study was undertaken to evaluate potentially actionable biomarkers in a large cohort of TNBC and compare them with non-TNBCs. Materials and Methods: We evaluated 6341 (2111 TNBC and 4230 non-TNBC) breast cancer samples at a central laboratory for biomarkers of potential drug response across multiple platforms, including gene sequencing, protein expression, and gene copy number. Results: TNBC expresses androgen receptor (AR) in a significantly (P < .05) lower percentage of cases (17%) than hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas (59% and 79%, respectively), and gene comutations were differentially associated with AR-positive versus AR-negative cases. Higher AR expression levels in TNBC predicted for lower Ki-67 levels. Seventy percent of TNBC harbored a phosphatidylinositol- 4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), or phosophatase and tensin homolog (PTEN) aberration. TNBC patients had a significantly lower PIK3CA mutation rate (13%) than all other subtypes (P < .05) and a higher tumor protein p53 (TP53) mutation rate (64%) than the estrogen receptor (ER)-positive cases (approximately 30%; P < .05). Topoisomerase 2 (TOP2A) amplification was observed in 1.3% of TNBC and in 1.6% of HER2-negative, HR-positive cancers; in contrast, HER2-positive, HR-negative or HR-positive cancers exhibited TOP2A amplification in 19% and 40% of cases, respectively (P < .05). Conclusion: Multi-platform molecular profiling identifies subgroups of TNBC with different biomarker profiles, suggesting numerous potentially targetable alterations in TNBC. TNBC is further characterized by different gene mutations and proliferative activity relative to AR expression, highlighting a need for comprehensive pathologic examination with potential to develop different, individualized treatment options. (C) 2015 The Authors. Published by Elsevier Inc.