Association of a four-gene decision tree signature with response to platinum-based chemotherapy in patients with triple negative breast cancer.

Abstract

1006 Background: Approaches to capture the molecular complexity of triple negative breast cancers (TNBCs) are lacking. We sought to classify TNBCs into subgroups with common biological features based on transcriptomic and genomic data using a Bayesian algorithm. Methods: Matched gene expression and copy number microarray data was available for the Guy’s (n = 88) and METABRIC (n = 112) TNBC cohorts. CONEXIC was used to derive a decision tree signature for classification. Performance of the signature was tested in 7 TNBC cohorts (total n: 1,368), including 2 clinical trials assessing the efficacy of gemcitabine and carboplatin with and without iniparib. In the early-stage PrECOG 0105 Phase II neoadjuvant trial (n = 43), subtypes were evaluated in relation to response by residual cancer burden (RCB). In the metastatic Sanofi Phase III trial (n = 224), subtypes were assessed by RECIST. Results were compared to the BL1 TNBCtype-4 subtype and assessed using a multivariate analysis. Results: The integrative analysis using CONEXIC identified a four-gene signature. Across 7 TNBC cohorts this classification identified 6 entities, including 5 smaller groups and 1 major. Characterisation of the latter subgroup, referred to as MC6, revealed enrichment of CD4+ and CD8+ immune signatures, increased genomic instability and reduction in negative regulation of the MAPK signalling pathway. In PrECOG, 25 out of 41 MC6-TNBCs (61%, OR = 1.19, 95% CI = 0.37 to 3.81, P = 0.79) had RCB 0/I. Similarly, 65% of the BL1-TNBCs had an RCB 0/I, however in a smaller population (11 out of 17, OR = 1.30, 95% CI = 0.35 to 5.31), P = 0.77). In Sanofi Phase III, the objective response rate (ORR) in MC6-TNBCs was 46% versus 30% in non-MC6-TNBCs (OR = 1.97, 95% CI = 1.03 to 3.77, P = 0.04), in comparison to BL1-TNBCs with an ORR of 41% versus 32% in non-BL1-TNBCs (OR = 1.47, 95% CI = 0.75 to 2.86), P = 0.26). Conclusions: These results demonstrate that a four-gene signature can identify a subgroup of TNBCs responsive to platinum-based chemotherapy in the metastatic setting. The distinct features of these TNBCs suggest investigation of alternative actionable interventions with immunotherapy or MEK inhibitors in relation to this signature.