Genomic and epigenomic alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas.

Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with promoter methylation (meth) respond more poorly to alkylating agents compared to those bearing mutations in and (mut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with meth and mut states, meth uniformly associates with poor outcomes. Exposure of meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of methylation and increased expression and platinum resistance. These data suggest that, unlike mut cancers, where loss is a genetically "fixed" deficiency state, meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of mutations results in more accurate predictions of patient response when compared to either HRD status or status alone. This underscores the importance of defining heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa.