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

Abstract

Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation ( BRCA1 meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 ( BRCA mut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA 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 BRCA1 meth and BRCA mut states, BRCA1 meth uniformly associates with poor outcomes. Exposure of BRCA1 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 BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCA mut cancers, where BRCA loss is a genetically “fixed” deficiency state, BRCA1 meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 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 BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa.

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

“…Different platinum-resistant BRCA1 methylated models show significant BRCA1 gene expression, associated with a low percentage of BRCA1 methylation and increased levels of RAD51 foci upon cisplatin treatment, supporting incomplete promoter methylation as potential mechanism of platinum resistance in these tumours. This is in accordance with recent studies demonstrating that biallelic BRCA1/2 inactivation was required for response to PARP inhibitors and platinum 31 – 33 .…”

“…A positive correlation between the presence of BRCA1/2 mutations and platinum-based therapy was found in several studies both in the neo-adjuvant and metastatic setting 7 , 25 – 27 , although not in others 28 , 29 . We find no correlation between cisplatin response and BRCA1 methylation, in line with recent studies 25 , 30 , 31 . Different platinum-resistant BRCA1 methylated models show significant BRCA1 gene expression, associated with a low percentage of BRCA1 methylation and increased levels of RAD51 foci upon cisplatin treatment, supporting incomplete promoter methylation as potential mechanism of platinum resistance in these tumours.…”

Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer

“…Moreover, the 3D-HRD assay did not include BRCA1 promoter DNA methylation, which was considered in the Myriad HRD assay. A recent study has found that BRCA1 promoter DNA methylation is a functionally plastic state that is depleted rapidly after exposure to chemotherapy, and BRCA1 methylation status was not associated with a survival advantage 52 .…”

Targeting Breast Cancer: An Overlook on Current Strategies

“…BReast CAncer genes ( BRCA ) 1 and 2 encode DNA repair enzymes and took their name just because of their association with BC [ 33 , 34 ]. BRCA mutations are highly associated with TNBC, as well as the loss of BRCA1 or BRCA2 activity [ 35 ]. Phosphatase and Tensin homolog deleted on chromosome 10 ( PTEN ) is a tumor suppressor gene located in the 10q23 region of chromosome 10 that has been found to be mutated in many types of cancers, including BC, and encodes for a dual lipid and protein phosphatase [ 36 ].…”