BRCA Promoter Methylation in Triple-negative Breast Cancer is Preserved in Xenograft Models and Represents a Potential Therapeutic Marker for PARP Inhibitors

Purpose: Most triple-negative breast cancers (TNBC) are sporadic in nature and often associated with dysfunction of the BRCA1 or BRCA2 genes. Since somatic BRCA mutations are rare in breast cancer (BC), this dysfunction frequently is the result of BRCA promoter methylation. Despite the phenotypic similarities of these tumors to those with germline or somatic BRCA mutation, the evidence of response to PARP inhibitors is unclear.

Methods: We analyzed the prevalence of BRCA promoter methylation in 29 BC metastases through the well-established Illumina Infinium EPIC Human Methylation Bead Chip. In cases with BRCA methylation, the xenograft of the same tumor was tested. Additionally, we compared BC xenografts with an identified BRCA methylation to their matched primary tumors and subsequently investigated the efficacy of PARP inhibitors on tumor organoids from a BRCA2 promoter-methylated BC.

Results: BRCA2 promotor hypermethylation was identified in one pleural metastasis of a young patient as well as in the xenograft tissue. We also identified five more xenograft models with BRCA2 promotor hypermethylation. Analysis of one matched primary tumor confirmed the same BRCA2 methylation. PARP inhibitor treatment of tumor organoids derived from the BRCA2 methylated xenograft tumor tissue of the young patient showed a significant decline in cell viability, similar to organoids with somatic BRCA1 mutation, while having no effect on organoids with BRCA1 wildtype.

Conclusion: BRCA promotor hypermethylation seems to be a rare event in metastatic BC but is preserved in subsequent xenograft models and might represent an attractive therapeutic marker for PARP inhibitors.