BRCA1 -Mutated Estrogen Receptor-Positive Breast Cancer Shows BRCAness, Suggesting Sensitivity to Drugs Targeting Homologous Recombination Deficiency.

Purpose: As estrogen receptor-positive (ER+ ) breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER- ) BRCA1 -mutated breast cancer, it has been suggested that these tumors are "sporadic" and not BRCA1 driven. With the introduction of targeted treatments specific for tumors with a nonfunctioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling of BRCA1 -mutated ER+ tumors. Experimental Design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1 -mutated ER+ tumors. Results were compared with 57 BRCA1 -mutated ER- tumors, 36 BRCA2 -mutated ER+ -associated tumors, and 182 sporadic ER+ tumors. Results: The genomic profile of BRCA1 -mutated ER+ tumors was different from BRCA1 -mutated ER- breast tumors, but highly similar to BRCA2 -mutated ER+ tumors. In 83% of the BRCA1 -mutated ER+ tumors, loss of the wild-type BRCA1 allele was observed. In addition, clinicopathologic variables in BRCA1 -mutated ER+ cancer were also more similar to BRCA2 -mutated ER+ and sporadic ER+ breast cancer than to BRCA1 -mutated ER- cancers. Conclusions: As BRCA1 -mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1 -mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER+ breast cancer. Clin Cancer Res; 23(5); 1236-41. ©2016 AACR .