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.

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