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

Abstract

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