Simple SummaryThe clinical significance of next-generation sequencing coupled with HRR gene analysis of the benefit of poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) treatment in patients with breast cancer is unknown. We analyzed the tumor mutations in homologous recombination (HRR) genes and the loss of heterozygosity (LOH) score in 63 patients with advanced-stage breast carcinoma. We found an HRR gene mutation and an LOH-high score were associated with unfavorable pathological features. Comprehensive genomic profiling revealed that a subset of breast carcinomas with an HRR gene mutation other thanBRCA1/2had a low LOH score. In order to identify potential eligible patients for PARPi therapy, appropriate testing is warranted and requires further investigation.AbstractPoly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) have demonstrated antitumor activity in cancers with a homologous recombination deficiency (HRD) and have recently been approved by the FDA for the treatment of germlineBRCA1/2-mutation-associated breast cancer. PARPis have also been found to be efficacious inBRCAwild-type (BRCAwt) lesions with high genomic loss of heterozygosity (LOH-high). The goal of this study was to retrospectively investigate the tumor mutations in homologous recombination (HRR) genes and the LOH score in advanced-stage breast carcinomas (BCs). Sixty-three patients were included in our study, 25% of whom had HRR gene mutations in their tumors, including 6%BRCA1/2and 19% non-BRCA-containing gene mutations. An HRR gene mutation was associated with a triple-negative phenotype. Twenty-eight percent of the patients had an LOH-high score, which, in turn, was associated with a high histological grade, a triple-negative phenotype, and a high tumor mutational burden (TMB). Among the six patients who received PARPi therapy, one had a tumor with aPALB2mutation other thanBRCAand had a clinical partial response. Twenty-two percent of the LOH-low tumors hadBRCAwt–HRR gene mutations, compared with 11% of the LOH-high tumors. Comprehensive genomic profiling revealed a subset of breast cancer patients with aBRCAwt–HRR gene mutation that would be missed by an LOH test. The necessity of next-generation sequencing coupled with HRR gene analysis for PARPi therapy requires further investigation in clinical trials.