Mutations in Homologous Recombination Genes and Loss of Heterozygosity Status in Advanced-Stage Breast Carcinoma

Poly (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 germline mutation-associated breast cancer. PARPis have also been found to be efficacious in wild-type ( ) 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% and 19% non- -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 a mutation other than and had a clinical partial response. Twenty-two percent of the LOH-low tumors had -HRR gene mutations, compared with 11% of the LOH-high tumors. Comprehensive genomic profiling revealed a subset of breast cancer patients with a -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.