<i>BRCA</i> Mutations, Homologous DNA Repair Deficiency, Tumor Mutational Burden, and Response to Immune Checkpoint Inhibition in Recurrent Ovarian Cancer.

Abstract

Homologous DNA repair-deficient (HRD) ovarian cancers (OCs), including those with <i>BRCA1/2</i> mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair-proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between <i>BRCA1/2</i> mutations, HRD, and other genomic parameters and response to ICIs and survival in OC. This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. <i>BRCA1/2</i> mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of <i>BRCA1/2</i> status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models. Of the 143 women treated with ICIs, 134 had known <i>BRCA1/2</i> mutation status. Deleterious germline or somatic <i>BRCA1/2</i> mutations were present in 31 women (24%). There was no association between presence of <i>BRCA1/2</i> mutations and response (<i>P</i> = .796) or survival. Genomic analysis in 73 women found no association between TMB (<i>P</i> = .344) or HRD (<i>P</i> = .222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS (<i>P</i> = .014) and OS (<i>P</i> = .01). TMB, <i>BRCA1/2</i> mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC.