Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic BRCA1/2, Germline PALB2, or Homologous Recombination Deficiency Signature

Abstract

PURPOSE Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the BRCA1/ 2 genes (g BRCA); however, clinical benefit has also been demonstrated in mBC with somatic BRCA1/ 2 mutations (s BRCA) or germline PALB2 mutations (g PALB2). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g BRCA compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). METHODS A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record–derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared. RESULTS Of 28,920 patients with mBC, g BRCA was detected in 3.4%, whereas the population with any BRCA alteration or g PALB2 increased to 9.5%. HRDsig+ represented 21% of patients with mBC. BRCA and g PALB2 had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and g BRCA and s BRCA/ gPALB2 cohorts were similar: g BRCA versus s BRCA/g PALB2 rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig– had longer rwPFS (6.3 v 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 v 13.0 months; HR, 0.72 [0.46-1.14]). CONCLUSION Patients with s BRCA and g PALB2 derive similar benefit from PARPi as those with g BRCA alterations. In combination, HRDsig+, s BRCA, and g PALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.