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

Abstract

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 <i>BRCA1</i>/<i>2</i> genes (g<i>BRCA</i>); however, clinical benefit has also been demonstrated in mBC with somatic <i>BRCA1</i>/<i>2</i> mutations (s<i>BRCA</i>) or germline <i>PALB2</i> mutations (g<i>PALB2</i>). 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<i>BRCA</i> compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). 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. Of 28,920 patients with mBC, g<i>BRCA</i> was detected in 3.4%, whereas the population with any <i>BRCA</i> alteration or g<i>PALB2</i> increased to 9.5%. HRDsig+ represented 21% of patients with mBC. <i>BRCA</i> and g<i>PALB2</i> had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and g<i>BRCA</i> and s<i>BRCA</i>/<i>gPALB2</i> cohorts were similar: g<i>BRCA</i> versus s<i>BRCA</i>/g<i>PALB2</i> 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 <i>v</i> 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 <i>v</i> 13.0 months; HR, 0.72 [0.46-1.14]). Patients with s<i>BRCA</i> and g<i>PALB2</i> derive similar benefit from PARPi as those with g<i>BRCA</i> alterations. In combination, HRDsig+, s<i>BRCA</i>, and g<i>PALB2</i> represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.