Research Spotlight: 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

Batalini, F. et al. 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. JCO Precision Oncology. no. 7 (2023) e2300091. Published online November 22, 2023. DOI: 10.1200/PO.23.00091

Background:

PARP inhibitors (PARPi) are approved for patients with HER2-negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant, however, clinical benefit has also been demonstrated in mBC with somatic BRCA1/2 mutations or germline PALB2 (gPALB2) mutations. 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 germline BRCA compared to other HRR-genes and by status of a novel HRD signature (HRDsig).

Study details:

A real-world clinico-genomic database of comprehensive genomic profiling linked to de-identified, electronic health record-derived clinical data was used. Comprehensive genomic profiling was analyzed for HRR-genes and HRDsig. The clinico-genomic database enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. Real-world progression-free survival and overall survival were compared.

Of 28,920 patients with mBC, germline BRCA was detected in 3.4%, whereas the population with any BRCA alteration or gPALB2 increased to 9.5%. HRDsig(+) represented 21% of patients with mBC. BRCA and gPALB2 had higher levels of biallelic loss and HRDsig(+) than other HRR alterations. Outcomes on PARPi were assessed for 177 patients. For germline BRCA and somatic BRCA/gPALB2 cohorts were similar: germline BRCA vs somatic BRCA/gPALB2 real world progression free survival was 6.3 vs 5.4 months; real world overall survival was 16.2 vs 21.2 months. Additionally, patients with HRDsig(+) vs HRDsig(-) had longer real world progression free survival (6.3 vs 2.8 months) and numerically longer real world overall survival (17.8 vs 13.0 months).

Why this matters:

Patients with somatic BRCA and gPALB2 derive similar benefit from PARPi as those with germline BRCA alterations. In combination, HRDsig(+), somatic BRCA, and gPALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.

View the full publication in the JCO Precision Oncology.