Purpose: Mutations in BRCA1 and/or BRCA2 (BRCAm), other homologous recombination repair genes (HRRm), and homologous recombination deficiency (HRD) lead to an accumulation of genomic alterations that can drive tumorigenesis. The prognostic impact of these HRR pathway defects on overall survival (OS) in patients not receiving poly (ADP-ribose) polymerase inhibitors (PARPi) or immunotherapy is unclear. We evaluated the association of HRR biomarkers with OS in patients with advanced solid tumors receiving therapy excluding PARPi and immunotherapy.
Methods: Deidentified data were collected through December 31, 2020, from a real-world clinicogenomic database (CGDB) with data originating from approximately 280 cancer clinics in the United States. Patients age 18 years and older with an advanced/metastatic diagnosis between 2018 and 2019 for 1 of 15 solid tumors and available data in the CGDB were included. The primary analysis evaluated the association between HRR pathway biomarkers and OS, using start of second-line therapy as the index date (to reduce immortal time bias).
Results: A total of 9,457 patients had available data for BRCA/HRR and 5,792 for HRD status; 4,890 (51.7%) were women and mean (SD) age was 65.9 (11.5) years. For the primary analysis, adjusted hazard ratios for OS were BRCAm (n = 156) versus BRCA wild-type (wt; n = 3,131; 0.83 [95% CI, 0.60 to 1.17]); for HRRm (n = 467) versus HRRwt (n = 282; 0.95 [95% CI, 0.79 to 1.14]); and for HRD-positive (n = 447) versus -negative (n = 1,687; 1.22 [95% CI, 1.02 to 1.47]). Results were similar using start of first-line and start of third-line therapy as index dates.
Conclusion: This large, real-world study found no association between OS and either BRCA or HRR status but identified a possible linkage between HRD positivity and shorter median OS in patients with advanced solid tumors who did not receive PARPi or immunotherapy.