Homologous Recombination Deficiency Alterations in Colorectal Cancer: Clinical, Molecular, and Prognostic Implications.

BACKGROUND Tumors with homologous recombination (HR) deficiency (HRD) show high sensitivity to platinum salts and PARP-inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown. METHODS Next generation sequencing, whole transcriptome sequencing and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Tumors with pathogenic/presumed pathogenic mutations in 33 genes involved in the HR pathway were considered HRD, the others HR proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab versus FOLFOX/bevacizumab were analyzed with next generation sequencing. The analyses were separately conducted in microsatellite stable/proficient mismatch repair (MSS/pMMR) and microsatellite instable-high/deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided. RESULTS Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%, p and q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2% P and q < 0.001) and PD-L1 positive (5.0% vs 2.4%, P and q = 0.001), enriched in all immune cell and fibroblast populations, and genomic loss of heterozygosity-high (16.2% vs 9.5%, P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared to MSS/pMMR and HRP ones (40.2 vs 23.8 months; hazard ratio = 0.66; 95% confidence interval = 0.45-0.98, P = .04). Consistent results were reported in the multivariable model (hazard ratio = 0.67; 95% confidence ratio = 0.45-1.02, P = .07). No interaction effect was evident between HR groups and treatment arm. CONCLUSIONS HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the HR system and immune check-point inhibitors in this subgroup is worth of clinical investigation.