Exploring the Prognostic and Predictive Impact of Genomic Loss of Heterozygosity and Homologous Recombination Deficiency Alterations in Patients With Metastatic Colorectal Cancer.

Abstract

Genomic loss-of-heterozygosity (gLOH) consists in the loss of chromosomal regions and is associated with homologous recombination repair (HRR) system deficiency. We explored the role of gLOH and HRR-related gene alterations in metastatic colorectal cancer (mCRC). FoundationOne CDx assay was used to determine the percentage of gLOH and the presence of alterations in 27 HRR-related genes in archival chemo-naïve tumor tissues of patients with mCRC treated with first-line oxaliplatin- or irinotecan-based doublets and triplet ± anti-PD-L1. Overall, 243 samples were analyzed. None of the nine deficient mismatch repair/microsatellite instability high tumors were gLOH-high, while 16 (7%) of 234 proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors were gLOH-high. In the pMMR/MSS population, six (3%) and 18 (8%) had at least a biallelic or monoallelic HRR-related gene alteration, respectively. Among patients receiving FOLFOXIRI alone (n = 68) or with an anti-PD-L1 (N = 90), higher benefit from the addition of the immune checkpoint inhibitor (ICI) was observed in the gLOH-high subgroup (n = 12), in terms of both progression-free survival (PFS; <i>P</i>_int = .02) and overall survival (OS; <i>P</i>_int = .03). No differences in PFS or OS were reported between patients treated with first-line oxaliplatin- (n = 40) versus irinotecan-based doublets (n = 25) or with the triplet FOLFOXIRI (n = 68) versus doublets (n = 65), according to the gLOH <i>status</i>. Among patients not receiving an anti-PD-L1, longer PFS was observed in the gLOH-low group (n = 138) versus the gLOH-high (n = 6) group (5.1 <i>v</i> 12.1 months; hazard ratio, 8.73 [95% CI, 3.64 to 20.9]; <i>P</i> < .001), and this was confirmed in the multivariate analysis (<i>P</i> < .001). No prognostic impact of monoallelic or biallelic HRR-related gene alterations was shown. In pMMR/MSS mCRC, gLOH-high was associated with worse prognosis and higher benefit from the addition of anti-PD-L1 agents to chemotherapy. If confirmed in larger series, these results may inform the design of clinical trials.