PURPOSE 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). METHODS 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 6 anti–PD-L1. RESULTS 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 5 68) or with an anti–PD-L1 (N 5 90), higher benefit from the addition of the immune checkpoint inhibitor (ICI) was observed in the gLOH-high subgroup (n 5 12), in terms of both progression-free survival (PFS; Pint 5 .02) and overall survival (OS; Pint 5 .03). No differences in PFS or OS were reported between patients treated with first-line oxaliplatin-(n 5 40) versus irinotecan-based doublets (n 5 25) or with the triplet FOLFOXIRI (n 5 68) versus doublets (n 5 65), according to the gLOH status. Among patients not receiving an anti–PD-L1, longer PFS was observed in the gLOH-low group (n 5 138) versus the gLOH-high (n 5 6) group (5.1 v 12.1 months; hazard ratio, 8.73 [95% CI, 3.64 to 20.9]; P < .001), and this was confirmed in the multivariate analysis (P < .001). No prognostic impact of monoallelic or biallelic HRR-related gene alterations was shown. CONCLUSION 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.
Exploring the Prognostic and Predictive Impact of Genomic Loss of Heterozygosity and Homologous Recombination Deficiency Alterations in Patients With Metastatic Colorectal Cancer
Germani, Marco Maria;Carullo, Martina;Conca, Veronica;Antoniotti, Carlotta;Ugolini, Clara;Masi, Gianluca;Cremolini, Chiara
2025-01-01
Abstract
PURPOSE 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). METHODS 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 6 anti–PD-L1. RESULTS 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 5 68) or with an anti–PD-L1 (N 5 90), higher benefit from the addition of the immune checkpoint inhibitor (ICI) was observed in the gLOH-high subgroup (n 5 12), in terms of both progression-free survival (PFS; Pint 5 .02) and overall survival (OS; Pint 5 .03). No differences in PFS or OS were reported between patients treated with first-line oxaliplatin-(n 5 40) versus irinotecan-based doublets (n 5 25) or with the triplet FOLFOXIRI (n 5 68) versus doublets (n 5 65), according to the gLOH status. Among patients not receiving an anti–PD-L1, longer PFS was observed in the gLOH-low group (n 5 138) versus the gLOH-high (n 5 6) group (5.1 v 12.1 months; hazard ratio, 8.73 [95% CI, 3.64 to 20.9]; P < .001), and this was confirmed in the multivariate analysis (P < .001). No prognostic impact of monoallelic or biallelic HRR-related gene alterations was shown. CONCLUSION 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
