TY - JOUR
T1 - Homologous Recombination Deficiency Alterations in Colorectal Cancer
T2 - Clinical, Molecular, and Prognostic Implications
AU - Moretto, Roberto
AU - Elliott, Andrew
AU - Zhang, Jian
AU - Arai, Hiroyuki
AU - Germani, Marco Maria
AU - Conca, Veronica
AU - Xiu, Joanne
AU - Stafford, Phillip
AU - Oberley, Matthew
AU - Abraham, Jim
AU - Spetzler, David
AU - Rossini, Daniele
AU - Antoniotti, Carlotta
AU - Marshall, John
AU - Shields, Anthony
AU - Lopes, Gilberto
AU - Lonardi, Sara
AU - Pietrantonio, Filippo
AU - Tomasello, Gianluca
AU - Passardi, Alessandro
AU - Tamburini, Emiliano
AU - Santini, Daniele
AU - Aprile, Giuseppe
AU - Masi, Gianluca
AU - Falcone, Alfredo
AU - Lenz, Heinz Josef
AU - Korn, Michael
AU - Cremolini, Chiara
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - Background: Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-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 certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or 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 <. 001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P <. 001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P <. 001; 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 with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P =. 04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P =. 07). No interaction effect was evident between homologous recombination 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 homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.
AB - Background: Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-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 certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or 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 <. 001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P <. 001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P <. 001; 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 with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P =. 04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P =. 07). No interaction effect was evident between homologous recombination 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 homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.
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U2 - 10.1093/jnci/djab169
DO - 10.1093/jnci/djab169
M3 - Article
C2 - 34469533
AN - SCOPUS:85124435386
VL - 114
SP - 271
EP - 279
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 2
ER -