Roberto Moretto1, Andrew Elliott2, Jian Zhang2, Hiroyuki Arai3, Marco Maria Germani1,4, Veronica Conca1,4, Joanne Xiu2, Phillip Stafford2, Matthew Oberley2, Jim Abraham2, David Spetzler2, Daniele Rossini1,4, Carlotta Antoniotti1,4, John Marshall5, Anthony Shields6, Gilberto Lopes7, Sara Lonardi8,9, Filippo Pietrantonio10,11, Gianluca Tomasello12,13, Alessandro Passardi14, Emiliano Tamburini15, Daniele Santini16, Giuseppe Aprile17, Gianluca Masi1,4, Alfredo Falcone1,4, Heinz-Josef Lenz3, Michael Korn2, Chiara Cremolini1,4. 1. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 2. Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ, USA. 3. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. 4. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. 5. Division of Hematology/Oncology, Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. 6. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. 7. Division of Medical Oncology, Department of Medicine, Miller School of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA. 8. Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 9. Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 10. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 11. Oncology and Hemato-oncology Department, University of Milan, Milan, Italy. 12. Oncology Unit, Oncology Department, ASST of Cremona, Cremona, Italy. 13. UOC Medical Oncology, IRCCS Foundation Ca' Granda Maggiore Hospital Policlinic, Milan, Italy. 14. Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola, Italy. 15. Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy. 16. Department of Medical Oncology, University Campus Biomedico, Rome, Italy. 17. Department of Oncology, San Bortolo General Hospital, Vicenza, Italy.
Abstract
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.
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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