Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRAS(G12)) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS(G12) mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRAS(G12) mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRAS(G12) mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRAS(G13) mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRAS(G12) mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS(G12) mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.A combination of real-world evidence and a reanalysis of phase 3 clinical trial data unveils KRAS codon G12 mutations as a biomarker of resistance to trifluridine/tipiracil in metastatic colorectal cancer.

Van De Haar, J., Ma, X., Ooft, S. N., Van Der Helm, P. W., Hoes, L. R., Mainardi, S., Pinato, D. J., Sun, K., Salvatore, L., Tortora, G., Zurlo, I. V., Leo, S., Giampieri, R., Berardi, R., Gelsomino, F., Merz, V., Mazzuca, F., Antonuzzo, L., Rosati, G., Stavraka, C., Ross, P., Rodriquenz, M. G., Pavarana, M., Messina, C., Iveson, T., Zoratto, F., Thomas, A., Fenocchio, E., Ratti, M., Depetris, I., Cergnul, M., Morelli, C., Libertini, M., Parisi, A., De Tursi, M., Zanaletti, N., Garrone, O., Graham, J., Longarini, R., Gobba, S. M., Petrillo, A., Tamburini, E., La Verde, N., Petrelli, F., Ricci, V., Wessels, L. F. A., Ghidini, M., Cortellini, A., Voest, E. E., Valeri, N., Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer, <<NATURE MEDICINE>>, 2023; 29 (3): 605-614. [doi:10.1038/s41591-023-02240-8] [https://hdl.handle.net/10807/232266]

Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer

Salvatore, Lisa;Tortora, Giampaolo;Zurlo, Ina Valeria;Morelli, Cristina;Libertini, Michela;
2023

Abstract

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRAS(G12)) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS(G12) mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRAS(G12) mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRAS(G12) mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRAS(G13) mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRAS(G12) mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS(G12) mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.A combination of real-world evidence and a reanalysis of phase 3 clinical trial data unveils KRAS codon G12 mutations as a biomarker of resistance to trifluridine/tipiracil in metastatic colorectal cancer.
2023
Inglese
Van De Haar, J., Ma, X., Ooft, S. N., Van Der Helm, P. W., Hoes, L. R., Mainardi, S., Pinato, D. J., Sun, K., Salvatore, L., Tortora, G., Zurlo, I. V., Leo, S., Giampieri, R., Berardi, R., Gelsomino, F., Merz, V., Mazzuca, F., Antonuzzo, L., Rosati, G., Stavraka, C., Ross, P., Rodriquenz, M. G., Pavarana, M., Messina, C., Iveson, T., Zoratto, F., Thomas, A., Fenocchio, E., Ratti, M., Depetris, I., Cergnul, M., Morelli, C., Libertini, M., Parisi, A., De Tursi, M., Zanaletti, N., Garrone, O., Graham, J., Longarini, R., Gobba, S. M., Petrillo, A., Tamburini, E., La Verde, N., Petrelli, F., Ricci, V., Wessels, L. F. A., Ghidini, M., Cortellini, A., Voest, E. E., Valeri, N., Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer, <<NATURE MEDICINE>>, 2023; 29 (3): 605-614. [doi:10.1038/s41591-023-02240-8] [https://hdl.handle.net/10807/232266]
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