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.

Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer / van de Haar, Joris; Ma, Xuhui; Ooft, Salo N; van der Helm, Pim W; Hoes, Louisa R; Mainardi, Sara; Pinato, David J; Sun, Kristi; Salvatore, Lisa; Tortora, Giampaolo; Zurlo, Ina Valeria; Leo, Silvana; Giampieri, Riccardo; Berardi, Rossana; Gelsomino, Fabio; Merz, Valeria; Mazzuca, Federica; Antonuzzo, Lorenzo; Rosati, Gerardo; Stavraka, Chara; Ross, Paul; Rodriquenz, Maria Grazia; Pavarana, Michele; Messina, Carlo; Iveson, Timothy; Zoratto, Federica; Thomas, Anne; Fenocchio, Elisabetta; Ratti, Margherita; Depetris, Ilaria; Cergnul, Massimiliano; Morelli, Cristina; Libertini, Michela; Parisi, Alessandro; De Tursi, Michele; Zanaletti, Nicoletta; Garrone, Ornella; Graham, Janet; Longarini, Raffaella; Gobba, Stefania Maria; Petrillo, Angelica; Tamburini, Emiliano; La Verde, Nicla; Petrelli, Fausto; Ricci, Vincenzo; Wessels, Lodewyk F A; Ghidini, Michele; Cortellini, Alessio; Voest, Emile E; Valeri, Nicola. - In: NATURE MEDICINE. - ISSN 1078-8956. - 29:3(2023), pp. 605-614. [10.1038/s41591-023-02240-8]

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

Giampieri, Riccardo;Berardi, Rossana;Parisi, Alessandro;
2023-01-01

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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/314963
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