Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.
Рандомизированное исследованиеСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 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 KRASG12 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 KRASG12 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 KRASG13 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, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 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.