Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.
Date
2023-03-01ICR Author
Author
van de Haar, J
Ma, X
Ooft, SN
van der Helm, PW
Hoes, LR
Mainardi, S
Pinato, DJ
Sun, K
Salvatore, L
Tortora, G
Zurlo, IV
Leo, S
Giampieri, R
Berardi, R
Gelsomino, F
Merz, V
Mazzuca, F
Antonuzzo, L
Rosati, G
Stavraka, C
Ross, P
Rodriquenz, MG
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, SM
Petrillo, A
Tamburini, E
La Verde, N
Petrelli, F
Ricci, V
Wessels, LFA
Ghidini, M
Cortellini, A
Voest, EE
Valeri, N
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Proto-Oncogene Proteins p21(ras)
Uracil
Trifluridine
Colorectal Neoplasms
Frontotemporal Dementia
Pyrrolidines
Colonic Neoplasms
Rectal Neoplasms
Drug Combinations
Mutation
Antineoplastic Combined Chemotherapy Protocols
Research team
GI Cancer Biol & Genomics
Language
eng
Date accepted
2023-01-26
License start date
2023-03-01
Citation
Nature Medicine, 2023, 29 (3), pp. 605 - 614
Publisher
NATURE PORTFOLIO