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

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ICR Authors

Valeri, Nicola

Authors

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

Document Type

Journal Article

Date

2023-03-01

Date Accepted

2023-01-26

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 (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.

Citation

Nature Medicine, 2023, 29 (3), pp. 605 - 614

DOI

10.1038/s41591-023-02240-8

URI

https://repository.icr.ac.uk/handle/internal/5808

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Medicine

Publisher

NATURE PORTFOLIO

ISSN

1078-8956

eISSN

1546-170X
1546-170X

Collections

Other ICR Research

Research Team

GI Cancer Biol & Genomics

Notes