dc.contributor.author | van de Haar, J | |
dc.contributor.author | Ma, X | |
dc.contributor.author | Ooft, SN | |
dc.contributor.author | van der Helm, PW | |
dc.contributor.author | Hoes, LR | |
dc.contributor.author | Mainardi, S | |
dc.contributor.author | Pinato, DJ | |
dc.contributor.author | Sun, K | |
dc.contributor.author | Salvatore, L | |
dc.contributor.author | Tortora, G | |
dc.contributor.author | Zurlo, IV | |
dc.contributor.author | Leo, S | |
dc.contributor.author | Giampieri, R | |
dc.contributor.author | Berardi, R | |
dc.contributor.author | Gelsomino, F | |
dc.contributor.author | Merz, V | |
dc.contributor.author | Mazzuca, F | |
dc.contributor.author | Antonuzzo, L | |
dc.contributor.author | Rosati, G | |
dc.contributor.author | Stavraka, C | |
dc.contributor.author | Ross, P | |
dc.contributor.author | Rodriquenz, MG | |
dc.contributor.author | Pavarana, M | |
dc.contributor.author | Messina, C | |
dc.contributor.author | Iveson, T | |
dc.contributor.author | Zoratto, F | |
dc.contributor.author | Thomas, A | |
dc.contributor.author | Fenocchio, E | |
dc.contributor.author | Ratti, M | |
dc.contributor.author | Depetris, I | |
dc.contributor.author | Cergnul, M | |
dc.contributor.author | Morelli, C | |
dc.contributor.author | Libertini, M | |
dc.contributor.author | Parisi, A | |
dc.contributor.author | De Tursi, M | |
dc.contributor.author | Zanaletti, N | |
dc.contributor.author | Garrone, O | |
dc.contributor.author | Graham, J | |
dc.contributor.author | Longarini, R | |
dc.contributor.author | Gobba, SM | |
dc.contributor.author | Petrillo, A | |
dc.contributor.author | Tamburini, E | |
dc.contributor.author | La Verde, N | |
dc.contributor.author | Petrelli, F | |
dc.contributor.author | Ricci, V | |
dc.contributor.author | Wessels, LFA | |
dc.contributor.author | Ghidini, M | |
dc.contributor.author | Cortellini, A | |
dc.contributor.author | Voest, EE | |
dc.contributor.author | Valeri, N | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-05-30T12:12:36Z | |
dc.date.available | 2023-05-30T12:12:36Z | |
dc.date.issued | 2023-03-01 | |
dc.identifier | 10.1038/s41591-023-02240-8 | |
dc.identifier.citation | Nature Medicine, 2023, 29 (3), pp. 605 - 614 | |
dc.identifier.issn | 1078-8956 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5808 | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.doi | 10.1038/s41591-023-02240-8 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 605 - 614 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.ispartof | Nature Medicine | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Humans | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Uracil | |
dc.subject | Trifluridine | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Frontotemporal Dementia | |
dc.subject | Pyrrolidines | |
dc.subject | Colonic Neoplasms | |
dc.subject | Rectal Neoplasms | |
dc.subject | Drug Combinations | |
dc.subject | Mutation | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.title | Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-01-26 | |
dc.date.updated | 2023-05-30T12:10:10Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41591-023-02240-8 | |
rioxxterms.licenseref.startdate | 2023-03-01 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36864254 | |
pubs.issue | 3 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Gastrointestinal Cancer Biology and Genomics | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41591-023-02240-8 | |
pubs.volume | 29 | |
icr.researchteam | GI Cancer Biol & Genomics | |
dc.contributor.icrauthor | Valeri, Nicola | |
icr.provenance | Deposited by Mr Arek Surman on 2023-05-30. Deposit type is initial. No. of files: 1. Files: Codon-specific KRAS mutations predict survival benefit of trifluridinetipiracil in metastatic colorectal cancer.pdf | |