Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer
© 2023. The Author(s)..
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.
Errataetall: |
CommentIn: Nat Rev Gastroenterol Hepatol. 2023 May;20(5):269. - PMID 37012321 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
---|---|
Enthalten in: |
Nature medicine - 29(2023), 3 vom: 02. März, Seite 605-614 |
Sprache: |
Englisch |
---|
Links: |
---|
Anmerkungen: |
Date Completed 24.03.2023 Date Revised 16.05.2023 published: Print-Electronic CommentIn: Nat Rev Gastroenterol Hepatol. 2023 May;20(5):269. - PMID 37012321 Citation Status MEDLINE |
---|
doi: |
10.1038/s41591-023-02240-8 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM35370184X |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM35370184X | ||
003 | DE-627 | ||
005 | 20231226060620.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s41591-023-02240-8 |2 doi | |
028 | 5 | 2 | |a pubmed24n1178.xml |
035 | |a (DE-627)NLM35370184X | ||
035 | |a (NLM)36864254 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a van de Haar, Joris |e verfasserin |4 aut | |
245 | 1 | 0 | |a Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 24.03.2023 | ||
500 | |a Date Revised 16.05.2023 | ||
500 | |a published: Print-Electronic | ||
500 | |a CommentIn: Nat Rev Gastroenterol Hepatol. 2023 May;20(5):269. - PMID 37012321 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2023. The Author(s). | ||
520 | |a 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 | ||
650 | 4 | |a Randomized Controlled Trial | |
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 7 | |a tipiracil |2 NLM | |
650 | 7 | |a NGO10K751P |2 NLM | |
650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
650 | 7 | |a EC 3.6.5.2 |2 NLM | |
650 | 7 | |a Uracil |2 NLM | |
650 | 7 | |a 56HH86ZVCT |2 NLM | |
650 | 7 | |a Trifluridine |2 NLM | |
650 | 7 | |a RMW9V5RW38 |2 NLM | |
650 | 7 | |a Pyrrolidines |2 NLM | |
650 | 7 | |a Drug Combinations |2 NLM | |
650 | 7 | |a KRAS protein, human |2 NLM | |
700 | 1 | |a Ma, Xuhui |e verfasserin |4 aut | |
700 | 1 | |a Ooft, Salo N |e verfasserin |4 aut | |
700 | 1 | |a van der Helm, Pim W |e verfasserin |4 aut | |
700 | 1 | |a Hoes, Louisa R |e verfasserin |4 aut | |
700 | 1 | |a Mainardi, Sara |e verfasserin |4 aut | |
700 | 1 | |a Pinato, David J |e verfasserin |4 aut | |
700 | 1 | |a Sun, Kristi |e verfasserin |4 aut | |
700 | 1 | |a Salvatore, Lisa |e verfasserin |4 aut | |
700 | 1 | |a Tortora, Giampaolo |e verfasserin |4 aut | |
700 | 1 | |a Zurlo, Ina Valeria |e verfasserin |4 aut | |
700 | 1 | |a Leo, Silvana |e verfasserin |4 aut | |
700 | 1 | |a Giampieri, Riccardo |e verfasserin |4 aut | |
700 | 1 | |a Berardi, Rossana |e verfasserin |4 aut | |
700 | 1 | |a Gelsomino, Fabio |e verfasserin |4 aut | |
700 | 1 | |a Merz, Valeria |e verfasserin |4 aut | |
700 | 1 | |a Mazzuca, Federica |e verfasserin |4 aut | |
700 | 1 | |a Antonuzzo, Lorenzo |e verfasserin |4 aut | |
700 | 1 | |a Rosati, Gerardo |e verfasserin |4 aut | |
700 | 1 | |a Stavraka, Chara |e verfasserin |4 aut | |
700 | 1 | |a Ross, Paul |e verfasserin |4 aut | |
700 | 1 | |a Rodriquenz, Maria Grazia |e verfasserin |4 aut | |
700 | 1 | |a Pavarana, Michele |e verfasserin |4 aut | |
700 | 1 | |a Messina, Carlo |e verfasserin |4 aut | |
700 | 1 | |a Iveson, Timothy |e verfasserin |4 aut | |
700 | 1 | |a Zoratto, Federica |e verfasserin |4 aut | |
700 | 1 | |a Thomas, Anne |e verfasserin |4 aut | |
700 | 1 | |a Fenocchio, Elisabetta |e verfasserin |4 aut | |
700 | 1 | |a Ratti, Margherita |e verfasserin |4 aut | |
700 | 1 | |a Depetris, Ilaria |e verfasserin |4 aut | |
700 | 1 | |a Cergnul, Massimiliano |e verfasserin |4 aut | |
700 | 1 | |a Morelli, Cristina |e verfasserin |4 aut | |
700 | 1 | |a Libertini, Michela |e verfasserin |4 aut | |
700 | 1 | |a Parisi, Alessandro |e verfasserin |4 aut | |
700 | 1 | |a De Tursi, Michele |e verfasserin |4 aut | |
700 | 1 | |a Zanaletti, Nicoletta |e verfasserin |4 aut | |
700 | 1 | |a Garrone, Ornella |e verfasserin |4 aut | |
700 | 1 | |a Graham, Janet |e verfasserin |4 aut | |
700 | 1 | |a Longarini, Raffaella |e verfasserin |4 aut | |
700 | 1 | |a Gobba, Stefania Maria |e verfasserin |4 aut | |
700 | 1 | |a Petrillo, Angelica |e verfasserin |4 aut | |
700 | 1 | |a Tamburini, Emiliano |e verfasserin |4 aut | |
700 | 1 | |a La Verde, Nicla |e verfasserin |4 aut | |
700 | 1 | |a Petrelli, Fausto |e verfasserin |4 aut | |
700 | 1 | |a Ricci, Vincenzo |e verfasserin |4 aut | |
700 | 1 | |a Wessels, Lodewyk F A |e verfasserin |4 aut | |
700 | 1 | |a Ghidini, Michele |e verfasserin |4 aut | |
700 | 1 | |a Cortellini, Alessio |e verfasserin |4 aut | |
700 | 1 | |a Voest, Emile E |e verfasserin |4 aut | |
700 | 1 | |a Valeri, Nicola |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature medicine |d 1995 |g 29(2023), 3 vom: 02. März, Seite 605-614 |w (DE-627)NLM074659804 |x 1546-170X |7 nnns |
773 | 1 | 8 | |g volume:29 |g year:2023 |g number:3 |g day:02 |g month:03 |g pages:605-614 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41591-023-02240-8 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 29 |j 2023 |e 3 |b 02 |c 03 |h 605-614 |