| Autor: |
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 |
| Zdroj: |
Nature Medicine; March 2023, Vol. 29 Issue: 3 p605-614, 10p |
| Abstrakt: |
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 KRAScodon 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 KRASG12mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAFmutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n= 800 patients) and found that KRASG12mutations (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 KRASG12mutations 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 KRASG13mutant 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, KRASG12mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12mutations 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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
Full text from SpringerLink