Dataset Information

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

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 (KRAS^G12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS^G12 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 KRAS^G12 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 KRAS^G12 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 KRAS^G13 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, KRAS^G12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS^G12 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.

SUBMITTER: van de Haar J

PROVIDER: S-EPMC10033412 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

van de Haar Joris J Ma Xuhui X Ooft Salo N SN van der Helm Pim W PW Hoes Louisa R LR Mainardi Sara S Pinato David J DJ Sun Kristi K Salvatore Lisa L Tortora Giampaolo G Zurlo Ina Valeria IV Leo Silvana S Giampieri Riccardo R Berardi Rossana R Gelsomino Fabio F Merz Valeria V Mazzuca Federica F Antonuzzo Lorenzo L Rosati Gerardo G Stavraka Chara C Ross Paul P Rodriquenz Maria Grazia MG Pavarana Michele M Messina Carlo C Iveson Timothy T Zoratto Federica F Thomas Anne A Fenocchio Elisabetta E Ratti Margherita M Depetris Ilaria I Cergnul Massimiliano M Morelli Cristina C Libertini Michela M Parisi Alessandro A De Tursi Michele M Zanaletti Nicoletta N Garrone Ornella O Graham Janet J Longarini Raffaella R Gobba Stefania Maria SM Petrillo Angelica A Tamburini Emiliano E La Verde Nicla N Petrelli Fausto F Ricci Vincenzo V Wessels Lodewyk F A LFA Ghidini Michele M Cortellini Alessio A Voest Emile E EE Valeri Nicola N

Nature medicine 20230302 3

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 (KRAS<sup>G12</sup>) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated ...[more]

PMID: 36864254

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Project description:BackgroundMutations in KRAS, BRAF and PIK3CA are the most common somatic alterations found in the colorectal cancer (CRC) patients from Western countries; but their prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of these genes in Chinese CRC patients and to investigate their impact on prognosis.MethodsThe sequences of exon 2 of KRAS, exon 15 of BRAF and exons 9 and 20 of PIK3CA were evaluated by PCR and direct sequencing using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues from primary CRC tumors of 214 patients (colon/rectum: 126/88).ResultsKRAS, BRAF and PIK3CA mutations were identified in 44.9% (96/214), 4.2% (9/214) and 12.3% (26/212) CRCs, respectively. The most frequent mutations in KRAS, BRAF and PIK3CA were G12D, V600E and H1047R, respectively. All BRAF and 80.8% PIK3CA mutations were from colon cancer patients. BRAF V600E was associated with advanced TNM (P < 0.001), more distant metastases (P = 0.025), and worse overall survival (OS, P < 0.001; multivariate HR = 4.2, P = 0.004) in colon cancer patients. Compared with KRAS wt/BRAF wt CRC patients (N = 109), those with KRAS codon 13 mutations (N = 25) had significantly worse OS (P = 0.016; multivariate HR = 2.7, P = 0.011), whereas KRAS codon 12-mutated cases were not significantly associated with survival. Among the three most common KRAS mutations, G13D (N = 23) showed significant association with poor OS (P = 0.024; multivariate HR = 2.6, P = 0.016) compared with KRAS wt/BRAF wt patients.ConclusionOur findings indicate that PI3K/RAS-RAF signaling pathway genes are frequently mutated in Chinese CRC patients, but have different characteristics than found in Western patients. BRAF V600E is an independent prognostic factor for Chinese patients. Our finding that KRAS codon 13 mutations (in particular G13D) are associated with inferior survival in BRAF wild-type CRCs in Chinese patients was not reported thus far. Our data emphasizes the importance of prospective evaluation of molecular features in CRC patients, because a single mutation type may represent a distinct biologic effect and clinical implication.

Project description:BackgroundThe phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.Patients and methodsA total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results.ResultsIn the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort.ConclusionsIn RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS.Gov identifierNCT01607957 (RECOURSE).Japan pharmaceutical information center numberJapicCTI-090880 (J003).

Dataset Information

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

Publications

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

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