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 (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.

Efferocytosis Nanoinhibitors to Promote Secondary Necrosis and Potentiate the Immunogenicity of Conventional Cancer Therapies for Improved Therapeutic Benefits

“…Despite the rapid progress in the development of innovative cancer therapy modalities in recent years, chemotherapy and radiotherapy are still the most extensively applied cancer treatment methods in the clinic nowadays. − In the meanwhile, owing to the increasing understanding in the area of immune-oncology, it is now well recognized that tumor immunity could be affected by existing cancer therapies and would in turn determine their final therapeutic responses . For instance, the tumor microenvironment (TME) may be altered during chemotherapy or radiotherapy, and the immunosuppressive TME would largely protect tumor cells from immune attacks and limit the efficacies of those treatment .…”

Third-line treatment patterns and clinical outcomes for metastatic colorectal cancer: a retrospective real-world study

“…39 The latest discovery TherapeuTic advances in chronic disease suggests that codon-specific KRAS mutations can predict survival benefit of TAS-102. 40 In our study, we found that the benefits from front-line therapy was an independent indicator for PFS of third-line therapy. The similar results were reported in another chemotherapy rechallenge study from Turkey.…”

Predicting Trifluridine/Tipiracil Treatment Outcomes in Refractory Metastatic Colorectal Cancer Patients: A Multicenter Exploratory Analysis

“…The results of a meta-analysis suggest maintained efficacy regardless of the mutation in codon 12 or 13 [27]; however, the presence of a KRAS codon 12 mutation was associated with lesser OS benefit of TTP relative to placebo unlike the mutation in codon 13 which did not reduce the OS benefit. Furthermore, a more recent study that included patients treated in a real-world setting, as well as patients from RECOURSE, showed the KRAS G12 mutations may be considered biomarkers for reduced OS benefit of TTP treatment [28].…”