Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial. (September 2020)

• Record Type: Journal Article
• Authors: Stahler, Arndt; Stintzing, Sebastian; von Einem, Jobst C.; Westphalen, Christoph B. Benedikt; Heinrich, Kathrin; Krämer, Nicole; Michl, Marlies; Modest, Dominik P.; von Weikersthal, Ludwig Fischer; Decker, Thomas; Kiani, Alexander; Heintges, Tobias; Kahl, Christoph; Kullmann, Frank; Scheithauer, Werner; Moehler, Markus; Kaiser, Florian; Kirchner, Thomas; Jung, Andreas; Heinemann, Volker
• Is Part Of: European journal of cancer. Volume 137(2020)
• Page Start: 250
• Page End: 259
• Publication Date: 2020-09
• Subjects: Metastatic colorectal cancer -- Sidedness -- Primary tumour location -- Next-generation -- Sequencing -- Tumour mutational burden; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.07.003
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Molecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology. Material and methods: FoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB ( TMB-H ) and high-grade microsatellite instability ( MSI-H ) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Three hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34–1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10–0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours. Conclusions: RAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS. Highlights: Next-generation sequencing identified additional mutations of KRAS and BRAF . SMAD4- mutated tumours were associated with lower susceptibility to cetuximab. BRAF non-V600E–mutated tumours were associated with favourable prognosis and CMS4. Tumours of the right, transverse and left colon differed in mutational profiles.