Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial.
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.
['Stahler|Arndt|A|', 'Stintzing|Sebastian|S|', 'von Einem|Jobst C|JC|', 'Westphalen|Christoph B|CB|', 'Heinrich|Kathrin|K|', 'Krämer|Nicole|N|', 'Michl|Marlies|M|', 'Modest|Dominik P|DP|', 'von Weikersthal|Ludwig Fischer|LF|', 'Decker|Thomas|T|', 'Kiani|Alexander|A|', 'Heintges|Tobias|T|', 'Kahl|Christoph|C|', 'Kullmann|Frank|F|', 'Scheithauer|Werner|W|', 'Moehler|Markus|M|', 'Kaiser|Florian|F|', 'Kirchner|Thomas|T|', 'Jung|Andreas|A|', 'Heinemann|Volker|V|']
D000328:Adult D000368:Aged D015179:Colorectal Neoplasms D005260:Female D059014:High-Throughput Nucleotide Sequencing D006801:Humans D008297:Male D053842:Microsatellite Instability D008875:Middle Aged D009362:Neoplasm Metastasis D020641:Polymorphism, Single Nucleotide D012189:Retrospective Studies D047368:Tumor Burden
Tumour mutational burden Metastatic colorectal cancer Next-generation Sequencing Sidedness Primary tumour location