Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial.
Metastatic colorectal cancer
Next-generation
Primary tumour location
Sequencing
Sidedness
Tumour mutational burden
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
20
04
2020
revised:
26
06
2020
accepted:
04
07
2020
pubmed:
19
8
2020
medline:
9
2
2021
entrez:
19
8
2020
Statut:
ppublish
Résumé
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. 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). 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32810748
pii: S0959-8049(20)30386-5
doi: 10.1016/j.ejca.2020.07.003
pii:
doi:
Types de publication
Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
250-259Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest statement A.S. received honoraria for talks and travel expenses from Roche. C.B.W. received honoraria for talks, advisory boards and travel expenses from Bayer, Celgene, Ipsen, Rafael, RedHill, Roche, Shire/Baxalta and Servier and scientific grant support from Roche. V.H., S.S. and D.P.M. received honoraria for talks, advisory boards and travel expenses from Merck, Amgen, Roche, Takeda, Servier, Pierre Fabre, Taiho, Lilly Oncology, Servier, Sanofi and Bayer Pharmaceuticals. A.J. and T.K. received honoraria for talks, advisory boards and travel expenses from Amgen, AstraZeneca, Bayer Pharmaceuticals, BMS, Boehringer Ingelheim, Merck KGA, Novartis, Qiagen, Roche Pharma and Takeda. Marl.M. received honoraria for talks from SIRTeX, Roche and MSD and travel expenses from SIRTeX, Amgen and Merck. All remaining authors declared no potential conflict of interest in regard with this manuscript.