Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer.
Antineoplastic Agents, Immunological
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Bevacizumab
/ therapeutic use
Biomarkers, Tumor
/ genetics
Cetuximab
/ therapeutic use
Clinical Trials, Phase III as Topic
Colorectal Neoplasms
/ drug therapy
Genetic Predisposition to Disease
Humans
Nanog Homeobox Protein
/ genetics
Neoplasm Metastasis
Neoplastic Stem Cells
/ drug effects
Phenotype
Polymorphism, Single Nucleotide
Progression-Free Survival
Randomized Controlled Trials as Topic
Retrospective Studies
Time Factors
Biomarker
Cancer stem cell
Cetuximab
Colorectal cancer
NANOG
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:
06 2021
06 2021
Historique:
received:
26
02
2021
revised:
17
03
2021
accepted:
25
03
2021
pubmed:
27
4
2021
medline:
26
10
2021
entrez:
26
4
2021
Statut:
ppublish
Résumé
Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC). Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes. In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis. Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.
Sections du résumé
BACKGROUND
Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS
Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes.
RESULTS
In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis.
CONCLUSIONS
Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.
Identifiants
pubmed: 33901792
pii: S0959-8049(21)00215-X
doi: 10.1016/j.ejca.2021.03.048
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
Biomarkers, Tumor
0
NANOG protein, human
0
Nanog Homeobox Protein
0
Bevacizumab
2S9ZZM9Q9V
Cetuximab
PQX0D8J21J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
133-142Subventions
Organisme : NCI NIH HHS
ID : P30 CA014089
Pays : United States
Informations de copyright
Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Conflict of interest statement The authors have declared no conflicts of interest regarding the content discussed in the manuscript.