Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer
Open accessAbstract
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.
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Single-nucleotide polymorphisms of PTFs were significantly associated with PFS of the cetuximab cohort in the FIRE-3 trial.
“Single-nucleotide polymorphisms of PTFs were significantly associated with PFS of the cetuximab cohort in the FIRE-3 trial [141].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [141]
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- Authors
- Arai, H., Millstein, J., Loupakis, F., Stintzing, S., Wang, J., Battaglin, F., Kawanishi, N., Jayachandran, P., Soni, S., Zhang, W., Mumenthaler, S. M., Cremolini, C., Heinemann, V., Falcone, A., & Lenz, H.-J.
- Affiliations
- University of Southern California (US)
- Istituto Oncologico Veneto (IT)
- Stiftung Charité (DE)
- University of Pisa (IT)
- LMU Klinikum (DE)
- Corresponding author
- Lenz, Heinz-Josef
- ORCID
- Venue
- European Journal of Cancer
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 150
- Pages
- 133-142
- ISSN
- 0959-8049 (ISSN-L)
- PMC
- PMC12047410
- OpenAlex
- W3157337076
- Cited by
- 2
- References
- 45
- Citations by year
- 2024: 1 · 2021: 1
- FWCI
- 0.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- metastatic colorectal cancer, cetuximab, bevacizumab, single nucleotide polymorphisms, pluripotency transcription factors, cancer stem cells, Nanog, progression-free survival, predictive biomarkers, epidermal growth factor receptor, vascular endothelial growth factor, FOLFIRI, FIRE-3 trial, TRIBE trial
- MeSH terms
- Bevacizumab, Cetuximab, Nanog Homeobox Protein, Antineoplastic Agents, Immunological, Progression-Free Survival, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Metastasis, Phenotype, Retrospective Studies, Time Factors, Biomarkers, Tumor, Neoplastic Stem Cells, Colorectal Neoplasms, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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