A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.

Aged Alleles Antineoplastic Combined Chemotherapy Protocols / therapeutic use Bevacizumab / therapeutic use Biomarkers, Tumor / genetics Camptothecin / analogs & derivatives Clinical Trials, Phase III as Topic Colorectal Neoplasms / drug therapy Drug Resistance, Neoplasm / genetics Female Fluorouracil / therapeutic use Follow-Up Studies Genotyping Techniques Humans Intercellular Signaling Peptides and Proteins / genetics Leucovorin / therapeutic use Male Middle Aged Mutation Patient Selection Polymorphism, Single Nucleotide Progression-Free Survival Proto-Oncogene Proteins p21(ras) Randomized Controlled Trials as Topic

Bevacizumab Biomarker Colorectal cancer Polymorphisms R-spondin

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:
05 2020

Historique:

received: 12 01 2020

revised: 16 02 2020

accepted: 17 02 2020

pubmed: 20 4 2020

medline: 28 10 2020

entrez: 20 4 2020

Statut: ppublish

Résumé

Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab. 773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated. RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009). Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status.

Sections du résumé

BACKGROUND

PATIENTS AND METHODS

773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated.

RESULTS

RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009).

CONCLUSION

Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status.

Identifiants

DOI: 10.1016/j.ejca.2020.02.048 PMID: 32305727 PMC: PMC7513926

pubmed: 32305727

pii: S0959-8049(20)30122-2

doi: 10.1016/j.ejca.2020.02.048

pmc: PMC7513926

mid: NIHMS1585691

pii:

doi:

Substances chimiques

Biomarkers, Tumor 0

Intercellular Signaling Peptides and Proteins 0

KRAS protein, human 0

Rspo2 protein, human 0

Bevacizumab 2S9ZZM9Q9V

Proto-Oncogene Proteins p21(ras) EC 3.6.5.2

Leucovorin Q573I9DVLP

Fluorouracil U3P01618RT

Camptothecin XT3Z54Z28A

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study

Langues

eng

Sous-ensembles de citation

Pagination

89-97

Subventions

Organisme : NCI NIH HHS

ID : P30 CA014089

Pays : United States

Informations de copyright

Déclaration de conflit d'intérêts

Conflict of interest statement The authors declare no conflict of interest regarding the content discussed in the manuscript.

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