Highlights
- •Markers predicting efficacy of bevacizumab in metastatic colon cancer are warranted.
- •R-spondins play a role in angiogenesis and progression of colorectal cancer.
- •R-spondins exert their oncogenic role through activation of the Wnt pathway.
- •A polymorphism in RSPO2 predicts outcome in patients receiving FOLFIRI/bevacizumab.
- •Potential to identify patients who will benefit most from FOLFIRI/bevacizumab.
Abstract
Background
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.
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.
Keywords
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Article info
Publication history
Published online: April 19, 2020
Accepted:
February 17,
2020
Received in revised form:
February 16,
2020
Received:
January 12,
2020
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
