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. (May 2020)

• Record Type: Journal Article
• Authors: Berger, Martin D.; Ning, Yan; Stintzing, Sebastian; Heinemann, Volker; Cao, Shu; Zhang, Wu; Yang, Dongyun; Miyamoto, Yuji; Suenaga, Mitsukuni; Schirripa, Marta; Hanna, Diana L.; Soni, Shivani; Puccini, Alberto; Tokunaga, Ryuma; Naseem, Madiha; Battaglin, Francesca; Cremolini, Chiara; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef
• Is Part Of: European journal of cancer. Volume 131(2020)
• Page Start: 89
• Page End: 97
• Publication Date: 2020-05
• Subjects: R-spondin -- Colorectal cancer -- Polymorphisms -- Bevacizumab -- Biomarker; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.02.048
• Languages: English
• ISSNs: 0959-8049

Abstract

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. 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.