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

Martin D Berger, Yan Ning, Sebastian Stintzing, Volker Heinemann, Shu Cao, Wu Zhang, Dongyun Yang, Yuji Miyamoto, Mitsukuni Suenaga, Marta Schirripa, Diana L Hanna, Shivani Soni, Alberto Puccini, Ryuma Tokunaga, Madiha Naseem, Francesca Battaglin, Chiara Cremolini, Alfredo Falcone, Fotios Loupakis, Heinz-Josef Lenz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)89-97
Number of pages9
JournalEur. J. Cancer
Volume131
DOIs
Publication statusPublished - May 2020

Keywords

  • 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

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