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.

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 and Lenz, Heinz-Josef (2020). 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. European journal of cancer, 131, pp. 89-97. Elsevier 10.1016/j.ejca.2020.02.048

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0959-8049

Publisher:

Elsevier

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

12 Aug 2020 12:08

Last Modified:

12 Aug 2020 12:08

Publisher DOI:

10.1016/j.ejca.2020.02.048

PubMed ID:

32305727

Uncontrolled Keywords:

Bevacizumab Biomarker Colorectal cancer Polymorphisms R-spondin

BORIS DOI:

10.7892/boris.145784

URI:

https://boris.unibe.ch/id/eprint/145784

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