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

doi:10.1016/j.ejca.2020.02.048

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

Istituto Oncologico Veneto

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	89-97
Number of pages	9
Journal	Eur. J. Cancer
Volume	131
DOIs	https://doi.org/10.1016/j.ejca.2020.02.048
Publication status	Published - 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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Berger, M. D., Ning, Y., Stintzing, S., Heinemann, V., Cao, S., Zhang, W., Yang, D., Miyamoto, Y., Suenaga, M., Schirripa, M., Hanna, D. L., Soni, S., Puccini, A., Tokunaga, R., Naseem, M., Battaglin, F., Cremolini, C., Falcone, A., Loupakis, F., & Lenz, H-J. (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. Eur. J. Cancer, 131, 89-97. https://doi.org/10.1016/j.ejca.2020.02.048

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; Lenz, Heinz-Josef.

In: Eur. J. Cancer, Vol. 131, 05.2020, p. 89-97.

Research output: Contribution to journal › Article › peer-review

Berger, MD, Ning, Y, Stintzing, S, Heinemann, V, Cao, S, Zhang, W, Yang, D, Miyamoto, Y, Suenaga, M, Schirripa, M, Hanna, DL, Soni, S, Puccini, A, Tokunaga, R, Naseem, M, Battaglin, F, Cremolini, C, Falcone, A, Loupakis, F & Lenz, H-J 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', Eur. J. Cancer, vol. 131, pp. 89-97. https://doi.org/10.1016/j.ejca.2020.02.048

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. / 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. In: Eur. J. Cancer. 2020 ; Vol. 131. pp. 89-97.

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title = "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",

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 = "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",

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

year = "2020",

month = may,

doi = "10.1016/j.ejca.2020.02.048",

language = "English",

volume = "131",

pages = "89--97",

journal = "Eur. J. Cancer",

issn = "0959-8049",

}

TY - JOUR

T1 - 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

AU - Berger, Martin D

AU - Ning, Yan

AU - Stintzing, Sebastian

AU - Heinemann, Volker

AU - Cao, Shu

AU - Zhang, Wu

AU - Yang, Dongyun

AU - Miyamoto, Yuji

AU - Suenaga, Mitsukuni

AU - Schirripa, Marta

AU - Hanna, Diana L

AU - Soni, Shivani

AU - Puccini, Alberto

AU - Tokunaga, Ryuma

AU - Naseem, Madiha

AU - Battaglin, Francesca

AU - Cremolini, Chiara

AU - Falcone, Alfredo

AU - Loupakis, Fotios

AU - Lenz, Heinz-Josef

PY - 2020/5

Y1 - 2020/5

N2 - 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.

AB - 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.

KW - Aged

KW - Alleles

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Bevacizumab/therapeutic use

KW - Biomarkers, Tumor/genetics

KW - Camptothecin/analogs & derivatives

KW - Clinical Trials, Phase III as Topic

KW - Colorectal Neoplasms/drug therapy

KW - Drug Resistance, Neoplasm/genetics

KW - Female

KW - Fluorouracil/therapeutic use

KW - Follow-Up Studies

KW - Genotyping Techniques

KW - Humans

KW - Intercellular Signaling Peptides and Proteins/genetics

KW - Leucovorin/therapeutic use

KW - Male

KW - Middle Aged

KW - Mutation

KW - Patient Selection

KW - Polymorphism, Single Nucleotide

KW - Progression-Free Survival

KW - Proto-Oncogene Proteins p21(ras)

KW - Randomized Controlled Trials as Topic

U2 - 10.1016/j.ejca.2020.02.048

DO - 10.1016/j.ejca.2020.02.048

M3 - Article

C2 - 32305727

VL - 131

SP - 89

EP - 97

JO - Eur. J. Cancer

JF - Eur. J. Cancer

SN - 0959-8049

ER -