Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy

Ryuma Tokunaga, Shu Cao, Madiha Naseem, Jae Ho Lo, Francesca Battaglin, Alberto Puccini, Martin D Berger, Shivani Soni, Joshua Millstein, Wu Zhang, Sebastian Stintzing, Fotios Loupakis, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Heinz-Josef Lenz

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.

PATIENTS AND METHODS: We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.

RESULTS: In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.

CONCLUSION: Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

Original languageEnglish
JournalClinical Colorectal Cancer
DOIs
Publication statusE-pub ahead of print - Sep 13 2018

Fingerprint

Adenosine
Colorectal Neoplasms
Drug Therapy
Single Nucleotide Polymorphism
oxaliplatin
irinotecan
Confidence Intervals
Survival
Tumor Microenvironment
Leucovorin
Immunosuppressive Agents
Fluorouracil
Disease-Free Survival
Bevacizumab
Alleles
DNA
Cetuximab

Cite this

Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy. / Tokunaga, Ryuma; Cao, Shu; Naseem, Madiha; Lo, Jae Ho; Battaglin, Francesca; Puccini, Alberto; Berger, Martin D; Soni, Shivani; Millstein, Joshua; Zhang, Wu; Stintzing, Sebastian; Loupakis, Fotios; Cremolini, Chiara; Heinemann, Volker; Falcone, Alfredo; Lenz, Heinz-Josef.

In: Clinical Colorectal Cancer, 13.09.2018.

Research output: Contribution to journalArticle

Tokunaga, R, Cao, S, Naseem, M, Lo, JH, Battaglin, F, Puccini, A, Berger, MD, Soni, S, Millstein, J, Zhang, W, Stintzing, S, Loupakis, F, Cremolini, C, Heinemann, V, Falcone, A & Lenz, H-J 2018, 'Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy', Clinical Colorectal Cancer. https://doi.org/10.1016/j.clcc.2018.09.003
Tokunaga, Ryuma ; Cao, Shu ; Naseem, Madiha ; Lo, Jae Ho ; Battaglin, Francesca ; Puccini, Alberto ; Berger, Martin D ; Soni, Shivani ; Millstein, Joshua ; Zhang, Wu ; Stintzing, Sebastian ; Loupakis, Fotios ; Cremolini, Chiara ; Heinemann, Volker ; Falcone, Alfredo ; Lenz, Heinz-Josef. / Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy. In: Clinical Colorectal Cancer. 2018.
@article{7cfc212ff2124dcc827f7c5fbe3a0beb,
title = "Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy",
abstract = "BACKGROUND: Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.PATIENTS AND METHODS: We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.RESULTS: In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95{\%} confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95{\%} CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95{\%} CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.CONCLUSION: Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.",
author = "Ryuma Tokunaga and Shu Cao and Madiha Naseem and Lo, {Jae Ho} and Francesca Battaglin and Alberto Puccini and Berger, {Martin D} and Shivani Soni and Joshua Millstein and Wu Zhang and Sebastian Stintzing and Fotios Loupakis and Chiara Cremolini and Volker Heinemann and Alfredo Falcone and Heinz-Josef Lenz",
note = "Copyright {\circledC} 2018 Elsevier Inc. All rights reserved.",
year = "2018",
month = "9",
day = "13",
doi = "10.1016/j.clcc.2018.09.003",
language = "English",
journal = "Clinical Colorectal Cancer",
issn = "1533-0028",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy

AU - Tokunaga, Ryuma

AU - Cao, Shu

AU - Naseem, Madiha

AU - Lo, Jae Ho

AU - Battaglin, Francesca

AU - Puccini, Alberto

AU - Berger, Martin D

AU - Soni, Shivani

AU - Millstein, Joshua

AU - Zhang, Wu

AU - Stintzing, Sebastian

AU - Loupakis, Fotios

AU - Cremolini, Chiara

AU - Heinemann, Volker

AU - Falcone, Alfredo

AU - Lenz, Heinz-Josef

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/9/13

Y1 - 2018/9/13

N2 - BACKGROUND: Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.PATIENTS AND METHODS: We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.RESULTS: In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.CONCLUSION: Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

AB - BACKGROUND: Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.PATIENTS AND METHODS: We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.RESULTS: In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.CONCLUSION: Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

U2 - 10.1016/j.clcc.2018.09.003

DO - 10.1016/j.clcc.2018.09.003

M3 - Article

C2 - 30293873

JO - Clinical Colorectal Cancer

JF - Clinical Colorectal Cancer

SN - 1533-0028

ER -