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.

Keywords: A2AR; CD39; CD73; SNP; mCRC.

Conflict of interest statement

Conflict of interest:

The authors declare that they have no conflict of interest.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Mechanism of adenosine pathway in tumor microenvironment. Adenosine is autonomously produced from ATP through ADP via CD39 and CD73 expressed mainly on the surface of cancer cells, B cells or Tregs. The work of extracellular adenosine is mainly divided into two directions. For immune cells, adenosine has a potent immunosuppressive ability through A2AR and A2BR. For cancer cells, adenosine stimulates tumor growth and metastasis through A2BR. Abbreviations: CTL, cytotoxic lymphocyte; DC, dendritic cell; NK, natural killer; M2, M2 macrophage; MDSC, myeloid derived suppressor cell; Th1, T helper 1; Th17, T helper 17; Treg, regulatory T cell.

Figure 2.

Overall survivals of patients with CD39 rs11188513variants, T/T or any C (T/C or C/C), in the discovery cohort (A) and validation cohort (B).