Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Clin Colorectal Cancer. 2019 Mar;18(1):e8-e19. doi: 10.1016/j.clcc.2018.09.003. Epub 2018 Sep 13.
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.
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.
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.
Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.
腺苷对肿瘤微环境具有免疫抑制和血管生成调节作用。本研究探讨了单核苷酸多态性（SNPs）在与接受贝伐珠单抗为基础的化疗的转移性结直肠癌患者相关的腺苷分子中的作用。
我们分析了来自 3 个独立队列的 451 个样本中的基因组 DNA：FIRE-3 （临床试验标识符，NCT00433927）中 107 例接受 FOLFIRI（5-氟尿嘧啶、亚叶酸、奥沙利铂、伊立替康）联合贝伐珠单抗治疗的患者的发现队列；TRIBE （临床试验标识符，NCT00719797）中 215 例接受 FOLFIRI 联合贝伐珠单抗治疗的患者的验证队列；以及 FIRE-3 中接受 FOLFIRI 联合西妥昔单抗治疗的 129 例患者的对照组。分析了所选 SNPs 与临床结果之间的关系。
在发现队列中，与 T/T 变异体相比，CD39 rs11188513 存在任何 C 等位基因的患者中位无进展生存期明显缩短（11.3 与 13.1 个月；风险比 [HR]，1.70；95%置信区间 [CI]，1.04-2.77；P =.022）。此外，他们的总生存期（OS）也较短（27.4 与 49.9 个月；HR，2.10；95%CI，1.07-4.10；P =.031），这在单变量和多变量分析中都是如此。CD39 rs11188513 与 OS 的显著关联在验证队列中得到了证实（25.8 与 31.6 个月；HR，1.53；95%CI，1.09-2.15；P =.013）。发现队列中的 CD73 rs2229523 和 A2BR rs2015353 以及验证队列中的 CD39 rs2226163 在单变量和多变量分析中均与 OS 显著相关。在西妥昔单抗对照组中，没有一个 SNP 具有统计学意义。
腺苷通路中的选定 SNPs 可能会影响接受 FOLFIRI 联合贝伐珠单抗治疗的转移性结直肠癌患者的临床结局。
