Supplementary Material for: Single-Nucleotide Polymorphisms in the Vascular Endothelial Growth Factor Pathway and Outcomes of Patients Treated with First-Line Cytotoxic Chemotherapy Combined with Bevacizumab for Advanced Colorectal Cancer

Objective: The aim of this study was to evaluate the association between the efficacy of first-line cytotoxic chemotherapy plus bevacizumab and single-nucleotide polymorphisms (SNPs) of angiogenic genes in patients with advanced colorectal cancer (CRC). Methods: DNA was extracted from blood samples of 125 patients, and 12 SNPs were evaluated for association with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: The vascular endothelial growth factor A (VEGFA) rs833061 T/T was associated with superior ORR compared to its alternative genotypes (75.9 vs. 50.8%; p = 0.008), and the interleukin 8 rs4073 A/A genotype tended to be associated with poor ORR (45.0 vs. 66.0%; p = 0.067). The median PFS and OS were superior in patients with the fms-related tyrosine kinase 1 (FLT1) rs9513070 A/A genotype (8.7 vs. 6.6 months; p = 0.001 and 26.4 vs. 16.1 months; p = 0.038, respectively). The kinase insert domain receptor rs1531289 G/G genotype tended to be associated with improved PFS (8.0 vs. 7.1 months; p = 0.069). In haplotype analysis, the FLT1 rs9513070/rs9554320/rs9582036 GCA haplotype was associated with inferior PFS and OS (p = 0.004 and p = 0.041, respectively). Conclusion: The VEGFA rs833061 SNP is associated with the ORR, and the FLT1 rs9513070 SNP and FLT1 GCA haplotypes are associated with PFS and OS in advanced CRC patients treated with cytotoxic chemotherapy plus bevacizumab.

本研究旨在探讨一线细胞毒性化疗联合贝伐珠单抗（bevacizumab）的疗效，与晚期结直肠癌（advanced colorectal cancer, CRC）患者体内血管生成基因的单核苷酸多态性（single-nucleotide polymorphisms, SNPs）之间的关联。方法：本研究从125例患者的血液样本中提取基因组DNA，并对12个单核苷酸多态性位点与客观缓解率（objective response rate, ORR）、无进展生存期（progression-free survival, PFS）及总生存期（overall survival, OS）的相关性进行评估。结果：血管内皮生长因子A（vascular endothelial growth factor A, VEGFA）rs833061位点的T/T基因型相较于其他基因型，客观缓解率更优（75.9% vs. 50.8%；p=0.008）；白细胞介素8 rs4073位点的A/A基因型则倾向于与较低的客观缓解率相关（45.0% vs. 66.0%；p=0.067）。携带Fms相关酪氨酸激酶1（fms-related tyrosine kinase 1, FLT1）rs9513070位点A/A基因型的患者，其中位无进展生存期及总生存期均显著更优（中位无进展生存期：8.7个月 vs. 6.6个月，p=0.001；中位总生存期：26.4个月 vs. 16.1个月，p=0.038）。激酶插入域受体rs1531289位点的G/G基因型则倾向于与更长的无进展生存期相关（8.0个月 vs. 7.1个月，p=0.069）。单倍型分析结果显示，FLT1 rs9513070/rs9554320/rs9582036位点构成的GCA单倍型与较差的无进展生存期和总生存期均相关（分别对应p=0.004和p=0.041）。结论：在接受细胞毒性化疗联合贝伐珠单抗治疗的晚期结直肠癌患者中，VEGFA rs833061单核苷酸多态性与客观缓解率显著相关，而FLT1 rs9513070单核苷酸多态性及FLT1 GCA单倍型则与无进展生存期和总生存期密切相关。