Influence of KDR Genetic Variation on the Effectiveness and Safety of Bevacizumab in the First-Line Treatment for Patients with Advanced Colorectal Cancer

Fei Wang,1 Gang Liu2 1Department of Oncology, The Seventh Medical Center of People’s Liberation Army General Hospital, Beijing, People’s Republic of China; 2Department of General Surgery, The First Medical Center of People’s Liberation Army General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Gang Liu, Department of General Surgery, the first Medical Center of People’s Liberation Army General Hospital, No. 28 FuXing Road, HaiDian District, Beijing, 100048, People’s Republic of China, Tel +86 18600310565, Email liug0921@163.comObjective: Bevacizumab is usually considered a first-line anti-tumor therapy, which inhibits tumor growth by downregulating the vascular endothelial growth factor (VEGF) that further silences the activity of the kinase insert region receptor (KDR) gene. In the current study, we investigated the treatment response of bevacizumab in advanced colorectal cancer (CRC) patients bearing 889 C>T mutation in the KDR gene.Methods: A total of 135 advanced CRC patients were treated with bevacizumab along with chemotherapy at the seventh medical center of the People’s Liberation Army general hospital from January 2012 to June 2021 and were analyzed retrospectively. The KDR genotyping and mRNA expression analyses were performed in 57 patients.Results: The KDR genotyping revealed 97 (71.85%) cases with CC genotype, 34 (25.19%) cases with CT, and 4 (2.96%) cases with TT genotype, while the minor allele frequency of 889 C>T was found as 0.16. The median progression-free survival (PFS) of the patients with CT/TT genotype and CC genotype was found to be 6.1 and 9.7 months, respectively (P = 0.009). The median overall survival (OS) of the two genotypes was 13.7 and 19.7 (P = 0.025), respectively. Multivariable Cox regression analysis of PFS, CT/TT genotype was found to be an independent factor for PFS (odds ratio (OR) = 1.88, P = 0.023). Additionally, the mRNA expression of KDR in 57 biopsies taken from patients with CT/TT genotypes was significantly higher than that of patients with CC genotype (P < 0.001). Additionally, in terms of safety, 55 patients experienced grade 2 or higher fatigue (incidence rate 40.74%) after receiving bevacizumab along with chemotherapy.Conclusion: The 889 C>T mutation in KDR gene affects the KDR expression in colorectal cancer patients, thereby affecting the effectiveness of bevacizumab therapy.Keywords: colorectal cancer, bevacizumab, kinase insert domain receptor, polymorphism, clinical outcomes