Bai Ming, Li Zhi-Guo, Ba Yi
Department of Gastrointestinal Oncology, Affiliated Tumor Hospital of Tianjin Medical University, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China.
Department of Minimally Invasive Digestive Surgery, Shanxi Cancer Hospital, Taiyuan, People's Republic of China.
Int J Gen Med. 2021 Mar 25;14:1041-1055. doi: 10.2147/IJGM.S300968. eCollection 2021.
The aim of the present study was to investigate the influence of kinase insert domain containing receptor (KDR) genetic variation on the efficacy of treatment and safety of patients with chemotherapy-refractory metastatic colorectal cancer (CRC) receiving apatinib.
A total of 108 patients with chemotherapy refractory metastatic CRC who were treated with apatinib participated in this study retrospectively. Efficacy of the patients' treatment was evaluated. Prognosis was carried out and safety profile was documented, respectively. Blood specimens and peripheral blood mononuclear cells (PBMC) of the patients were obtained for the analysis of genetic variation and KDR gene mRNA expression, respectively. The association between genotype status and clinical outcomes was presented.
Objective response rate (ORR) and disease control rate (DCR) of the 108 patients with metastatic CRC receiving apatinib treatment were 5.6% and 69.4%, respectively. Survival analysis results exhibited that the median progression-free survival (PFS) and overall survival (OS) of the 108 patients with metastatic CRC was 3.6 months (95% confidence interval (CI): 3.03-4.17 months) and 8.9 months (95% CI: 7.57-10.23 months), respectively. Subsequently, the analysis of KDR genetic variation indicated that rs2071559 was of clinical significance. The minor allele frequency of rs2071559 was 0.22 and the genotype status corresponded with Hardy-Weinberg equilibrium (=0.949). Prognosis analysis in a dominant inheritance manner through the combination of patients with TC and CC genotype showed that the median PFS of patients with TT genotype and TC/CC genotype was 4.1 and 3.0 months, respectively (=0.012). Furthermore, the median OS of patients with the two genotypes was 10.5 and 6.1 months, respectively (=0.007). Additionally, multivariate Cox regression analysis of OS showed that TC/CC genotype was an independent factor for OS (Hazard ratio (HR)=0.65, =0.021). Interestingly, mRNA expression analysis suggested that the mRNA expression of KDR in PBMC differed significantly according to rs2071559 genotype status (<0.001).
Apatinib demonstrated a potentially superior clinical outcome for patients with chemotherapy-refractory metastatic CRC. KDR polymorphism rs2071559 could be used as a potential biomarker for the prognosis evaluation of patients with CRC receiving apatinib therapy.
本研究旨在探讨含激酶插入结构域受体（KDR）基因变异对接受阿帕替尼治疗的化疗难治性转移性结直肠癌（CRC）患者治疗疗效和安全性的影响。
共有108例接受阿帕替尼治疗的化疗难治性转移性CRC患者回顾性参与本研究。评估患者的治疗疗效。分别进行预后分析并记录安全性概况。获取患者的血液标本和外周血单个核细胞（PBMC），分别用于分析基因变异和KDR基因mRNA表达。呈现基因型状态与临床结局之间的关联。
108例接受阿帕替尼治疗的转移性CRC患者的客观缓解率（ORR）和疾病控制率（DCR）分别为5.6%和69.4%。生存分析结果显示，108例转移性CRC患者的中位无进展生存期（PFS）和总生存期（OS）分别为3.6个月（95%置信区间（CI）：3.03 - 4.17个月）和8.9个月（95%CI：7.57 - 10.23个月）。随后，KDR基因变异分析表明rs⁴⁴⁶⁰⁰⁰⁰具有临床意义。rs⁴⁴⁶⁰⁰⁰⁰的次要等位基因频率为0.22，基因型状态符合Hardy - Weinberg平衡（P = 0.949）。通过将TC和CC基因型患者合并以显性遗传方式进行预后分析，结果显示TT基因型和TC/CC基因型患者的中位PFS分别为4.1和3.0个月（P = 0.012）。此外，两种基因型患者的中位OS分别为10.5和6.1个月（P = 0.007）。另外，OS的多因素Cox回归分析显示TC/CC基因型是OS的独立因素（风险比（HR）= 0.65，P = 0.021）。有趣的是，mRNA表达分析表明，PBMC中KDR的mRNA表达根据rs⁴⁴⁶⁰⁰⁰⁰基因型状态存在显著差异（P < 0.001）。
阿帕替尼对化疗难治性转移性CRC患者显示出潜在的优越临床结局。KDR基因多态性rs⁴⁴⁶⁰⁰⁰⁰可作为接受阿帕替尼治疗的CRC患者预后评估的潜在生物标志物。
