Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece; Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece; Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.
Clin Colorectal Cancer. 2019 Dec;18(4):e370-e384. doi: 10.1016/j.clcc.2019.07.007. Epub 2019 Jul 15.
Alternative splicing of vascular endothelial growth factor A (VEGFA) results in VEGFAxxxb antiangiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (CRC), binds both VEGFA and VEGFAxxxb isoforms.
Formalin-fixed, paraffin-embedded primary tumors from metastatic CRC patients treated with first-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) + bevacizumab (n = 285) or FOLFIRI only (n = 75) were collected. The relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom TaqMan-MGB assays and quantitative PCR.
At a median follow-up of 101.5 months, left-sided primary CRC was a favorable prognosticator (median survival, 29.2 vs. 18.2 months; P = .015). Positive high VEGFA145b was an unfavorable factor for progression-free survival (PFS; hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.13-2.44; P = .009) in patients who received FOLFIRI + bevacizumab, without prognostic significance in FOLFIRI-only patients (HR = 0.70; 95% CI, 0.34-1.44; P = .33). The adverse effect on PFS of 145b was more pronounced in patients with right-sided colon cancer (HR = 2.62; 95% CI, 1.35-5.12; P = .005), especially in those who received bevacizumab (HR = 2.85; 95% CI, 1.31-6.21; P = .008). In patients with right-sided colon primary tumors, isoform 121b correlated with inferior PFS (HR = 1.73; 95% CI, 0.94-3.18; P = .076) and overall survival (OS; HR = 2.0; 95% CI, 1.08-3.72; P = .028). In patients with left-sided primary tumors, positive high 165b correlated with superior PFS (HR = 0.76; 95% CI, 0.59-0.99; P = .044) and OS (HR = 0.68; 95% CI, 0.52-0.90; P = .006). At multivariate analysis, right-sided primary tumor was associated with inferior PFS (HR = 1.28; 95% CI, 1.00-1.64), while 145b consistently retained predictive significance for lack of benefit in PFS with bevacizumab (HR = 1.71; 95% CI, 1.16-2.53). Multivariate analysis for OS showed that VEGFA165b expression was favorable in patients with left-sided but unfavorable in patients with right-sided primary tumors (P < .001).
The antiangiogenic isoform VEGFA145b messenger RNA may predict resistance to bevacizumab. Differences in biological relevance and prognostic significance of various VEGFA isoforms were found for right- versus left-sided primary tumors.
血管内皮生长因子 A（VEGFA）的选择性剪接导致 VEGFAxxxb 抗血管生成同工型无法激活血管生成。贝伐单抗广泛用于转移性结直肠癌（CRC）患者，可结合 VEGFA 和 VEGFAxxxb 同工型。
收集接受一线 FOLFIRI（亚叶酸钙、5-氟尿嘧啶、伊立替康和奥沙利铂）+贝伐单抗（n=285）或仅 FOLFIRI（n=75）治疗的转移性 CRC 患者的福尔马林固定、石蜡包埋的原发肿瘤。使用定制的 TaqMan-MGB 测定法和定量 PCR 评估 VEGFA121a、121b、145a、145b、165a 和 165b 的相对表达。
在中位随访 101.5 个月时，左侧原发性 CRC 是有利的预后因素（中位生存期 29.2 与 18.2 个月；P=0.015）。阳性高 VEGFA145b 是接受 FOLFIRI+贝伐单抗治疗的患者无进展生存期（PFS）的不利因素（危险比 [HR]1.66；95%置信区间 [CI]，1.13-2.44；P=0.009），但在接受 FOLFIRI 治疗的患者中无预后意义（HR=0.70；95%CI，0.34-1.44；P=0.33）。145b 对 PFS 的不利影响在右半结肠癌患者中更为明显（HR=2.62；95%CI，1.35-5.12；P=0.005），尤其是接受贝伐单抗治疗的患者（HR=2.85；95%CI，1.31-6.21；P=0.008）。在右侧结肠原发肿瘤患者中，同工型 121b 与较差的 PFS（HR=1.73；95%CI，0.94-3.18；P=0.076）和总生存期（OS）（HR=2.0；95%CI，1.08-3.72；P=0.028）相关。在左侧结肠原发肿瘤患者中，阳性高 165b 与较好的 PFS（HR=0.76；95%CI，0.59-0.99；P=0.044）和 OS（HR=0.68；95%CI，0.52-0.90；P=0.006）相关。多变量分析显示，右侧原发肿瘤与较差的 PFS 相关（HR=1.28；95%CI，1.00-1.64），而 145b 始终与贝伐单抗治疗缺乏 PFS 获益相关（HR=1.71；95%CI，1.16-2.53）。OS 的多变量分析显示，VEGFA165b 表达在左侧患者中是有利的，但在右侧患者中是不利的（P<0.001）。
抗血管生成同工型 VEGFA145b mRNA 可能预测贝伐单抗耐药。在右侧和左侧原发性肿瘤中，不同的 VEGFA 同工型在生物学相关性和预后意义方面存在差异。
