Chromosomal instability is associated with prognosis and efficacy of bevacizumab after resection of colorectal cancer liver metastasis

Individualized treatment of colorectal cancer liver metastases (CRLM) remains challenging due to differences in the severity of metastatic disease and tumour biology. Exploring specific prognostic risk subgroups is urgently needed. The current study aimed to investigate the prognostic value of chromosomal instability (CIN) in patients with initially resectable CRLM and the predictive value of CIN for the efficacy of bevacizumab. Ninety-one consecutive patients with initially resectable CRLM who underwent curative liver resection from 2006 to 2018 at Sun Yat-sen University Cancer Center were selected for analysis. CIN was evaluated by automated digital imaging systems. Immunohistochemistry (IHC) was performed to detect interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA) and CD31 expression in paraffin-embedded specimens. Recurrence-free survival (RFS) and overall survival (OS) were analysed using the Kaplan–Meier method and Cox regression models. Patients with high chromosomal instability (CIN-H) had a worse 3-year RFS rate (HR, 1.953; 95% CI, 1.001–3.810; <i>p</i> = 0.049) and a worse 3-year OS rate (HR, 2.449; 95% CI, 1.150–5.213; <i>p</i> = 0.016) than those with low chromosomal instability (CIN-L). CIN-H was identified as an independent prognostic factor for RFS (HR, 2.569; 95% CI, 1.078–6.121; <i>p</i> = 0.033) and OS (HR, 3.852; 95% CI, 1.173–12.645; <i>p</i> = 0.026) in the multivariate analysis. The protein levels of IL-6, VEGFA and CD31 were upregulated in patients in the CIN-H group compared to those in the CIN-L group in both primary tumour and liver metastases tissues. Among them, 22 patients with recurrent tumours were treated with first-line bevacizumab treatment and based on the clinical response assessment, disease control rates were adversely associated with chromosomal instability (<i>p</i> = 0.043). Our study showed that high chromosomal instability is a negative prognostic factor for patients with initially resectable CRLM after liver resection. CIN may have positive correlations with angiogenesis through expression of IL-6–VEGFA axis and be used as a potential predictor of efficacy of bevacizumab.

由于转移性疾病严重程度与肿瘤生物学特性存在差异，结直肠癌肝转移（colorectal cancer liver metastases, CRLM）的个体化治疗仍具有挑战性，探索特异性预后风险亚组的需求极为迫切。本研究旨在探讨染色体不稳定性（chromosomal instability, CIN）在初始可切除结直肠癌肝转移患者中的预后价值，以及CIN对贝伐珠单抗治疗疗效的预测价值。本研究纳入2006年至2018年于中山大学肿瘤防治中心接受根治性肝切除术的91例连续性初始可切除结直肠癌肝转移患者进行分析。采用自动化数字成像系统评估染色体不稳定性；通过免疫组化（immunohistochemistry, IHC）检测石蜡包埋标本中白细胞介素-6（interleukin-6, IL-6）、血管内皮生长因子A（vascular endothelial growth factor A, VEGFA）及CD31的表达水平。采用Kaplan-Meier法与Cox回归模型分析无复发生存期（recurrence-free survival, RFS）与总生存期（overall survival, OS）。与染色体不稳定性低（CIN-L）患者相比，染色体不稳定性高（CIN-H）患者的3年无复发生存率更差（风险比[HR]=1.953，95%置信区间[CI]=1.001~3.810，P=0.049），3年总生存率亦更差（HR=2.449，95%CI=1.150~5.213，P=0.016）。多因素分析显示，CIN-H是无复发生存期（HR=2.569，95%CI=1.078~6.121，P=0.033）与总生存期（HR=3.852，95%CI=1.173~12.645，P=0.026）的独立预后因素。CIN-H组患者的原发肿瘤及肝转移灶组织中，IL-6、VEGFA及CD31的蛋白表达水平均较CIN-L组上调。其中22例复发肿瘤患者接受了一线贝伐珠单抗治疗，基于临床疗效评估结果，疾病控制率与染色体不稳定性呈负相关（P=0.043）。本研究表明，高染色体不稳定性是初始可切除结直肠癌肝转移患者肝切除术后的不良预后因素。CIN可能通过调控IL-6-VEGFA轴的表达参与血管生成过程，有望成为贝伐珠单抗治疗疗效的潜在预测标志物。