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

Abstract

Introduction: 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.

Methods: 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.

Results: Patients with high chromosomal instability (CIN-H) had a worse 3-year RFS rate (HR, 1.953; 95% CI, 1.001-3.810; p = 0.049) and a worse 3-year OS rate (HR, 2.449; 95% CI, 1.150-5.213; p = 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; p = 0.033) and OS (HR, 3.852; 95% CI, 1.173-12.645; p = 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 (p = 0.043).

Conclusions: 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.

Keywords: Colorectal cancer; antiangiogenesis; chromosomal instability; liver metastases; prognosis.

Figure 1.

Flow chart of the total patient selection process.

Figure 2.

Kaplan–Meier Curves of patients with initially resectable colorectal cancer liver metastases (CRLM) grouped by chromosomal instability. (A) Comparison of recurrence-free survival (RFS) between the high chromosomal instability (CIN-H) group and the low chromosomal instability (CIN-L) group. (B) Comparison of overall survival (OS) between the CIN-H group and the CIN-L group.

Figure 3.

Chromosomal instability showed positive correlations with angiogenesis through expression of Interleukin-6 (IL-6)–vascular endothelial growth factor A (VEGFA) axis in primary tumour and liver metastasis. (A) Two representative cases show expression of IL-6, VEGFA and CD31 in high compared with low levels of chromosomal instability human CRC tumour tissues analysed by immunohistochemistry (IHC) staining (scale bar: black, 200 μm; red, 100 μm;). (B) Comparison of IL-6, VEGFA and CD31 expression in primary tumour between the high chromosomal instability (CIN-H) group and the low chromosomal instability (CIN-L) group. (C) Correlation between IL-6 and VEGFA, CD31 expression levels in primary tumour. (D) Two representative cases show expression of IL-6, VEGFA and CD31 in high compared with low levels of chromosomal instability human CRC tumour liver metastasis tissues analysed by immunohistochemistry (IHC) staining (scale bar: black, 200 μm; red, 100 μm;). (E) Comparison of IL-6, VEGFA and CD31 expression in liver metastasis between the CIN-H group and the CIN-L group. (F) Correlation between IL-6 and VEGFA, CD31 expression levels in liver metastasis. *p ≤ 0.05, **p ≤ 0.01.

Figure 4.

Evaluation of bevacizumab treatment efficacy in CRLM grouped by chromosomal instability. (A) Best percentage change from baseline in the tumour burden (defined as the sum of the longest diameters of all target lesions) in all 22 patients with measurements of target lesions after baseline. (B) Number of CRLM patients with bevacizumab treated partial response (PR)/stable disease (SD) or bevacizumab-treated progressive disease (PD) in the high chromosomal instability (CIN-H) group or the low chromosomal instability (CIN-L) group.