Prognostic models based on postoperative circulating tumor cells can predict poor tumor recurrence-free survival in patients with stage II-III colorectal cancer

Abstract

Background: It is urgent to develop robust prognostic biomarkers for non-metastatic colorectal cancer (CRC) patients undergoing surgery. The current study aimed to explore and compare the clinical significance of preoperative and postoperative blood tumor biomarkers including circulating tumor cells (CTCs), and develop prognostic models based on tumor biomarkers in patients with stage II-III CRC receiving surgery. Methods: A prospective study was performed to enroll 130 patients with stage II-III CRC receiving surgery between January 2015 and December 2017. Preoperative and postoperative blood tumor biomarkers including CTCs were detected and their prognostic value in predicting tumor recurrence-free survival (RFS) in stage II-III CRC were identified by Kaplan-Meier curves and Cox proportional hazard regression models. Results: CTCs counts within three postoperative days were significantly higher than preoperative CTCs (pre-CTCs). No significant association of pre-CTCs with clinical characteristics and tumor biomarkers was observed while positive postoperative CTCs (post-CTCs) were associated with female, older onset age, high TNM stage, tumor recurrence, and preoperative CEA. Kaplan-Meier curve with log-rank test and univariate Cox proportional hazard regression analysis suggested high N stage, TNM stage, positive pre-carbohydrate antigen (CA) 125, pre-CA19-9, post-CA125, post-CA19-9, post-CA72-4, post-carcinoembryonic antigen (CEA), and post-CTCs were correlated with poor RFS. In multivariate analysis, only TNM stage (adjusted HR=3.786, 95% CI=1.330-10.780; P=0.013), post-CA72-4 (adjusted HR=5.675, 95% CI=2.064-15.604; P=0.001), and post-CTCs (adjusted HR=2.739, 95% CI=1.042-7.200; P=0.041) were significantly correlated with poor RFS. We then developed prognostic models combining post-CTCs and post-CA72-4 with TNM stage or not to stratify the patients into different risk groups. These prognostic models exert a similar good performance in predicting tumor RFS in stage II-III CRC patients. Conclusions: Postoperative CTCs were prior to preoperative CTCs in predicting tumor recurrence survival in non-metastatic CRC patients undergoing surgery. We also developed CTCs-based prognostic models to predict tumor recurrence in stage II-III CRC, which might be used to identify the patients with high risk of recurrence and guide aggressive treatment to improve the clinical outcomes of those patients.

Keywords: circulating tumor cells; non-metastatic colorectal cancer; prognostic model; tumor recurrence survival.

Figure 1

Comparison of preoperative and postoperative blood tumor biomarkers in patients with stage II-III CRC. (A) CTCs; (B) CEA; (C) CA19-9; (D) CA72-4; (E) CA125. Abbreviations: CRC, colorectal cancer; CTCs, circulating tumor cells; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; CA72-4, carbohydrate antigen 72-4; CA125, carbohydrate antigen 125.

Figure 2

Correlations of postoperative CTCs numbers with preoperative CTCs numbers (A) and preoperative CA125 levels (B) in stage II-III CRC determined by Pearson's correlation analysis. Abbreviations: CRC, colorectal cancer; CTCs, circulating tumor cells; CA125, carbohydrate antigen 125.

Fig 3

Effects of TNM stage (A), postoperative CA72-4 (B), postoperative CTCs (C), and N stage (D) on RFS in stage II-III CRC analyzed by Kaplan-Meier curves. Abbreviations: CRC, colorectal cancer; CTCs, circulating tumor cells; RFS, recurrence-free survival; CA72-4, carbohydrate antigen 72-4; RFS, recurrence-free survival.

Figure 4

Prognostic value of constructed prognostic models based on postoperative CTCs in stage II-III CRC. Prognostic models were constructed by combining TNM stage, postoperative CA72-4 and postoperative CTCs (A and B) or combining only postoperative CA72-4 and postoperative CTCs (C and D). Using the prognostic models, the patients were stratified into three risk groups (multiple classifications, A and C) or two risk groups (binary classification, B and D). Abbreviations: CRC, colorectal cancer; CTCs, circulating tumor cells; CA72-4, carbohydrate antigen 72-4; RFS, recurrence-free survival.

Figure 5

Effects of postoperative CTCs on RFS in stage II-III rectal cancer (A) or colon cancer (B) analyzed by Kaplan-Meier curves. Abbreviations: CTCs, circulating tumor cells; RFS, recurrence-free survival.

Figure 6

Prognostic value of constructed prognostic models based on postoperative CTCs in stage II-III rectal cancer. Prognostic models were constructed by combining TNM stage, postoperative CA72-4 and postoperative CTCs (A and B) or combining only postoperative CA72-4 and postoperative CTCs (C and D). Using the prognostic models, the patients were stratified into three risk groups (multiple classifications, A and C) or two risk groups (binary classification, B and D). Abbreviations: CTCs, circulating tumor cells; CA72-4, carbohydrate antigen 72-4; RFS, recurrence-free survival.

Fig 7

Prognostic value of constructed prognostic models based on postoperative CTCs in stage II-III colon cancer. Prognostic models were constructed by combining TNM stage, postoperative CA72-4 and postoperative CTCs (A and B) or combining only postoperative CA72-4 and postoperative CTCs (C and D). Using the prognostic models, the patients were stratified into three risk groups (multiple classifications, A and C) or two risk groups (binary classification, B and D). Abbreviations: CTCs, circulating tumor cells; CA72-4, carbohydrate antigen 72-4; RFS, recurrence-free survival.