Association of preoperative serum CA72-4 with prognosis in stage I-III colorectal cancer patients and its interaction with preoperative CEA: a multicenter retrospective cohort study Running head: Preoperative CA 72-4 and CEA in outcomes of colorectal cancer

Abstract BACKGROUND AND AIMS: Whether preoperative serum carbohydrate antigen (CA) 72-4 is an independent predictor of outcome and whether has an interaction between CA72-4 and the impact of carcinoembryonic antigen (CEA) on colorectal cancer (CRC) patients' risk of recurrence is still unknown. PATIENTS AND METHODS: Patients with pathologically confirmed stage I-III colorectal adenocarcinoma who received direct radical resection at 2 hospitals from 2008 to 2017 were collected. According to the levels of CEA and CA72-4 before operation, the patients were divided into 4 groups: Group A with normal CEA and CA72-4 levels preoperatively (CEA≤5.0 ng/mL,CA72-4≤6.9 U/mL, n=952) ;Group B had normal preoperative CEA but high CA72-4 levels (CEA≤5.0 ng/mL,CA72-4>6.9 U/mL, n=217) ；Group C had elevated preoperative CEA but normal CA72-4 (CEA>5.0 ng/mL,≤6.9 U/mL, n=574) ；Group D had both elevated preoperative CEA and CA72-4 (CEA>5.0 ng/mL, CA72-4>6.9 U/mL, n=182). The Kaplan-Meier survival curve and a COX regression model was used to estimate the correlation between preoperative CA72-4 and overall survival (OS) and recurrence-free survival (RFS). Results: A total of 3,651 patients (52.7%) are included in this study. Median age (IQR) : 60.0 (50.0, 68.0) years; Mean body mass index (BMI) (SD) : 22.718(3.256) kg/m2. Compared with normal CA 72-4 (≤6.9 U/mL, n=3252), patients with increased CA 72-4 (>6.9U/mL, n=399) had higher OS(HR:1.4;95% CI, 1.07-1.83; P = 0.0072). In Cox multivariate analysis, increased preoperative CEA and CA72-4 were associated with shorter RFS(HR:1.69;95% CI, 1.23- 2.32; P = 0.001) and OS (HR, 2.92;95% CI, 2.14-3.98; P < 0.001). However, patients with normal preoperative CEA, no matter if CA72-4 is increased or normal, were not associated with RFS and OS shortening, while patients with high CEA but normal CA72-4 were only associated with OS(HR:1.82;95% CI, 1.42-2.33; P <0.001). Conclusion: CA72-4 is an independent predictor of outcome for patients with elevated preoperative CEA. The influence of preoperative CA72-4 level on prognosis is different under different CEA stratification. It is necessary to combine CA72-4 with CEA to predict the prognosis of patients.