Prognostic Value Of E-cadherin,CD44 And MSH2 Associated Nomograms In Patients With Stage Ⅱ And Ⅲ Colorectal Cancer

Colorectal cancer(CRC)is the third most commonly diagnosed cancer in men and the second in women worldwide,and surgery remains the mainstay of curative treatment.The application of regular screening as well as adjuvant and neoadjuvant therapeutic regimens have contributed to the improved prognosis of colorectal cancer patients.However,a subset of patients will develop local recurrences and metachronous metastases after resection of the primary tumor.The current American Joint Committee on Cancer(AJCC)TNM staging system is widely used as a guideline for staging and survival estimates.However,patients within the same AJCC stage vary considerably in prognosis.Although the seventh edition of AJCC staging provided improved prognostic prediction within each stage,the clear rank ordering between stages was lost.The survival of stage ⅢA and ⅢB patients is superior compared with stage IIC colon cancer patients,and there have been many’prognostic marker’ studies that have aimed to improve the prognostic prediction of the TNM system.However,most proposed biomarkers for CRC are not clinically implemented due to the lack of reproducibility and/or standardization.This study was conducted to evaluate the potential prognostic significance of ECAD,CD44 and MSH2 expression in CRC and to determine the relationships with various clinicopathologic variables.We then developed and validated two nomograms that incorporated these biomarkers and clinicopathologic risk factors for the individual prediction of overall survival(OS)and disease-free survival(DFS)in patients with stage Ⅱ and Ⅲ CRC.We retrospectively analyzed the expression of E-cadherin,CD44,and MSH2 in 223 paraffin-embedded stage Ⅱ and Ⅲ CRC specimens using immunohistochemistry in the training cohort.Their prognostic values were assessed using Kaplan-Meier curves and univariate and multivariate COX regression models.Moreover,a number of risk factors were used to form nomograms to evaluate survival,and Harrell’s concordance index(C-index)was used to evaluate the predictive accuracy.Further validation of the nomograms was performed in an independent cohort of 115 cases.The results showed that low E-cadherin expression and low CD44 expression were significantly associated with diminished overall survival(OS)and disease-free survival(DFS)in stage Ⅱ and Ⅲ CRC patients and patients with negative MSH2 expression had better clinical outcomes.Moreover,the multivariate COX analysis identified E-cadherin,CD44 and MSH2 expression as independent prognostic factors for DFS and OS.Using these three markers and three clinicopathological risk variables,two nomograms were constructed and externally validated for predicting OS and DFS(C-index:training cohort,0.779(95%CI 0.722-0.835)and 0.771(0.720-0.822),respectively;validation cohort,0.773(0.709-0.837)and 0.670(0.594-0.747),respectively).We conclude that the expression levels of E-cadherin,CD44 and MSH2 were independent prognostic factors for stage Ⅱ and Ⅲ CRC patients.By incorporating clinicopathological features and these biomarkers,we have established two nomograms that could be used to make individualized predictions for OS and DFS.