A Nomogram Model Predicting The Prognosis After Radical Chemoradiotherapy For Patients With Esophageal Squamous Cell Carcinoma Based On DSBs Repair Proteins' Expression

Objective: To investigate the relationship between DSBs repair proteins ATM,DNA-PKcs,BRCA1,BRCA2,Rad51 and P16 expression and clinicopathological characteristics and long-term prognosis of patients with radical chemoradiotherapy for esophageal squamous cell carcinoma,and to establish nomogram prediction model and verify its accuracy.Methods: A total of 283 patients with ESCC who underwent radical radio(chemo)therapy from 2012 to 2017 were enrolled,and their biopsy specimens and clinical data were collected.They were randomly divided into a modeling group(n = 189)and a validation group(n = 94)according to a 2: 1ratio.The expression levels of ATM,DNA-PKcs,BRCA1,BRCA2,Rad51 and P16 proteins in tumor tissues were detected by immunohistochemistry(SP method).Chi-square test for comparison of categorical variables,survival curves were drawn by Kaplan-Meier method,univariate prognosis analysis was performed by Log-rank test,and multivariate prognosis analysis was performed by Cox proportional hazard regression model.Using R software,according to the results of multivariate analysis,including clinical parameters such as T and N stages and different repair proteins expression levels to construct a nomogram model,and calculate the concordance index(C-index).The model with the highest C-index was selected as the prediction model to verify itsaccuracy,and using the validation group to verify its accuracy.Results: With a median follow-up time of 34 months(range from 18 to 80months),283 patients in the entire group died of 188,and 95 patients survived.The median overall survival was 17 months(range from 2 to 78 months),and the overall survival rates at 3 and 5 years were 34.6% and 17.7%.In modeling group,the results showed that the expression of DNA-PKcs,ATM,BRCA1,BRCA2,Rad51,and P16 proteins had no significant correlation with age,smoking,clinical stage,tumor length and tumor site(all P> 0.05).Smoking or male patients had higher DNA-PKcs protein positive rate(P=0.008?P=0.043).Patients with later T or clinical stage had higher ATM protein positive rate(P<0.001,P = 0.009).smoking patients had higher BRCA1 protein positive rate(P = 0.005).P16 protein positive rate was higher in patients with N stage later(P <0.001).Univariate analysis results showed that age,tumor length,tumor location,radiation dose,and whether chemotherapy was not significantly related to patient prognosis(all P> 0.05).gender,smoking,drinking,T stage,N stage,clinical stage,and ATM,DNA-PKcs,BRCA1,BRCA2 and P16 protein expression were all independent prognostic factors of OS in patients(all P<0.05).The median OS of the five protein negative and positive patients were25 and 13 months,28 and 14 months,24 and 14 months,21 and 15 months,and13 and 20 months,respectively.Significant indicators from the univariate analysis were included in the multivariate analysis.The results showed that the T and N stages and the expression of ATM,DNA-PKcs,BRCA1,BRCA2,and P16 proteins were significantly related to the OS of patients(all P<0.05).Basedon the results of multivariate analysis,clinical parameters such as T and N staging and DSBs repair proteins ATM,DNA-PKcs and P16 proteins were included in the nomogram prediction model.This model predicts that the 3-year5-year overall survival rate of patients with a C-index is 0.724(95% CI:0.657-0.791),which is significantly higher than 0.533(95% CI: 0.445-0.655,P<0.001)in the seventh stage of AJCC clinical stage.For the validation group,the C-index of the nomogram model and 7th AJCC staging system were0.792(95%CI:0.718-0.865)and 0.550(95%CI:0.445-0.655)respectively(P< 0.001).The calibration curve also shows that the survival rate of ESCC patients predicted by this nomogram is in good agreement with the survival rate of actual patients,indicating that the accuracy of the model prediction is high.Conclusions: T and N staging and the expression of DSBs repair proteins DNA-PKcs,ATM,BRCA1,BRCA2 and P16 protein are independent prognostic factors of esophageal squamous cell carcinoma patients.The nomogram model based on the T and N stages and the expression of the DSBs repair proteins ATM,DNA-PKcs and P16 can predict the long-term survival of patients with radical chemotherapeutic esophageal squamous cell carcinoma.The nomogram model has certain clinical significance for guiding the individualized treatment of patients.