Prognostic Analysis Of Cervical Neuroendocrine Carcinoma And Its Expression And Therapeutic Significance Of PD-L1 And PARP1

Objective: To study the relationship between clinicopathological features,treatment and prognosis of Neuroendocrine cervical cancer(NECC),and further establish and verify the clinical prognostic prediction model.Considering that NECC is characterized by strong aggressiveness and poor prognosis,and that PD-1/PD-L1 inhibitors and PARP inhibitors have shown therapeutic potential in neuroendocrine tumors at other sites and refractory cervical cancers,we evaluate the expression of PD-L1 and PARP1 in NECC and find biomarkers for targeted and immunotherapy.To investigate the application value of PD-1/PD-L1 inhibitor and PARP1 inhibitor in the treatment of NECC.Method: A total of 495 patients with primary NECC who met inclusion and exclusion criteria were collected from the Surveillance,Epidemiology,and End Results(SEER)database and randomly divided into a modeling cohort and a validation cohort in a 7:3ratio.Univariate and multivariate COX regression were used to screen for independent prognostic factors and a clinical prediction model--Nomogram was established to predict Overall Survival(OS)of NECC patients.Use C-index,Relative Operating Characteristic Curve(ROC),calibration curve and decision curve Analysis(DCA)to verify the Nomogram.The clinicopathological data of primary NECC patients admitted to The Affiliated Hospital of Qingdao University from January 2010 to December 2019 were collected,and the expressions of PD-L1,PARP1,4 mismatch repair proteins(MMRs)and p53 in NECC patients were analyzed by immunohistochemistry(IHC).The positive rate was calculated to evaluate the therapeutic potential of corresponding targeted therapies,and the correlation between protein expressions was analyzed by Chi-square test to further explore biomarkers for targeted immunotherapy.Finally,individual cases of patients with clinical use of targeted and immunotherapy were analyzed.Results: The age,T stage,N stage,M stage,local treatment and chemotherapy were independent factors affecting the prognosis of NECC patients(P<0.05).The C-index of modeling cohort and a validation cohort were 0.780 and 0.734,respectively.All results of area under ROC curve(AUC)were greater than 0.75(modeling cohort:1y-0.893,3y-0.762,5y-0.750;Validation cohort: 1y-0.801,3y-0.769,5y-0.790);Calibration curves and DCA curves show that the model has high accuracy and reliability,and has obvious clinical benefits.The risk stratification system divided patients into high and low risk groups,with significant differences in survival between the two groups in both the modeling and validation cohorts(P<0.05).After rigorous screening,20 NECC patients were included.3 cases did not receive surgical treatment due to late stage.Distant metastasis or recurrence occurred in 12patients(60%)within 5 years,most within 2 years.The positive rate of PD-L1 and PARP1 was 70% and 75%,respectively.In addition,microsatellite instability(MSI)was detected in 6 cases(30%),and PD-L1 positive and/or MSI accounted for 85%.P53 expression was abnormal in 15 cases(75%).PD-L1 was correlated with PARP1 expression in MSI subgroup(P =0.004).Clinically,the clinical symptoms,tumor markers and tumor size of a patient with NECC treated with chemotherapy +antiangiogenic agents + PD-1 inhibitor were significantly improved.Conclusion:1.The age,T stage,N stage,M stage,type of local treatment(surgery and radiotherapy),and chemotherapy were the main factors affecting the prognosis of NECC patients.The constructed and verified Nomogram can provide more accurate and personalized survival prediction for patients,and also have important reference significance for treatment and prognosis.2.Immunohistochemical results of PD-L1 and PARP1 suggest that PD-1/PD-L1 inhibitors and PARP inhibitors may be applicable to NECC patients,and combined with the results of MMRs,the target population of PD-1/PD-L1 inhibitors will be further expanded.At the same time,MSI patients who are treated with immune checkpoint inhibitors are most likely to be treated with PARP inhibitors.3.Our case confirms that immune checkpoint therapy is effective in NECC patients with PD-L1 positive and MSI.