Correlation Between Ki-67 And PD-L1 ExPression In Non-small Cell Lung Cancer And Its Effect On Prognosis

ObjectiveTo analyze the relationship between the cell proliferation index Ki-67 and programmed death ligand-1(PD-L1)in non-small cell lung cancer(NSCLC)and their effects on prognosis.Methods1.Patients selection401patients who met the inclusion criteria and were tested for immunohistochemical PD-L1 and Ki-67 were diagnosed as NSCLC in Changhai Hospital were collected from January 2012 to August 2018.Clinical and pathological data were collected including: age.,gender,smoking,PS score,clinical manifestations at the first visit,tumor site,tumor maximum diameter,postoperative stage,tumor pathological type,growth pattern,degree of differentiation,EGFR/ALK/ROS-1 gene mutation,etc.;121 Patients were followed up and the time of recurrence,reassessment of staging,recurrence of genetic testing gene mutations,postoperative recurrence treatment,and postoperative recurrence of first-line treatment.The follow-up period ranged from 10 months to 83 months.The median followup time was 43 months.The follow-up deadline was November 30,2018.The study was approved by the Shanghai Changhai Hospital Ethics Committee and all patients signed informed consent.2.Statistical analysisPD-L1≥1% was used as the positive threshold,and the risk factors affecting PD-L1 expression were analyzed by single factor and multivariate logistic regression.The correlation between Ki-67 and PD-L1 was analyzed by curve fitting and threshold effect analysis was applied.Finding nodes,using segmentation multivariate logistic regression analysis and receiver operating characteristic curve(ROC curve)model to analyze the predictive power of different nodes of Ki-67 for PD-L1 expression.Postoperative DFS,post-relapse chemotherapy,and targeted drug therapy for PFS survival analysis were performed using the Kaplan-Meier method.Results1.Baseline demographic characteristcs401 Patients with NSCLC,152(37.9%)in PD-L1≥1% group,249(62.1%)in PDL1<1% group,mean age 61.27±10.28 years old,228 male cases(56.86%)173 female patients(43.14%),288(71.82%)lung adenocarcinoma,113(28.18%)lung squamous cell carcinoma;121 patients with recurrence after follow-up,73 Patients with negative PD-L1 expression(60.33%)and 48 cases(39.67%)with positive PD-L1 expression,mean age 60.21±10.76 years old,63 male patients(52.07%),58 female patients(47.93%),and 106 patients with lung adenocarcinoma(87.6%).15 cases of lung squamous cell carcinoma(12.4%).2.Immunohistochemical expression of Ki-67 and PD-L1Ki-67 expression was positive in 386 cases(96.3%),negative in 15 cases(3.7%),Ki-67 expression value of PD-L1 positive group was(36.64 ± 23.59)%,Ki-67 expression value of PD-L1 negative group was(11.49 ± 13.14)%.There was a statistically significant difference between the two groups(P<0.001).The expression of Ki-67 was significantly higher in the PD-L1 positive group than in the PD-L1 negative group.3.The relationship between Ki-67 and PD-L1 in NSCLC patientsGender,age,smoking,Ki-67,tissue EGFR mutation,lung cancer type,degree of differentiation,preoperative tumor maximum diameter,postoperative staging were included in the univariate analysis model.Ki-67 and degree of differentiation were risk factors for PD-L1 expression.The expression of Ki-67 was significantly different between PD-L1 positive group and PD-L1 negative group(P<0.0001),and was significantly higher in PD-L1 positive group than in PD-L1 negative group.Curve fitting analysis of Ki-67 and PD-L1 expression,found Ki-67 showed a nonsmooth linear positive correlation with PD-L1 expression.Further analysis of the threshold effect of Ki-67 and PD-L1 revealed that 14% and 45% were nodes.Ki-67 expressed 14% as node,Ki-67<14% and PD-L1 expression showed opposite trends,but no significant difference(P=0.2243),Ki-67≥14% and PD-L1 expression was positively correlated.The difference between Ki-67<14% regression coefficient and Ki-67>14% regression coefficient was(OR=0.75,95% CI=0.40 ~ 1.11,P<0.0001),and the slope of the two segments was significant.Ki-67 expressed 45% as node,Ki-67<45% and Ki-67≥45% Ki-67 and PD-L1 expression were positively correlated,but Ki-67<45% segment regression coefficient and Ki-67>45% segment regression coefficient difference is(OR=0.76,95% CI =0.51~1.01,P <0.0001),there is a significant difference between the slopes of the two segments.Multivariate logistic regression model was used to analyze the independent predictive effect of Ki-67 on PD-L1 expression.It was found that Ki-67 was an independent affecting factor for PD-L1 expression(OR=1.09,95% CI=1.07~1.11,P<0.001).Combined with the threshold effect analysis of 14% and 45% nodes,the multi-factor logistic regression analysis found,with Ki-67 expression 14% as node,Ki-67<14% had no independent predictive effect on PD-L1 expression(OR=1.13,95% CI=0.98~1.32,P=0.0871),Ki-67 ≥ 14% had independent predictive effect on PD-L1 expression(OR=1.07,95% CI=1.04~1.09,P<0.0001);Ki-67 expression 45% as node,Ki-67 <45% is an independent affecting factor for PD-L1 expression(OR=1.09,95% CI=1.07~1.13,P<0.0001),Ki-67 ≥ 45% was also an independent affecting factor for PD-L1 expression(OR=1.14,95% CI=1.02~1.28,P=0.0223).Diagnostic test and ROC analysis found that the AUC area of Ki-67 with 14% as the node model was greater than the node model of 45%,but there was no significant difference(P=0.183).The sensitivity and specificity of the 14% model were more balanced,and the model of Ki-67 expression was 45% better,but the sensitivity was poor.3.The effect of Ki-67 and PD-L1 expression on the prognosis of NSCLCThe postoperative follow-up of 121 patients was divided into Ki-67 high and low expression group with Ki-67 14% as node,and PD-L1 positive group and PD-L1 negative group with PD-L1 expression 1% as node..Based on these two nodes,patients were further divided into 4 groups.Kaplan-Meier analysis showed that postoperative DFS,Ki-67 high group was significantly shorter than Ki-67 low group [(21.88 ± 11.25 vs41.22 ± 16.25)m,P < 0.0001],PD-L1 positive group was significantly shorter than group PD-L1 negative group [(24.75 ± 14.59 vs38.27 ± 16.75)m,P <0.0001],The Ki-67 high/PD-L1 positive group was the shortest compared with the other three groups[(20.57 ± 11.33 vs 24.11 ± 10.79 vs36.00 ± 16.79 vs42.91 ± 15.77)m,P <0.0001).Chemotherapy PFS,Ki-67 high group was significantly longer than Ki-67 low group [(7.70 ± 3.01 vs5.80 ± 2.99)m,P = 0.016],there was no significant difference between PDL1 positive group and PD-L1 negative group [(7.04 ± 3.21 vs 6.33 ± 3.06)m,P=0.22),Ki-67 high groups were significantly longer than Ki-67 low groups [(7.74 ± 3.25 vs 7.43 ± 2.38 vs 4.91 ± 1.97 vs 6.02 ± 3.19)m,P=0.041).Targeted treatment of PFS,Ki-67 high group and Ki-67 low group,PD-L1 positive group and PD-L1 negative group,Ki-67/PD-L1 combined group showed no significant difference[(5.33 ± 3.98 vs 6.31 ± 4.14)m,P = 0.41],[(5.87 ± 4.02 vs 6.00 ± 4.15)m,P = 0.41],[(5.45 ± 3.97 vs 5.17 ± 4.00 vs 7.0 ± 4.21 vs 6.20 ± 4.20)m,P=0.82].Conlusions1.In NSCLC,Ki-67 was significantly higher in PD-L1 positive group than PD-L1 negative group,and Ki-67 was an independent affecting factor for PD-L1 expression,and there was a significant positive correlation between them.Besides,there are two nodes of Ki-67 expressing 14% and 45%;2.Ki-67 14% is a node that distinguishes the positive correlation between Ki-67 and PD-L1 expression and whether Ki-67 has independent Predictive effect on PD-L1 expression.Ki-67 45% is only a node with a significant Positive correlation with PD-L1 expression;14% of Ki-67 expression has a good sensitivity and specificity for the diagnosis and prediction of PD-L1.The diagnostic predictive effect of Ki-67 45% for PDL1 expression is well,but the sensitivity is poor.So 14% of Ki-67 expression is a suitable threshold for the combined application of PD-L1 expression;3.Ki-67 ≥14% is a poor predictor of recurrence after NSCLC,and a predictor of chemotherapy sensitivity.PD-L1≥1% is a poor predictor of recurrence after NSCLC,but it has no significant effect on chemotherapy.Effects;Ki-67 and PD-L1 had no significant effect on targeted therapy;4.Ki-67 ≥14% combined with PD-L1≥1% had a “superimposition effect” on the adverse predictive effect of recurrence of NSCLC,suggesting that patients with both high expression have a higher risk of postoperative recurrence.Postoperative adjuvant therapy shoud be more active;5.The sensitivity of Ki-67 ≥14% combined with PD-L1≥1% to NSCLC chemotherapy is mainly attributed to the efficacy of Ki-67,PD-L1 expression has a Predictive effect on PD-1/L1 inhibitor,suggesting that the efficacy of Ki-67 and PD-L1 exPression combined with predicting PD-1/L1 inhibitor combination chemotherapy may be superior to PD-L1 single.