Expression Of Ki67 And ERCC1 In Metastasis And Clinical Significance In First-line Treatment Of Metastatic Nasopharyngeal Carcinoma

Background: Nasopharyngeal carcinoma(NPC)is a common malignant tumor in Southern China.The local control rate of NPC is greatly improved by the combination of intensity modulated radiation therapy(IMRT)and chemotherapy,but distant metastasis still occurs in 20% of NPC patients.Chemotherapy combined with targeted treatment is the main treatment modality of metastatic NPC.How to choose a reasonable strategy to improve the efficacy of metastatic NPC is a hotspot and difficulty of clinical research.With the development of precise treatment,exploring the molecular markers of metastatic NPC is helpful to guide the clinical individualized precise diagnosis and treatment.The studies have shown that the change of EBV-DNA value in plasma is related to the efficacy and prognosis of NPC,but the domestic detection technology and methods are inconsistent,which result in the low repeatability of the results of detection and limit the widespread application in China.The immune combination detection of focus tissue is a universal detection method in clinic.It has better clinical operability to use it to predict the efficacy and prognosis of effective biological indicators.Studies have found that high expression of Proliferating cell nuclear antigen Ki67(Ki67)in NPC tumor tissues is involved in tumor metastasis and survival,and the expression of Excision repair cross complementing 1(ERCC1)is related to the curative effect and prognosis of the disease.Moreover,the results of our previous study also verified the correlation between the expression of Ki67 and ERCC1 in the primary NPC and the clinical prognosis.Many studies indicated that there were differences in the expression of Ki67 or ERCC1 between the primary tumor and metastasis,and the expression of Ki67 or ERCC1 in metastasis could better guide the treatment in tumors,such as breast cancer,cervical cancer,colon cancer,non-small cell lung cancer.However,there are few reports about the expression of Ki67 and ERCC1 in metastatic NPC.In addition,the study above only evaluated the role of single indicator Ki67 or ERCC1 in the treatment of metastatic tumors.The role of combination of two indicators in metastatic tumor care remains unclear.Therefore,based on the results of previous studies,we further explore the expression of molecular markers Ki67 and ERCC1 in metastatic NPC and the effect of their combination on the first-line treatment of the disease,providing new diagnosis and ideas for clinical individualized treatment.Objective: The aim of this study is to analyze the expression level of Ki67 and ERCC1 in metastatic and primary NPC and the effect on the first-line treatment of metastatic NPC.Methods: The clinical data of metastatic NPC patients diagnosed and treated in hospital from May 2013 to May 2018 were collected.The expression of Ki67 and ERCC1 in the primary and metastasis lesions was detected by immunohistochemistry.Chi-square test was used to analyze the correlation between the expression of Ki67 and ERCC1 in the metastasis and primary lesions and Distant metastases-free survival(DMFS)after radical treatment in the initial stage.Chi-square test was used to analyze the correlation between single index expression of Ki67 and ERCC1 and progression-free survival(PFS)after first-line treatment for metastatic NPC.Kaplan-Meier survival curve to further explore the correlation between the combined expression of Ki67 and ERCC1 in metastasis NPC and PFS after first-line treatment.Results:1.64 patients were included in the analysis.The ratio of male to female was about 2.56:1,and the median age was 47 years(27-69 years).All patients had completed the standard treatment of radical radiotherapy and chemotherapy,and the median DMFS was 17.0 months(3.8-61.4 months).The first-line treatment of metastasis was platin-based chemotherapy.2.Ki67 was highly expressed in 54.7%(35/64)of patients.The proportion of patients with hyperexpression of metastasis was higher(17.2% vs 34.4%).The change rate of ERCC1 expression was 43.8%(28/64).There was no significant difference of the rate between high expression group and low expression group.The expression of Ki67 and ERCC1 in metastasis were significantly correlated with DMFS after radical treatment(P=0.020 for Ki67,P=0.029 for ERCC1).3.To May 2019,the median follow-up time was 13.8 months.The median PFS was 7.9 months(2.3-23.0 months).The expression levels of Ki67 and ERCC1 in metastasis were significantly correlated with the(PFS)of first-line treatment(P=0.00 for Ki67;P=0.00 for ERCC1).These results suggested that-high expression of Ki67 and ERCC1 have shorter progression free survival(PFS)in metastatic NPC after first-line treatment.4.Kaplan Meier survival curve analysis showed that the combination expression of Ki67 and ERCC1 was significantly correlated with PFS after first-line treatment of metastatic nasopharyngeal carcinoma(P<0.001),and there was no significant difference between the PFS of patients with hyperexpression of Ki67 and low expression of ERCC1 and those with both(hyperexpression)high expression of Ki67 and high expression of ERCC1(P=0.079).The combination of Ki67 hyperexpression group with low ERCC1 expression and Ki67 and ERCC1 with(hyperexpression)high expression was found that the first-line PFS of metastatic nasopharyngeal carcinoma with low Ki67 expression and low ERCC1 expression was significantly superior to that of other combinations.(P < 0.001).Multivariate analysis of Cox risk ratio model of clinical prognostic factors showed that the combined expression of Ki67 and ERCC1 better predicted the risk of PFS after first-line chemotherapy for metastatic NPC compared with clinical factors(P< 0.001).Compared with the patients with hyperexpression of Ki67 or high expression of Ki67 and ERCC1,the patients with low and medium expression of Ki67 and low expression of ERCC1(HR=0.040;95% CI: 0.012-0.129;P=0.00)had lower PFS.High expression of Ki67 with low expression of ERCC1 or low and medium expression of Ki67 with high expression of ERCC1(HR = 0.193;95% CI:0.80-0.463;P=0.00)indicated that the risk of poor PFS was lower.Conclusions:1.Compared with the primary lesions,the expression of Ki67 and ERCC1 in the metastatic lesions changed significantly,and the high expression of Ki67 was more obvious.The expression of Ki67 and ERCC1 in metastasis were significantly correlated with DMFS after radical treatment.2.The expression level of Ki67 and ERCC1 in metastatic was significantly correlated with PFS in metastatic NPC after first-line treatment.The PFS of patients with high expression of Ki67 or hyperexpression and high expression of ERCC1 was shorter.3.Combination analysis of the expression level of Ki67 and ERCC1 in metastatic lesions could more accurately predict the PFS after the first-line treatment.The PFS of patients with low and medium expression of Ki67 and low expression of ERCC1 was significantly longer than that of patients with both expressions.Hyperexpression of Ki67 or both high expression of Ki67 and ERCC1 are the adverse prognostic factors of PFS of metastatic NPC after the first-line chemotherapy.