p16基因甲基化状态对吉西他滨联合顺铂治疗中晚期肺鳞癌疗效的影响

Effect of the methylation status of the p16 gene on efficacy of gemcitabine combined with cisplatin for patients with middle-stage and advanced lung squamous cell carcinoma

目的探讨p16基因甲基化状态对吉西他滨联合顺铂治疗中晚期肺鳞癌患者疗效的影响。方法本研究为前瞻性队列研究,采用非随机抽样的方法选取2017年3月至2022年6月岳池县人民医院收治的129例中晚期肺鳞癌患者为研究对象。根据患者p16基因甲基化状态分为甲基化组(44例)和未甲基化组(85例)。所有患者均接受4个疗程吉西他滨联合顺铂化疗,疗程结束后评估化疗疗效。收集患者的临床资料包括年龄、性别、吸烟情况、肿瘤分期、组织学分类、Karnofsky功能状态(KPS)评分、原发肿瘤大小、淋巴结转移、远处转移、合并疾病个数、美国东部肿瘤协作组(ECOG)评分和p16基因甲基化状态。分别于化疗前和第2次化疗后检测2组患者的血清肿瘤标志物水平,包括血管内皮生长因子(VEGF)、细胞角质蛋白19片段抗原21-1(CYFRA21-1)、癌胚抗原(CEA)、糖类抗原125(CA125)和糖类抗原50(CA50)。通过门诊复查、电话等方式对患者进行随访,随访时间截至2023年2月,记录患者的总生存期。多因素logistic回归分析影响吉西他滨联合顺铂化疗治疗中晚期肺鳞癌患者疗效的因素。通过Kaplan-Meier法绘制生存曲线,并采用Log-rank检验比较不同p16基因甲基化状态中晚期肺鳞癌患者的生存曲线。结果2组患者性别、年龄、临床分期、组织学分类、原发肿瘤大小比较差异均无统计学意义(均P>0.05)。未甲基化组淋巴结转移为N0、远处转移为M0比例均高于甲基化组[62.35%(53/85)比27.27%(12/44),70.59%(60/85)比40.91%(18/44),均P<0.05]。未甲基化组化疗前和第2次化疗后KPS评分均高于甲基化组[(71.74±3.36)分比(70.12±4.17)分,(75.93±5.28)分比(72.77±5.52)分,均P<0.05],且甲基化组和未甲基化组第2次化疗后KPS评分均高于化疗前(均P<0.05)。甲基化组患者化疗前和第2次化疗后VEGF、CYFRA21-1、CEA、CA125、CA50水平均高于未甲基化组,且甲基化组和未甲基化组第2次化疗后VEGF、CYFRA21-1、CEA、CA125、CA50水平均低于化疗前(均P<0.05)。未甲基化组化疗疗效较甲基化组好(Z=23.96,P<0.001),未甲基化组客观缓解率、疾病控制率均高于甲基化组[42.35%(36/85)比9.09%(4/44),80.00%(68/85)比40.91%(18/44),均P<0.001]。单因素分析结果显示,年龄≥70岁患者未缓解率高于年龄<70岁患者[76.62%(59/77)比57.69%(30/52)],合并疾病个数>3个患者未缓解率高于合并疾病个数≤3个患者[79.75%(63/79)比52.00%(26/50)],ECOG评分>1分患者未缓解率高于ECOG评分≤1分患者[85.92%(61/71)比48.28%(28/58)],p16基因甲基化患者未缓解率高于未甲基化患者[93.18%(41/44)比56.47%(48/85)],淋巴结转移为N1患者未缓解率高于N0患者[87.50%(56/64)比50.77%(33/65)],远处转移为M1患者未缓解率高于M0患者[80.39%(41/51)比61.54%(48/78)]。多因素logistic回归分析结果显示,年龄≥70岁、合并疾病个数>3个、ECOG评分>1分、p16基因甲基化、有淋巴结转移、有远处转移是影响中晚期肺鳞癌患者接受吉西他滨联合顺铂化疗疗效的独立危险因素。Log-rank检验结果显示未甲基化组患者的生存状态优于甲基化组患者(χ^(2)=5.33,P=0.001)。结论p16基因甲基化是影响吉西他滨联合顺铂治疗中晚期肺鳞癌患者疗效的独立危险因素。

ObjectiveTo investigate the effect of the methylation status of the p16 gene on efficacy of gemcitabine combined with cisplatin for patients with middle-stage and advanced lung squamous cell carcinoma(LSCC).MethodsIt was a prospective cohort study.One hundred and twenty-nine patients with middle-stage and advanced LSCC treated in the People′s Hospital of Yuechi County from March 2017 to June 2022 were enrolled by non-random sampling method.According to the methylation status of the p16 gene,patients were divided into methylation group(n=44)and non-methylation group(n=85).All patients received 4 chemotherapy courses of gemcitabine plus cisplatin,followed by the evaluation of the efficacy.Clinical data were collected,including age,sex,smoking status,tumor stage,histological classification,the Karnofsky performance status(KPS)score,primary tumor size,lymph node metastasis,distant metastasis,number of associated diseases,Eastern Cooperative Oncology Group(ECOG)performance status score,and methylation status of the p16 gene.Serum tumor markers,including vascular endothelial growth factor(VEGF),cyto-keratin 19 fragment antigen 21-1(CYFRA21-1),carcinoembryonic antigen(CEA),carbohydrate antigen 125(CA125)and carbohydrate antigen 50(CA50)were measured before chemotherapy and after the second course of chemotherapy.They were followed up by outpatient reexamination and telephone up to February 2023,and the overall survival was recorded.Multivariate logistic regression analysis was performed to identify risk factors for the chemotherapy efficacy of gemcitabine combined with cisplatin in patients with middle-stage and advanced LSCC.The survival curve was drawn by the Kaplan-Meier method,followed by comparing the survival curves in patients with middle-stage and advanced LSCC with different methylation statuses of the p16 gene by Log-rank test.ResultsThere were no significant differences in sex,age,clinical stage,histological classification and primary tumor size between the two groups(all P>0.05).The rates of patients with N0 of lymph node metastasis(62.35%[53/85]vs 27.27%[12/44])and M0 of distant metastasis(70.59%[60/85]vs 40.91%[18/44])were significantly higher in the non-methylation group than those of methylation group(both P<0.05).The KPS scores before chemotherapy([71.74±3.36]points vs[70.12±4.17]points)and after the second course of chemotherapy([75.93±5.28]points vs[72.77±5.52]points)were significantly higher in the non-methylation group than those of methylation group(both P<0.05),and the KPS scores after the second course of chemotherapy were significantly higher than those before chemotherapy in both groups(both P<0.05).The levels of VEGF,CYFRA21-1,CEA,CA125 and CA50 before chemotherapy and after the second course of chemotherapy were significantly higher in the methylation group than those of non-methylation group(all P<0.05),which,after the second course of chemotherapy were significantly lower than those before chemotherapy in both groups(all P<0.05).The chemotherapy efficacy was significantly better in the non-methylation group than that of the methylation group(Z=23.96,P<0.001).The objective remission rate(42.35%[36/85]vs 9.09%[4/44])and disease control rate(80.00%[68/85]vs 40.91%[18/44])in the non-methylation group were significantly higher than those of the methylation group(both P<0.001).Univariate analysis showed that the non-remission rates were significantly higher in patients aged≥70 years(76.62%[59/77]vs 57.69%[30/52]),with more than 3 diseases(79.75%[63/79]vs 52.00%[26/50]),ECOG score>1 point(85.92%[61/71]vs 48.28%[28/58]),p16 gene methylation(93.18%[41/44]vs 56.47%[48/85]),N1 of lymph node metastasis(87.50%[56/64]vs 50.77%[33/65])and M1 of distant metastases(80.39%[41/51]vs 61.54%[48/78])than those of counterparts.Multivariate logistic regression analysis showed that age≥70 years,concomitant diseases>3,ECOG score>1 point,p16 gene methylation,lymph node metastasis and distant metastasis were independent risk factors affecting the chemotherapy efficacy of gemcitabine and cisplatin for patients with middle-stage and advanced LSCC.Log-rank test showed that the survival was better in the non-methylation group than that of the methylation group(χ^(2)=5.33,P=0.001).ConclusionsThe p16 gene methylation is an independent risk factor affecting the efficacy of gemcitabine combined with cisplatin for patients with middle-stage and advanced LSCC.