雄激素受体剪接突变体7和雄激素受体表达量的比值在预测前列腺癌内分泌治疗预后中的作用

摘要

目的 分析雄激素受体(androgen receptor,AR)和雄激素受体剪接突变体7(androgen receptor splice variant-7,AR-V7)表达量的比值(AR-V7/AR)预测前列腺癌内分泌治疗预后的作用.方法 采用免疫组化染色法检测2010年1月至2015年12月我院行内分泌治疗的136例前列腺癌患者的活检穿刺标本,以HS评分评估其表达量.患者年龄53 ～96岁,中位年龄71岁.确诊时中位tPSA为110.00 ng/ml(2.61 ～4 003.40 ng/ml),中位fPSA为14.62 ng/ml(0.12～640.19 ng/ml),中位PSA密度为1.15 ng/(ml·cm3) [0.02～ 62.63 ng/(ml·cm3)].Gleason评分≥8分88例(64.7％),7分39例(28.7％),＜7分9例(6.6％);T3期57例(41.9％),T4期54例(39.7％),Tx期25例(18.4％);N0期46例(33.8％),N1期62例(45.6％),Nx期28例(20.6％);M0期30例(22.1％),M1期97例(71.3％),Mx期9例(6.6％).利用Cox模型分析患者各临床因素对前列腺癌内分泌治疗预后的影响,采用Kaplan-Meier法分析AR-V7/AR对前列腺癌内分泌治疗预后的预测作用.结果 本组136例中79例(58.1％)AR表达阳性,其中26例(19.1％) AR-V7表达阳性.Spearman相关性分析结果显示,AR与AR-V7的表达无相关性(r=0.042,P=0.629).本组136例中位随访时间为44个月(15 ～71个月).中位疾病无进展生存时间(PFS)为19个月(5～59个月);中位总生存时间(OS)为31个月(12 ～61个月).AR-V7阳性患者较阴性患者有较短的中位PFS(10.8个月与25.0个月,P＜0.001)和中位OS(20.3个月与42.8个月,P＜0.001);高AR-V7/AR值患者较低AR-V7/AR值患者有较短的中位PFS(12.0个月与24.8个月,P＜0.001)和中位OS(22.5个月与42.8个月,P＜0.001).在Cox单因素回归分析中,确诊时Gleason评分、前列腺癌T分期、tPSA、PSA密度、AR-V7/AR值可预测内分泌治疗的预后.在Cox多因素回归分析中,T4期(HR=2.597,95％ CI 1.351 ～4.995,P=0.004)和高AR-V7/AR值(HR=5.788,95％ CI2.530～13.242,P＜0.001)是前列腺癌内分泌治疗预后不良的独立危险因素.结论 高AR-V7/AR值是预测前列腺癌内分泌治疗预后不良的独立危险因素.AR-V7阳性、高AR-V7/AR值患者的中位PFS和OS均明显缩短.%Objective To evaluate the prognostic value of the ratio of AR and AR-V7 expression in prostate cancer treated by castration therapy.Methods Immunohistochemical staining was performed in biopsy specimen of 136 prostate cancer patients received hormone therapy in Tongji Hospital of Huazhong University of Science and Technology from January 2010 to December 2015.Expression was determined using modified H score method.Patients aged from 53-96,the median age was 71,median tPSA value at diagnosed was 110.00 ng/ml(2.61-4 003.4 ng/ml),median fPSA value was 14.62 ng/ml(0.12-640.19 ng/ml),median PSA density was 1.15 ng/(ml · cm3) [0.02-62.63 ng/(ml · cm3)].Among these,88 (64.7％)patients were diagnosed Gleason score≥8,39(28.7％) patients with Gleason score 7,while 7 (6.6％) patients Gleason score ＜7.There were 54(39.7％) patients diagnosed T4 stage,57(41.9％)patients T3 stage and 25 (18.4％) patients Tx stage;62 (45.6％) patients were diagnosed N 1 stage,46 (33.8％) N0 stage and 28(20.6％) patients Nx stage;97(71.3％) patients were diagnosed M1 stage,30(22.1％) M0 stage,9 (6.6％) patients Mx stage.Cause-specific Cox regression and Kaplan-Meier Analysis were used to analyze the prognosis risk.Results The median follow-up time was 44 months,ranged 15-71 months.During the surveillance,the disease progression-free survival time ranged from 5-59 month,median 19 months.The overall survival time ranged from 12-61 months,median 31 months.Among these,79(58.1％) patients were AR positive and 26(19.1％) patients were AR-V7 positive,while AR and AR-V7 expression had no significant correlation (Spearman-test r =0.042,P =0.629).The AR-V7 positive patients showed significantly lower CRPC progression free survival (10.8 months vs.25.0 months,P ＜ 0.001) and much lower overall survival (20.3 months vs.42.8 months,P ＜ 0.001).The high AR-V7/AR expression ratio group showed significantly lower CRPC progression free survival (12.0 months vs.24.8 months,P ＜ 0.001) and much lower overall survival (22.5 months vs.42.8 months,P ＜ 0.001).In univariate Cox regression analyses,Gleason score at diagnosis,T stage,tPSA,PSA density and high AR-V7/AR expression ratio could predict the prognosis of hormonal therapy.While in multivariate Cox regression analyses,T stage(HR =2.597,95％ CI 1.351-4.995,P =0.004) and high AR-V7/AR expression ratio(HR =5.788,95％ CI 2.530-13.242,P ＜ 0.001) could effectively and independently predict the prognosis of hormonal therapy.Conclusion High AR-V7/AR HS ratio is the independent predictor of the prognosis of prostate cancer hormone therapy.AR-V7 positive and high AR-V7/AR HS ratio patients may have shorter PFS and overall survival time than AR-V7 negative and low AR-V7/AR HS ratio patients.