前列腺癌组织中雄激素受体剪接变异体7表达对转移性前列腺癌患者激素敏感时间的预测作用

Predictive effect of androgen receptor splice variant 7 expression on time to castration resistance in patients with metastatic prostate cancer

目的 探讨前列腺癌组织中雄激素受体剪接变异体7（AR-V7）的表达对转移性前列腺癌患者激素敏感时间的预测作用.方法 回顾性收集2002年1月至2010年6月经前列腺穿刺活检确诊的113例晚期转移性前列腺癌患者的临床病理资料.确诊时年龄43 ～ 84岁,中位年龄70岁.确诊时血清PSA值3.0～6 006.2 μg/L,中位值120.0 μg/L.临床分期M1a期5例（4.4％）,M1b期94例（83.2％）,M1.期14例（12.4％）.患者均接受内分泌治疗.利用免疫组化技术和鼠抗人AR-V7特异性抗体检测前列腺癌组织中AR-V7的表达.利用Cox比例风险模型分析患者确诊年龄、确诊PSA值、确诊Gleason评分、临床分期、内分泌治疗过程中PSA最低值、到达PSA最低值时间以及PSA半衰期对激素敏感时间的预测作用.采用Kaplan-Meier法分析AR-V7的表达对激素敏感时间的影响,并用Log-rank法对结果进行显著性检验.结果 本组患者内分泌治疗过程中PSA最低值为0.0～143.0tμg/L,中位值0.7μg/L.到达PSA最低值的时间为0.9～71.0个月,中位时间8.1个月.PSA半衰期为0.1～41.0个月,中位值1.0个月.经过中位27（2～132）个月的随访后,100例患者进展至去势抵抗性前列腺癌,中位激素敏感时间为24（2～ 132）个月.113例前列腺癌组织中,23例（20.4％）阳性表达AR-V7.Cox多因素分析结果显示,前列腺癌组织中AR-V7的表达（P=0.004,HR=2.223）和内分泌治疗过程中PSA最低值（P=0.035,HR=1.011）是晚期转移性前列腺癌患者激素敏感时间的独立预测因素.前列腺癌组织中表达AR-V7和不表达AR-V7组患者的中位激素敏感时间分别为（16.0±3.4）和（30.0±6.0）个月,差异有统计学意义（P=0.001）.结论 前列腺癌组织中AR-V7的表达和内分泌治疗过程中PSA最低值为晚期转移性前列腺癌患者激素敏感时间的独立预测因素.AR-V7可能为晚期前列腺癌的治疗新靶点.

Objective To investigate the predictive effect of androgen receptor splice variant 7 （AR-V7） expression on time to castration resistance in patients with metastatic prostate cancer.Methods The data of 113 cases of advanced metastatic prostate cancer diagnosed by prostate biopsy in our institute from Jan.2002 to Jun.2010 were collected retrospectively.The median age at diagnosis was 70 years,ranged from 43 to 84 years.The median tPSA was 120.0 μg/L,ranged from 3.0 to 6 006.2 μg/L.There were 5 patients in M1a（4.4％）,94 patients in M1b（83.2％） and 14 patients in M1c（12.4％）.All patients received hormonal therapy.1mmunohistochemical staining and AR-V7 specific antibody were used to detect the expression of AR-V7 in prostate cancer tissues.Cox regression models were used to analyze the predictive role of patient characteristics including patient＇s age at diagnosis,tPSA level at diagnosis,Gleason score,clinical stage,PSA nadir during hormonal therapy,the time to PSA nadir and PSA half-life.The effect of AR-V7 expression on time to castration resistance was analyzed using Kaplan-Meier curves,and the differences were assessed using the log-rank test.Results The PSA nadir ranged from 0.0 to 143.0 μg/L and the median value was 0.7 μg/L.The time to PSA nadir ranged from 0.9 to 71.0 months and the median value was 8.1 months.The median PSA half life was 1.0 month,which ranged from 0.1 to 41.0 months.Followed up for a median time of 27 months,100 patients progressed to castration-resistant prostate cancer （CRPC） and the median time to castration resistance was 24 months.The expression of AR-V7 was positive in 23 out of 113 patients.Multivariate analysis showed that the expression of AR-V7 in prostate cancer （P=0.004,HR =2.223） and PSA nadir during hormonal therapy （P =0.035,HR =1.011） were independent predictive factors of time to castration resistance.The median time to castration resistance for patients with and without AR-V7 expression were （16.04±3.4） months and （30.04-6.0） months,respectively （P=0.001）.Conclusions The expression of AR-V7 in prostate cancer and PSA nadir during hormonal therapy are independent predictive factors of time to castration resistance.The AR-V7 could be a potential therapeutic target for advanced prostate cancer.