超过半个世纪以来，雄激素剥夺治疗（ADT）一直是初诊转移性前列腺癌（M1期PCa）的一线治疗方案。临床上，大多数此类患者对ADT治疗有效，然而也有一部分患者对ADT治疗并不敏感。在临床上进行ADT治疗之前，如何预测初诊的M1期PCa患者是否对ADT敏感非常重要。

　　在第31届欧洲泌尿外科学会年会（EAU16）上，来自瑞典哥德堡大学的研究者对29例初诊的M1期PCa患者在ADT治疗之前富集循环肿瘤细胞（CTC），并且检测了CTC上AR-V7， AKR1C3 和CYP17A1的表达情况。在这29例前列腺癌患者中，均在ADT治疗前检出CTC。其中，5例患者CTC表达AR-V7， 17例患者CTC表达AKR1C3，1例患者CTC表达CYP17A1。进一步分析表明，只有AR-V7是肿瘤特异性存活的预后指标。这5例AR-V7阳性的患者的中位生存期只有7.5月；而AR-V7未检出的患者中位生存期是32月。该研究结果表明，在初诊的M1期PCa患者的CTC上进行AR-V7表达检测，能够筛选出对ADT不敏感的人群。该研究也获得了本届年会的最佳壁报奖(Best Posters).

　　本研究具有以下几方面的临床意义

　　① 既往，多西他赛化疗都是在前列腺癌进展到去势抵抗阶段（CRPC）才被指南推荐。2015年，Chartted及Stampede的研究结果都表明，对初诊的M1期PCa患者在ADT治疗时同步给予多西他赛化疗，能明显延长总体生存期。Chartted的研究还发现，多西他赛化疗对高负荷的M1期PCa患者获益更明显，而对于低负荷的患者尚未得出显著性差异的结论。然而，目前还很难区分Chartted以及Stampede研究中针对某一个具体的患者，化疗的贡献到底有多大。在治疗要求越来越精准的今天，针对某一个具体的患者需要采取个体化精准化的治疗方案时，ADT治疗是否敏感就显得很重要。对ADT不敏感的患者，可能需要尽早选择化疗。

　　② 一些回顾性的研究表明，对于寡转移前列腺癌（转移灶<5个）的原发灶进行局部治疗（包括前列腺癌根治术或者放疗），能改善预后，延长总体生存期。如果这类患者CTC表达AR-V7，那么转移灶可能对ADT也是不敏感的，可能还需要辅助化疗以主要针对这些转移灶。

　　③ 几乎所有的前列腺癌患者在接受ADT治疗后，都会进入CRPC阶段。研究表明，如果在CRPC患者CTC检出AR-V7表达，这部分患者则会对阿比特龙和恩杂鲁胺耐药，然后，多西他赛和卡巴他赛化疗仍然有效。目前，阿比特龙已经在中国上市，且价格不菲。对CRPC患者，检测CTC上AR-V7的表达情况，能指导后续治疗方案的选择，避免不必要的医疗支出。

　　最后，需要说明的，目前对CTC进行富集并进行AR-V7检测的研究都来自国外的少数几个中心。就目前笔者的了解，国内尚无可靠的技术与平台进行这样的检测，这也是国内生物技术公司今后一个极具潜力的领域。可以预见的是，在初诊的M1期PCa患者中，进行CTC富集并检测AR-V7以筛选出合适的患者进行合适的治疗将是今后前列腺癌精准治疗的一个重要方向。

杨斌  博士

　　医学博士，上海市第十人民医院泌尿外科主治医师，擅长前列腺癌，膀胱癌和肾癌的早期诊断与微创根治术。从事泌尿系统肿瘤的转化研究，主持多项科研基金，其中包括国家自然科学基金2项，入选上海市浦江人才培养计划，医院攀登人才培养计划等。在国内外一流学术刊物上以第一作者和通讯作者发表科学论文20余篇，其中SCI收录论文12篇。

研究摘要

1065  Detection of AR-V7 in circulating tumour cells before ADT is a negative prognostic marker in castration-na?ve men with metastatic prostate cancer

Introduction & Objectives：For metastatic prostate cancer Androgen Deprivation Therapy (ADT) has been the first line of therapy since more than half a century. Inherent properties to sustained androgen signaling may include expression of AR-V7 (constitutively active androgen receptor)， AKR1C3 and CYP17A1 (steroidogenic enzymes)， and could mediate primary resistance to ADT. Circulating Tumor Cells (CTC) are a promising prognostic marker for metastatic castration-resistant prostate cancer and the detection of AR-V7 in CTC has been shown to predict the response to enzalutamide and abiraterone acetate. This study examined if the expression of AR-V7， AKR1C3 and CYP17A1 could be detected in CTC before initiation of ADT and if these suggested resistance mechanisms could predict cancer-specific survival.

Material & Methods：29 Castration-na?ve men with metastatic prostate cancer were included before initiation of ADT. CTC were isolated with AdnaGen ProstateCancer Select/Detect? (AdnaTest). Detection of mRNA for AR-V7， AKR1C3 and CYP17A1 were performed with qRT-PCR after multiplex pre-amplification. The prognostic potential of pre-treatment variables was evaluated for cancer-specific survival with Kaplan-Meier， uni- and multivariate Cox regression analysis.

Results：All patients had bone metastases， 46% had N1 disease， 79% had cT3-cT4 tumours and 83% had Gleason score >7. Median age was 78 years (46-95)， and median PSA-value was 580ng/ml (8.3-4000). Median follow-up time for those still alive is 24.6 (10-44) and of all 17 months (0.5 to 44 months). 12 men died of prostate cancer， 2 died of other causes and 15 are alive at last follow-up.?Neither PSA value， Gleason score， N-stage nor T-stage could prognosticate cancer-specific survival in uni-variate analysis. All men were CTC-positive with AdnaTest before ADT. Analysis of the isolated mRNA from CTC showed that AR-V7， AKR1C3 and CYP17A1 could be detected in 5 (17%)， 17 (59%) and 1 (3%) patients， respectively， before ADT. Only AR-V7 was a prognostic marker for cancer-specific survival. Median survival time was 7.5 months for patients with detected AR-V7 (5/29 (17%)) before ADT， compared to 32 months in the other patients (Log-rank chi square=8.9 and p-value <0.005). The hazard ratio for cancer-specific surival in patients with AR-V7 detection was 6.5 (95% CI 1.6-26.4， p-value<0.01) compared to patients without AR-V7 detection.

Conclusions：This is to our knowledge the first time AR-V7， AKR1C3 and CYP17A1 have been detected in CTC from patients without prior hormonal manipulation. Our results suggest that the detection of AR-V7 in CTC before ADT could identify patients with primary resistance to ADT with a median time of cancer-specific survival of only 7.5 months.