Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Eur Urol. 2011 Nov;60(5):897-904. doi: 10.1016/j.eururo.2011.07.011. Epub 2011 Jul 14.
Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors.
To study the role of transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA.
DESIGN, SETTING, AND PARTICIPANTS: The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials.
Patients received AA 1000 mg daily and continuously.
TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria.
Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7-103 cells per 7.5 ml). A PSA decline ≥50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes.
Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer-specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.
ClinicalTrials.gov: NCT00474383 (COU-AA-003), NCT00485303 (COU-AA-004).
醋酸阿比特龙（AA）是一种雄激素生物合成抑制剂，已被证明可延长已接受化疗的去势抵抗性前列腺癌（CRPC）患者的寿命。AA 治疗可使一些患者的前列腺特异性抗原（PSA）显著下降，而另一些患者则没有下降，这表明肿瘤存在对敏感性有影响的分子决定因素。
研究跨膜蛋白酶，丝氨酸 2（TMPRSS2）-v-ets 红细胞生成病毒 E26 癌基因同源物（ERG）融合，一种雄激素依赖性生长因子，作为 AA 敏感性的生物标志物在循环肿瘤细胞（CTC）中的作用。
设计、地点和参与者：对 48 名接受化疗治疗的 CRPC 男性中的 41 名患者进行了 TMPRSS2-ERG 状态的预测价值研究，这些患者按顺序进入了两项 AA 试验。
患者每天接受 1000 毫克 AA 并持续接受治疗。
在 AA 治疗前从乙二胺四乙酸抗凝的血液中富集 CTC 后，通过敏感的、分析有效的逆转录聚合酶链反应测定法来描述 TMPRSS2-ERG 状态。根据 PSA 工作组 1 标准测量结果。
使用经过验证的 TMPRSS2-ERG 检测方法在多重平台上进行的标本采集、处理和检测的标准程序得出的内试验和间试验变异系数<7%。15 名患者中有 15 名（37%）存在 TMPRSS2-ERG 融合，他们的基线 CTC 计数中位数为 17（四分位距：每 7.5ml 中有 7-103 个细胞）。融合组中有 7 名患者（47%）和 26 名患者中的 10 名（38%）PSA 下降≥50%。尽管患者人数有限，但相对于 CTC 计数为 5 或更多，治疗后 CTC 计数小于每 7.5ml 5 个与生存时间更长相关。TMPRSS2-ERG 状态不能预测 PSA 下降或其他临床结果。
用分析有效的检测方法对 CTC 的分子谱进行分析，可以确定前列腺癌特异性 TMPRSS2-ERG 融合的存在，但不能预测对 AA 治疗的反应。这一发现证明了 CTC 作为可以在常规实践环境中获得的替代组织的作用。
ClinicalTrials.gov：NCT00474383（COU-AA-003），NCT00485303（COU-AA-004）。
