Scher Howard I, Lu David, Schreiber Nicole A, Louw Jessica, Graf Ryon P, Vargas Hebert A, Johnson Ann, Jendrisak Adam, Bambury Richard, Danila Daniel, McLaughlin Brigit, Wahl Justin, Greene Stephanie B, Heller Glenn, Marrinucci Dena, Fleisher Martin, Dittamore Ryan
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York2Department of Medicine, Weill Cornell Medical College, New York, New York.
Epic Sciences, La Jolla, California.
JAMA Oncol. 2016 Nov 1;2(11):1441-1449. doi: 10.1001/jamaoncol.2016.1828.
A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane.
To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes.
DESIGN, SETTING, AND PARTICIPANTS: For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years.
Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS).
Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7-positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7-positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7-positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7-positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7-positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative to ARS inhibitors when AR-V7-positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035).
The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.
转移性去势抵抗性前列腺癌（mCRPC）治疗中的一个关键决策是何时给予雄激素受体信号传导（ARS）抑制剂或紫杉烷类药物。
确定治疗前循环肿瘤细胞（CTC）上的核雄激素受体剪接变体7（AR-V7）蛋白表达和定位是否是ARS抑制剂和紫杉烷类药物治疗反应及预后的治疗特异性标志物。
设计、设置和参与者：在纪念斯隆凯特琳癌症中心进行的这项横断面队列研究中，纳入了265例接受治疗方案改变的进展性mCRPC男性患者；86例因未开始ARS或紫杉烷类治疗而被排除；18例因处理时间限制被排除，最终161例患者纳入分析。2012年12月至2015年3月，在新的全身治疗方案开始前，对进展性mCRPC患者采集血液并进行处理。对患者进行了长达3年的随访。
前列腺特异性抗原（PSA）反应、接受治疗的时间、影像学无进展生存期（rPFS）和总生存期（OS）。
总体而言，在161例mCRPC男性患者前瞻性采集的193份血样中，191份可评估（128份在ARS抑制剂治疗前，63份在紫杉烷类治疗前）。在34份样本（18%）中发现了AR-V7阳性CTC，包括一线样本的3%、二线样本的18%以及三线或更高线样本的31%。在ARS抑制前样本中有AR-V7阳性CTC的患者，其治疗后PSA变化（PTPC）耐药、rPFS较短、治疗时间较短且OS较短，而没有AR-V7阳性CTC的患者则不然。总体而言，在112份样本中，65份（58%）在ARS抑制前未检测到AR-V7阳性CTC的患者出现了耐药PTPC。对于接受紫杉烷类治疗的患者，治疗前有或没有AR-V7阳性CTC的患者在OS上有统计学显著差异，但在PTPC、治疗时间或rPFS上无差异。一个调整了与生存相关的基线因素的多变量模型显示，当治疗前检测到AR-V7阳性CTC时，相对于ARS抑制剂，紫杉烷类药物的OS更优（风险比，0.24；95%CI，0.10 - 0.57；P = 0.035）。
结果证实mCRPC男性患者CTC中AR-V7蛋白的核表达是一种治疗特异性生物标志物，在临床实践中，与紫杉烷类治疗相比，其与ARS导向治疗相比具有更好的生存率。在前瞻性研究中继续对该生物标志物进行研究将进一步有助于临床应用。
