Scher Howard I, Graf Ryon P, Schreiber Nicole A, McLaughlin Brigit, Lu David, Louw Jessica, Danila Daniel C, Dugan Lyndsey, Johnson Ann, Heller Glenn, Fleisher Martin, Dittamore Ryan
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Epic Sciences, La Jolla, CA, USA.
Eur Urol. 2017 Jun;71(6):874-882. doi: 10.1016/j.eururo.2016.11.024. Epub 2016 Dec 12.
Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide.
To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi.
DESIGN, SETTING, AND PARTICIPANTS: The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs.
Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses.
A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used.
To reliably inform treatment selection using an AR-V7 protein biomarker in CTCs, nuclear-specific localization is required.
We analyzed outcomes for patients with metastatic castration-resistant prostate cancer on androgen receptor signaling inhibitors and standard chemotherapy. Patients with circulating tumor cells that had AR-V7 protein in the cellular nuclei were very likely to survive longer on taxane-based chemotherapy, and tests unable to distinguish where the protein is located in the cell are not as predictive of benefit.
表达定位于细胞核的AR-V7蛋白（核特异性）的循环肿瘤细胞（CTC）可识别出在紫杉烷治疗中总生存期（OS）相对于雄激素受体信号抑制剂（ARSi）醋酸阿比特龙、恩杂鲁胺和阿帕鲁胺有所改善的转移性去势抵抗性前列腺癌（mCRPC）患者。
评估将阳性标准扩大到包括细胞核和细胞质AR-V7定位（“核非特异性”）是否能识别出更多从紫杉烷而非ARSi中获益的患者。
设计、背景和参与者：本研究采用横断面队列研究。2012年12月至2015年3月期间，在纪念斯隆凯特琳癌症中心，从161例独特的mCRPC患者中收集并处理了193份治疗前血样，其中191份可评估，这些患者因疾病进展开始新的一线全身治疗。探讨了两种AR-V7评分标准（治疗后前列腺特异性抗原（PSA）变化（PTPC））与ARSi或紫杉烷治疗后的OS之间的关联。一种标准要求核特异性AR-V7定位，另一种要求有AR-V7信号，但对CTC中的蛋白定位不做区分。
研究了AR-V7状态与PTPC和OS的相关性。使用多变量Cox回归和对数秩分析分析与生存的关系。
使用核特异性标准，共有34份（18%）样本为AR-V7阳性，使用核非特异性标准有56份（29%）为AR-V7阳性。在ARSi治疗后，16份核特异性AR-V7阳性样本中无一例，32份（19%）核非特异性AR-V7阳性样本中有6例在12周时PTPC≥50%。影响OS的最强基线因素是核特异性AR-V7阳性CTC的存在与紫杉烷治疗之间的相互作用（风险比0.24，95%置信区间0.078-0.79；p=0.019）。使用核非特异性标准时，这种相互作用不显著。
为了使用CTC中的AR-V7蛋白生物标志物可靠地指导治疗选择，需要核特异性定位。
我们分析了接受雄激素受体信号抑制剂和标准化疗的转移性去势抵抗性前列腺癌患者的结局。细胞核中有AR-V7蛋白的循环肿瘤细胞患者在基于紫杉烷的化疗中很可能存活更长时间，而无法区分蛋白在细胞中位置的检测对获益的预测性较差。
