Rationale: Lu-177-PSMA-617 radioligand therapy (RLT) is currently under approval for treatment of metastatic castration resistant prostate cancer (mCRPC) patients with late stage disease. However, previous studies demonstrated both heterogeneity of prostate specific membrane antigen (PSMA) expression, as well as response to PSMA treatment among mCRPC patients. Thus, there is an unmet need for identifying predictive parametres prior or under PSMA-RLT treatment. We therefore aimed to correlate several clinical and molecular parameters with response to PSMA treatment in a cohort of mCRPC patients undergoing PSMA RLT followed by a detailed analysis of promising candidates./nMethods: Nineteen patients, median age 68.8 years (range: 56.9 - 83.3) with mCRPC were included in this study. We performed baseline analysis of clinical parameters based on PSMA PET/CT, (metabolic tumor volume (MTV), total tumor volume (TTV)), serum PSA, ALP, LDH and gene expression analysis of circulating tumor cells (expression of AR full length (AR-FL), AR splice variant 7 (AR-V7), PSA and PSMA) as well as common markers for neuroendocrine differentiation (NED)./nResults: Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment. Furthermore, none of these parameters was significantly correlated with baseline serum PSA values. Common NED markers were shown to be specifically high expressed and revealed impact on OS independent from AR-V7 gene expression./nConclusion: We demonstrate that AR-FL and its splice variant AR-V7 might serve as prognostic biomarkers displaying high tumor burden in mCRPC patient prior to PSMA-RLT. Contrary, PSMA, which has been discussed as a biomarker for PSMA targeted treatment, does not display strong prognostic ability - at least on the mRNA level. Surprisingly, none of these parameters correlates to response to PSMA treatment. In contrast, commom NED markers such as SYP and ENO2 as well as FOXA1 expression level seem to predict OS, but not PFS, more reliably. We admit that a limitation of our study is the focus on mRNA expression of potential biomarkers only. Further investigations analyzing the potential role of protein expression of these markers are therefore warranted.

中文翻译：

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接受177Lu-PSMA-617放射配体治疗的转移去势抵抗性前列腺癌患者循环肿瘤细胞的分子分析。

理由： Lu-177-PSMA-617放射配体疗法（RLT）目前正在批准用于治疗晚期疾病的转移性去势抵抗性前列腺癌（mCRPC）患者。但是，先前的研究表明mCRPC患者中前列腺特异性膜抗原（PSMA）表达的异质性以及对PSMA治疗的反应。因此，在PSMA-RLT治疗之前或之下识别鉴定预测参数的需求未得到满足。因此，我们的目的相关联的几个临床和分子参数与对PSMA治疗mCRPC患者进行PSMA RLT其次看好candidates./n的详细分析的队列方法：本研究纳入了19名中位年龄为68.8岁（范围：56.9-83.3）的mCRPC患者。我们基于PSMA PET / CT（代谢肿瘤体积（MTV），总肿瘤体积（TTV）），血清PSA，ALP，LDH和循环肿瘤细胞的基因表达分析（AR全长表达）进行了临床参数的基线分析（AR-FL），AR剪接变体7（AR-V7），PSA和PSMA）以及神经内分泌分化（NED）./ N条共通标记结果：患者出现骨，淋巴结转移和内脏转移（分别为89％，68％和21％）。所有患者均接受多西他赛，阿比特龙或恩杂鲁胺或两者联合治疗。PSA下降≥50或≥30％的生化反应分别为42％和63％。PSA和PSMA mRNA表达以及肿瘤体积（MTV和TTV），AR-FL和AR-V7 mRNA表达之间存在显着相关性。但是，与对PSMA治疗的反应没有相关性。此外，这些参数均未与基线血清PSA值显着相关。常见的NED标记显示出特别高的表达，并揭示了对OS的影响，而与AR-V7基因表达无关。/n结论：我们证明AR-FL及其剪接变体AR-V7可以作为预后生物标志物，在PSMA-RLT之前在mCRPC患者中显示高肿瘤负荷。相反，已被讨论为PSMA靶向治疗的生物标志物的PSMA没有显示出强大的预后能力-至少在mRNA水平上。令人惊讶的是，这些参数均不与对PSMA治疗的反应相关。相反，常用的NED标记（例如SYP和ENO2以及FOXA1表达水平）似乎可以更可靠地预测OS，但不能预测PFS。我们承认，我们研究的局限性在于仅关注潜在生物标志物的mRNA表达。因此，需要进行进一步的研究来分析这些标志物蛋白表达的潜在作用。