Epic Sciences, San Diego, California.
Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
Clin Cancer Res. 2023 May 15;29(10):1929-1937. doi: 10.1158/1078-0432.CCR-22-3233.
In men with metastatic castration-resistant prostate cancer (mCRPC), prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy.
We conducted a retrospective analysis of the prospective multicenter PROPHECY (Prospective CiRculating PrOstate Cancer Predictors in HighEr Risk mCRPC StudY) trial of men with mCRPC (n = 118) treated with abiraterone (abi) or enzalutamide (enza). Circulating tumor cells (CTC) were enriched (CTC/mL) and characterized for PSMA protein expression/heterogeneity at baseline and progression. We utilized proportional hazards modeling of the association between PSMA-positive (PSMA+) CTC enumeration with overall survival (OS) and progression-free survival (PFS).
Overall, 97 men with mCRPC had evaluable blood samples for baseline CTC PSMA detection; 78 men (80%) had detectable CTCs. Of these, 55% (43/78) of men had any PSMA CTC detection, 21% (16/78) had ≥2 PSMA+ CTCs/mL, and 19% (8/43) were 100% PSMA+. At progression on abi/enza, 88% (50/57) of men had detectable CTCs, 68% (34/50) had any PSMA CTCs, and 12% (4/34) had 100% PSMA+ CTCs. Among paired cases (n = 57), PSMA+ CTC detection increased slightly after abi/enza progression. Using an optimal cutoff of ≥2 PSMA+ CTCs/mL, median OS was 26, 21, and 11 months for men without CTCs, PSMA- CTCs, and PSMA+ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk score, and CTC enumeration, the HRs for OS and PFS for PSMA+ CTC+ were 3.0 [95% confidence interval (CI) = 1.1-7.8] and 2.3 (95% CI = 0.9-5.8).
We observed PSMA CTC heterogeneity between and within patients with mCRPC over time during abi/enza progression. CTC PSMA enumeration was adversely prognostic independent of clinical factors and disease burden. Further validation is warranted in the context of PSMA-targeted therapies.
在转移性去势抵抗性前列腺癌（mCRPC）患者中，前列腺特异性膜抗原（PSMA）靶向放射性配体疗法极大地改善了临床结局。对 PSMA 表达进行液体活检可能有助于指导最佳治疗。
我们对前瞻性多中心 PROPHECY（高风险 mCRPC 研究中前瞻性 CiRculating PrOstate 癌症预测因子）试验中 118 例 mCRPC 患者（n=118）进行了回顾性分析，这些患者接受了阿比特龙（abi）或恩扎鲁胺（enza）治疗。在基线和进展时，通过富集（CTC/mL）和特征分析循环肿瘤细胞（CTC）来检测 PSMA 蛋白表达/异质性。我们利用比例风险模型，将 PSMA+CTC 计数与总生存（OS）和无进展生存（PFS）之间的关联进行了分析。
总体而言，97 例 mCRPC 患者有可评估的基线 CTC PSMA 检测血样；78 例患者（80%）可检测到 CTC。其中，55%（43/78）的患者有任何 PSMA CTC 检测，21%（16/78）的患者有≥2 PSMA+CTC/mL，19%（8/43）的患者有 100% PSMA+。在 abiraterone/enzalutamide 进展时，57 例患者中有 88%（50/57）的患者可检测到 CTC，68%（34/50）的患者有任何 PSMA CTC，12%（4/34）的患者有 100% PSMA+CTC。在配对病例（n=57）中，在 abiraterone/enzalutamide 进展后，PSMA+CTC 的检测略有增加。使用≥2 PSMA+CTC/mL 的最佳截断值，无 CTC、PSMA-CTC 和 PSMA+CTC 的患者中位 OS 分别为 26、21 和 11 个月。调整abi/enza 治疗前、Halabi 临床风险评分和 CTC 计数后，PSMA+CTC+的 OS 和 PFS 的 HR 分别为 3.0（95%CI=1.1-7.8）和 2.3（95%CI=0.9-5.8）。
我们观察到在 abiraterone/enzalutamide 进展过程中，mCRPC 患者的 PSMA CTC 存在时间和患者内异质性。CTC PSMA 计数与临床因素和疾病负担无关，具有不良预后。在 PSMA 靶向治疗的背景下，需要进一步验证。
