Departments of Urology; Immunology.
Departments of Urology.
Int J Radiat Oncol Biol Phys. 2022 Nov 15;114(4):725-737. doi: 10.1016/j.ijrobp.2022.05.037. Epub 2022 Jun 4.
SABR has demonstrated clinical benefit in oligometastatic prostate cancer. However, the risk of developing new distant metastatic lesions remains high, and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which patients will benefit from SABR alone versus combination SABR and systemic agents. Herein we provide, to our knowledge, the first proof-of-concept of circulating prostate cancer-specific extracellular vesicles (PCEVs) as a noninvasive predictor of outcomes in oligometastatic castration-resistant prostate cancer (omCRPC) treated with SABR.
We analyzed the levels and kinetics of PCEVs in the peripheral blood of 79 patients with omCRPC at baseline and days 1, 7, and 14 after SABR using nanoscale flow cytometry and compared with baseline values from cohorts with localized and widely metastatic prostate cancer. The association of omCRPC PCEV levels with oncological outcomes was determined with Cox regression models.
Levels of PCEVs were highest in mCRPC followed by omCRPC and were lowest in localized prostate cancer. High PCEV levels at baseline predicted a shorter median time to distant recurrence (3.5 vs 6.6 months; P = .0087). After SABR, PCEV levels peaked on day 7, and median overall survival was significantly longer in patients with elevated PCEV levels (32.7 vs 27.6 months; P = .003). This suggests that pretreatment PCEV levels reflect tumor burden, whereas early changes in PCEV levels after treatment predict response to SABR. In contrast, radiomic features of C-choline positron emission tomography and computed tomography before and after SABR were not predictive of clinical outcomes. Interestingly, PCEV levels and peripheral tumor-reactive CD8 T cells (T; CD8 CD11a) were correlated.
This original study demonstrates that circulating PCEVs can serve as prognostic and predictive markers to SABR to identify patients with "true" omCRPC. In addition, it provides novel insights into the global crosstalk, mediated by PCEVs, between tumors and immune cells that leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies to investigate the underpinnings of metastatic progression and provide new therapeutic targets (eg, PCEVs) to improve SABR efficacy and clinical outcomes in treatment-resistant CRPC.
SABR 在寡转移去势抵抗性前列腺癌中显示出临床获益。然而，新发远处转移病灶的风险仍然很高，只有少数患者出现持久的无进展反应。因此，迫切需要确定哪些患者将从单纯 SABR 获益，哪些患者将从 SABR 联合系统治疗中获益。在此，我们提供了据我们所知的第一个证据，即循环前列腺癌特异性细胞外囊泡（PCEVs）作为寡转移去势抵抗性前列腺癌（omCRPC）患者接受 SABR 治疗后结局的非侵入性预测因子。
我们使用纳米流式细胞术分析了 79 例 omCRPC 患者 SABR 前后基线、第 1、7 和 14 天外周血中 PCEVs 的水平和动力学变化，并与局限性和广泛转移性前列腺癌队列的基线值进行了比较。采用 Cox 回归模型确定 omCRPC PCEV 水平与肿瘤学结局的相关性。
mCRPC 患者的 PCEV 水平最高，其次是 omCRPC，局限性前列腺癌患者的 PCEV 水平最低。基线时高水平的 PCEV 预示着远处复发的中位时间更短（3.5 个月 vs 6.6 个月；P=0.0087）。SABR 后，PCEV 水平在第 7 天达到峰值，高水平 PCEV 的患者中位总生存期显著延长（32.7 个月 vs 27.6 个月；P=0.003）。这表明治疗前 PCEV 水平反映肿瘤负荷，而治疗后 PCEV 水平的早期变化可预测 SABR 的反应。相比之下，SABR 前后 C-胆碱正电子发射断层扫描和计算机断层扫描的放射组学特征不能预测临床结局。有趣的是，PCEV 水平与外周肿瘤反应性 CD8 T 细胞（CD8 CD11a）呈正相关。
本研究首次证明，循环 PCEVs 可作为 SABR 的预后和预测标志物，以识别“真正”的 omCRPC 患者。此外，它提供了新的见解，即 PCEVs 介导的肿瘤与免疫细胞之间的全身性免疫抑制作用，导致肿瘤的全局串扰，导致对 CRPC 的系统抑制。这项工作为进一步研究转移进展的基础以及提供新的治疗靶点（如 PCEVs）奠定了基础，以提高治疗抵抗性 CRPC 的 SABR 疗效和临床结局。
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