前列腺特异性膜抗原的分子标志：治疗前前列腺癌中的特征

Molecular Hallmarks of Prostate-specific Membrane Antigen in Treatment-naïve Prostate Cancer

EUROPEAN UROLOGY

影响因子:25.2

分区:医学1区 Top / 泌尿学与肾脏学1区

发表日期:2024 Dec

作者: Adam B Weiner, Raag Agrawal, Nicholas K Wang, Ida Sonni, Eric V Li, Jaron Arbet, J J H Zhang, James A Proudfoot, Boon Hao Hong, Elai Davicioni, Nathanael Kane, Luca F Valle, Amar U Kishan, Alan Dal Pra, Pirus Ghadjar, Christopher J Sweeney, Nicholas G Nickols, R Jeffrey Karnes, John Shen, Matthew B Rettig, Johannes Czernin, Ashely E Ross, Melvin Lee Kiang Chua, Edward M Schaeffer, Jeremie Calais, Paul C Boutros, Robert E Reiter

DOI: 10.1016/j.eururo.2024.09.005

摘要

我们分析了肿瘤中前列腺特异性膜抗原（PSMA）水平，作为癌症生物学特性和治疗敏感性的反映。首先，将原发性前列腺癌中PSMA正电子发射断层扫描（PET）最大标准化摄取值（SUVmax）与肿瘤中的FOLH1（PSMA RNA表达量）相关联，以建立RNA作为指标（样本数：55）。随后，在两个大规模原发肿瘤队列中发现并验证了与PSMA RNA水平相关的分子通路。在18个独立队列（共5684个肿瘤样本）中验证了这些关联，以描述与PSMA相关的通路和治疗反应。PSMARNA的丰度与SUVmax呈中等相关（ρ=0.41）。在独立队列中，雄激素受体信号通路在高PSMA肿瘤中更为活跃。相应地，接受雄激素剥夺治疗以应对生化复发的高PSMA患者，其癌症特异性生存期更长（调整HR：0.54 [0.34-0.87]；样本数：174）。低PSMA肿瘤表现出抗放疗的分子标志。因此，接受原发放射治疗后，高PSMA肿瘤患者的复发时间更长（调整HR：0.50 [0.28-0.90]；样本数：248）。在SAKK09/10试验中（样本数：224），接受救援放疗的高PSMA肿瘤患者在64-Gy剂量组中表现出更长的无进展生存时间（限制平均生存时间+7.60 [0.05-15.16]），但在70-Gy剂量组中这一效果减弱（限制平均生存时间3.52 [-3.30-10.33]）。局限性包括将PSMA RNA作为PET SUVmax的替代指标。治疗前前列腺癌中PSMA水平区分肿瘤生物学特性与治疗敏感性。这些结果需要通过PET指标的验证以支持基于影像的管理决策。

Abstract

We characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer.We first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts. We validated those associations in independent cohorts (18 total; 5684 tumor samples) to characterize the pathways and treatment responses associated with PSMA.PSMA RNA abundance correlates moderately with SUVmax (ρ = 0.41). In independent cohorts, androgen receptor signaling is more active in tumors with high PSMA. Accordingly, patients with high PSMA tumors experienced longer cancer-specific survival when managed with androgen deprivation therapy for biochemical recurrence (adjusted hazard ratio [AHR] 0.54 [0.34-0.87]; n = 174). PSMA low tumors possess molecular markers of resistance to radiotherapy. Consistent with this, patients with high PSMA tumors experience longer time to recurrence following primary radiotherapy (AHR 0.50 [0.28-0.90]; n = 248). In the SAKK09/10 trial (n = 224), patients with high PSMA tumors who were managed with salvage radiotherapy experienced longer time to progression in the 64-Gy arm (restricted mean survival time [RMST] +7.60 [0.05-15.16]), but this effect was mitigated in the 70-Gy arm (RMST 3.52 [-3.30 to 10.33]). Limitations include using PSMA RNA as a surrogate for PET SUVmax.PSMA levels in treatment-naïve prostate cancer differentiate tumor biology and treatment susceptibilities. These results warrant validation using PET metrics to substantiate management decisions based on imaging.