Weiner Adam B, Agrawal Raag, Wang Nicholas K, Sonni Ida, Li Eric V, Arbet Jaron, Zhang J J H, Proudfoot James A, Hong Boon Hao, Davicioni Elai, Kane Nathanael, Valle Luca F, Kishan Amar U, Pra Alan Dal, Ghadjar Pirus, Sweeney Christopher J, Nickols Nicholas G, Karnes R Jeffrey, Shen John, Rettig Matthew B, Czernin Johannes, Ross Ashely E, Lee Kiang Chua Melvin, Schaeffer Edward M, Calais Jeremie, Boutros Paul C, Reiter Robert E
Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA.
Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Eur Urol. 2024 Dec;86(6):579-587. doi: 10.1016/j.eururo.2024.09.005. Epub 2024 Sep 17.
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.
我们对未经治疗的前列腺癌患者的肿瘤前列腺特异性膜抗原（PSMA）水平进行了特征分析，以反映癌症生物学特性和治疗敏感性。
我们首先将原发性前列腺癌中PSMA正电子发射断层扫描（PET）的最大标准化摄取值（SUVmax）与肿瘤FOLH1（PSMA RNA丰度）进行关联，以确定RNA作为替代指标（n = 55）。然后，我们在两个大型原发性肿瘤队列中发现并验证了与PSMA RNA水平相关的分子途径。我们在独立队列（共18个；5684个肿瘤样本）中验证了这些关联，以表征与PSMA相关的途径和治疗反应。
PSMA RNA丰度与SUVmax呈中度相关（ρ = 0.41）。在独立队列中，雄激素受体信号在PSMA水平高的肿瘤中更活跃。因此，对于生化复发采用雄激素剥夺治疗时，PSMA水平高的肿瘤患者的癌症特异性生存期更长（调整后风险比[AHR] 0.54 [0.34 - 0.87]；n = 174）。PSMA水平低的肿瘤具有放疗抵抗的分子标志物。与此一致的是，原发性放疗后，PSMA水平高的肿瘤患者的复发时间更长（AHR 0.50 [0.28 - 0.90]；n = 248）。在SAKK09/10试验（n = 224）中，接受挽救性放疗的PSMA水平高的肿瘤患者在64 Gy组的疾病进展时间更长（限制平均生存时间[RMST] +7.60 [0.05 - 15.16]），但在70 Gy组这种效应减弱（RMST 3.52 [-3.30至10.33]）。局限性包括使用PSMA RNA作为PET SUVmax的替代指标。
未经治疗的前列腺癌中的PSMA水平可区分肿瘤生物学特性和治疗易感性。这些结果需要使用PET指标进行验证，以证实基于影像学的管理决策。
