未经治疗的前列腺癌中前列腺特异性膜抗原的分子特征
Molecular Hallmarks of Prostate-specific Membrane Antigen in Treatment-naïve Prostate Cancer.
作者信息
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
机构信息
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.
出版信息
Eur Urol. 2024 Dec;86(6):579-587. doi: 10.1016/j.eururo.2024.09.005. Epub 2024 Sep 17.
BACKGROUND AND OBJECTIVE
We characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer.
METHODS
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.
KEY FINDINGS AND LIMITATIONS
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.
CONCLUSIONS AND CLINICAL IMPLICATIONS
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.
背景与目的
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。
方法
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。
主要发现与局限性
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。
结论与临床意义
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。
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