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

• Published in: European urology 2024-12, Vol.86 (6), p.579-587
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Aged; Antigens, Surface - genetics; Antigens, Surface - metabolism; Biomarkers; Biomarkers, Tumor - genetics; Gene expression; Gene expression profiling; Glutamate Carboxypeptidase II - genetics; Glutamate Carboxypeptidase II - metabolism; Humans; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Tumor
• ISSN: 0302-2838; 1873-7560; 1873-7560
• DOI: 10.1016/j.eururo.2024.09.005

Prostate-specific membrane antigen expression varies in treatment-naïve prostate cancer in a manner that reflects underlying tumor biology and might be leveraged as a biomarker of treatment susceptibility to personalize care for patients with prostate cancer. 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.