Molecular Hallmarks of Prostate-specific Membrane Antigen in Treatment-naïve Prostate Cancer.
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.
EDRN PI Authors
Medline Author List
- Agrawal R
- Arbet J
- Boutros PC
- Calais J
- Czernin J
- Davicioni E
- Ghadjar P
- Hong BH
- Kane N
- Karnes RJ
- Kishan AU
- Lee Kiang Chua M
- Li EV
- Nickols NG
- Pra AD
- Proudfoot JA
- Reiter RE
- Rettig MB
- Ross AE
- Schaeffer EM
- Shen J
- Sonni I
- Sweeney CJ
- Valle LF
- Wang NK
- Weiner AB
- Zhang JJH