Prostate-specific membrane antigen (PSMA; FOLH1) is a cell-surface target for diagnostics and treatment in prostate cancer. We utilized a database of molecularly-profiled prostate tumors to evaluate clinical, genomic, and immunologic correlates of high FOLH1 RNA expression.
Prostate cancer specimens (N = 7,082) underwent DNA/RNA sequencing and immunohistochemistry at Caris Life Sciences. FOLH1-High/Low expression was defined by upper/lower quartiles or median transcripts per million (TPM). Overall survival (OS) was calculated from insurance claims.
Prostate adenocarcinoma had 2.97-fold higher FOLH1 expression compared to high grade neuroendocrine prostate cancer (q < 0.0001). Of 7,020 adenocarcinomas, 4,464 were primary prostate samples, 828 were lymph node metastases, and 1,686 were distant metastases. FOLH1 expression varied across metastatic sites (highest in lymph node and lowest in liver; 1.2-fold difference, q < 0.05). FOLH1-High tumors were enriched in AR-V7 variants (10.1% vs. 4.5%, q < 0.05) and associated with higher androgen receptor (AR) signaling (0.82 vs 0.78, q < 0.05). Conversely, FOLH1-Low tumors were enriched with FOXA1 (12.2% vs. 6.4%), APC (11.4% vs. 3.0%), PIK3CA (5.8% vs. 2.7%) and PIK3R1 (2.6% vs. 0.48%) mutations (q < 0.05). FOLH1-High tumors had a lower M1: M2 ratio, fewer Tregs and CD8+ T cells, higher immune checkpoint expression, and lower interferon signature scores. FOLH1-High primary tumors were more frequently microsatellite instability (MSI)-High, tumor mutational burden (TMB)-High, and PD-L1-positive. Among patients with metastatic tumors, median OS was improved in the FOLH1-High group (31.9 vs 23.3 months, p < 0.001).
This enhanced understanding of the distinct molecular and clinical profiles of FOLH1-expressing prostate cancers may inform optimization of PSMA-directed treatments.
The oncologist. 2025 Oct 07 [Epub ahead of print]
Rana R McKay, Shayan S Nazari, Andrew Elliott, Jennifer R Ribeiro, Brent S Rose, Pedro C Barata, Deepak Kilari, Rohan Garje, Neeraj Agarwal, Norm Smith, Emmanuel S Antonarakis, Aditya Bagrodia, Himisha Beltran
University of California San Diego, La Jolla, CA., Caris Life Sciences, Phoenix, AZ., University of California, San Diego, San Diego, CA., University Hospitals Seidman Cancer Center, Cleveland, OH., Medical College of Wisconsin Division of Hematology and Oncology, Milwaukee, WI., Miami Cancer Institute, Baptist Health South Florida, Miami, FL., Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT., University of Minnesota, Masonic Cancer Center, Minneapolis, MN., Dana-Farber Cancer Institute, Boston, MA.