Molecular and clinical correlates of high FOLH1 (PSMA) RNA expression in primary and metastatic prostate cancer.

Abstract

Background: 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.

Patients and methods: 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.

Results: 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).

Conclusions: This enhanced understanding of the distinct molecular and clinical profiles of FOLH1-expressing prostate cancers may inform optimization of PSMA-directed treatments.