High folate receptor expression is associated with aggressive features in prostate cancer with low prostate‐specific membrane antigen expression

Objective This work aimed to analyse the expression of and correlation between folate transporters FOLR1, FOLR2, SLC19A1 (reduced folate carrier, RFC), and FOLH1 (PSMA mRNA) in a large cohort of prostate cancer samples, with the goal of better understanding the nature of aggressive disease with low PSMA expression. Subjects and Methods A total of 55 329 radical prostatectomy (RP) tumour specimens tested with the Decipher prostate genomic classifier (Veracyte, CA) were identified from the Decipher GRID database (NCT02609269). Transcriptome‐wide mRNA expression and baseline clinicopathologic data were retrieved. Logistic regression assessed associations between gene expression, pathological Gleason grade group (GG) 4–5, lymph node invasion (LNI), seminal vesicle invasion (SVI), and very high Decipher score (>0.85). Results This cohort had a median age of 65 years and PSA of 4.9 ng/mL. FOLR1and FOLR2 showed no correlation with PSMA. High FOLR2 and RFC were associated with very high Decipher scores and GG4–5. In the lowest 10% PSMA group, high FOLR2 correlated with high Decipher scores, GG4–5, LNI, and SVI (all p < 0.001). Limitations include the retrospective design and the inability to distinguish FR‐β expression from immune cell infiltration. Conclusions Our large‐scale study of transcriptome demonstrates FOLR2 gene expression is associated with aggressive prostate cancer in samples with low expression of PSMA. Future prediction of disease risk could be enhanced by using FOLR2 as a molecular target for identifying aggressive prostate cancer in cases of low PSMA.