Molecular and clinical correlates of high PSMA/FOLH1 mRNA expression in primary and metastatic prostate cancer (PC).
Authors: McKay Rana R. , Nazari Shayan , Elliott Andrew , Rose Brent S. , Barata Pedro C. , Kilari Deepak , Garje Rohan , Agarwal Neeraj , Nabhan Chadi , Beltran Himisha , Antonarakis Emmanuel S. , Bagrodia Aditya 
Published: June 2024

5051

Background: The FOLH1 gene encodes prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein that is expressed in PC cells. PSMA is a target for diagnostic imaging and treatment in PC. We utilized a database of molecularly profiled PC tumors to evaluate correlates of high FOLH1 mRNA expression. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed on PC specimens (n=7,558) through Caris Life Sciences. FOLH1-High/Low expression was defined as above/below median RNA transcripts per million (TPM). Androgen receptor (AR), neuroendocrine (NEPC), MAPK, and T-cell inflamed RNA signature scores were calculated. Tumor cell PD-L1+ expression (≥2+, ≥5%; SP142) was assessed by IHC. Overall survival (OS) and time on treatment (TOT) were calculated from time of diagnosis or therapy start. Results: Specimens were derived from the prostate gland (n=4495, 59.5%), lymph nodes (n=858, 11.4%), bone (n=568, 7.5%), liver (n=359, 4.7%), urinary tract (n=340, 4.5%), lung (n=116, 1.5%), and other metastatic sites (n=822, 10.9%). Relative to the prostate (390.9 TPM), FOLH1 mRNA expression varied by metastatic site, with highest expression in lymph nodes (518.2 TPM, p<0.001) and lowest expression in lung (209.7 TPM, p<0.001) and liver metastases (143.1 TPM, p<0.001). Higher FOLH1 expression significantly correlated with presence of AR-V7 variants (18% vs 15%) and ASXL1 (6% vs 3.9%) alterations, and fewer alterations in FOX1A (7.9% vs 10.6%), APC (4% vs 10.3%), PIK3CA(3.1% vs 6.4%), CTNNB1 (3.1% vs 4.8%), and PIK3R1 (0.7% vs 2%). High FOLH1 expression positively associated with AR signaling score, MAPK activation, and T-cell inflammation, and negatively correlated with NEPC signaling (all p<0.001). Tumors with high FOLH1 expression were more frequently PD-L1+ (3.9% vs 2.2%, p<0.01). Among primary tumors, OS was similar between FOLH1 high and low groups; however, among metastatic tumors, OS was improved in patients (pts) with high FOLH1 expression compared to low expression (96.3 vs 87.9 months, HR 0.82 95% CI 0.73-0.92). There was no difference in TOT among pts receiving ARSIs, taxanes, or PARPi. Among 149 pts that received 177Lu-PSMA-617, there was a trend towards improved TOT in FOLH1-high (n=78) versus -low (n=71) tumors (HR 0.76, 95%CI 0.55-1.05). Conclusions: This is the largest combined genomic, transcriptomic and survival outcomes analysis of PSMA ( FOLH1) expression in PC. In PC, greater FOLH1 mRNA expression was associated with higher AR signaling scores and AR-V7 expression, and fewer mutations in the Wnt and PI3K pathways. FOLH1-high pts showed greater T cell inflammation and PD-L1 expression, and lower NEPC signaling. High FOLH1 expression was associated with greater OS among patients with metastatic tumors, with a trend towards improved outcomes to 177Lu-PSMA-617. Such pts may benefit from distinct therapeutic strategies.