Molecular and immunologic correlates of high PSMA/FOLH1 mRNA expression in prostate cancer (PC)

BackgroundThe 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 multi-institutional clinicogenomics database to characterize molecular and immunologic features associated with FOLH1 mRNA expression in PC.MethodsNextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed on PC specimens (n=7,102) through Caris Life Sciences. FOLH1-High/Low expression was defined as >75th quartile/<25th quartile RNA transcripts per million (TPM). TME cell fractions were estimated by RNA deconvolution using quanTIseq. Tumor cell PD-L1+ expression (≥2+, ≥5%; SP142) was assessed by IHC. Overall survival (OS) was calculated from diagnosis.ResultsSpecimens were derived from the prostate gland (n=4495, 63.3%) or metastatic sites (n=2607, 36.7%). 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 GI (245.5 TPM, p<0.001), lung (209.7 TPM, p<0.001) and liver metastases (143.1 TPM, p<0.001). High FOLH1 expression significantly correlated with AR-V7 variants (21% vs 16%) and ASXL1 (7% vs 4%) alterations, and fewer alterations in APC (3% vs 14%), FOX1A (6% vs 11%), PIK3CA (2% vs 7%), CTNNB1 (2% vs 6%), and PIK3R1 (0.4% vs 2%) (all p<0.001). High FOLH1 expression correlated with increased mRNA expression of PD-L1, PD-L2, LAG-3, CD80, CD86, and IFN-.ConclusionsThis is the largest combined clinicogenomic analysis of FOLH1 expression in PC. Tumors with high FOLH1 are molecularly and immunologically distinct, providing insights for distinct therapeutic strategies in this group.Legal entity responsible for the studyThe authors.FundingCaris Life Sciences.DisclosureR.R. McKay: Financial Interests, Personal, Advisory Board: Aveo, AstraZeneca, Bayer, Calithera, Dendreon, Exelixis, JNJ, Merck, Pfizer, Sanofi, Tempus, BMS, Lilly, Sanofi, Seagen, Telix, Sorrento Therapeutics, Eisai, Blue Earth Diagnostics; Financial Interests, Personal, Other, Molecular tumor board: Caris; Financial Interests, Personal, Other, Consultant: Dendreon, Myovant; Financial Interests, Personal, Invited Speaker: Exelixis, Merck, Novartis, Pfizer; Financial Interests, Steering Committee Member: Aveo, Merck, Eli Lilly; Financial Interests, Local PI: JNJ, Seagen, Calibr, Poseida, Oncternal, Scholar Rock, Merck, Xencor, Genentech, Eli Lilly, BMS; Financial Interests, Trial Chair: Bayer, AstraZeneca; Financial Interests, Institutional, Local PI: Exelixis. S. Nazari: Financial Interests, Personal, Other, Employee: Caris Life Sciences. A. Elliott: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. N. Smith: Financial Interests, Personal, Full or part-time Employment: Caris. D. Kilari: Financial Interests, Personal, Invited Speaker: Janssen, Pfizer, Aveo Oncology, Seagen, MJH - life sciences; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Institutional, Coordinating PI: Exelixis, Genentech; Financial Interests, Institutional, Local PI: Jounce. N. Agarwal: Financial Interests, Personal, Invited Speaker, Invited speaker: Medscape; Financial Interests, Personal, Invited Speaker, Invited Speaker: Onclive, Research to Practice, Clinical Care Options; Financial Interests, Institutional, Other, I serve in the leadership of my cancer center (Huntsman Cancer Institute, University of Utah. Salt Lake City, UT, USA). There are multiple research projects sponsored by these companies which pay money to my institution: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, CRISPR, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, Telix, Tracon.; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharmas with no personal honorarium.: AstraZeneca, Calithera, CRISPR, Eli Lilly, Exelixis, Immunomedics, Merck, Pfizer,; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharma companies with no personal honorarium.: Merck, Nektar, New Link Genetics, Oric, Pfizer, Prometheus, Rexahn, Takeda, Telix,Tracon; Financial Interests, Trial Chair, One of the two co-chairs of the clinical trials sponsored by these pharma companies. I have not received any honorarium for these roles.: Pfizer, Exelixis, Janssen, Telix.; Non-Financial Interests, Member, I am a long-standing member of ASCO and a volunteer. I was awarded the fellow of ASCO in 2023. I also act as the editor of the ASCO Daily News as a volunteer.: Amercian Society of Clinical Oncology; Non-Financial Interests, Member, I am a member of this NCI and NCTN-sponsored cooperative clinical trial network group.: SWOG; Non-Financial Interests, Member, I am a member of these professional organizations.: AACR, AUA, PCF. H. Beltran: Financial Interests, Personal, Advisory Board: Pfizer, Janssen, Foundation Medicine, Blue Earth Diagnostics, AstraZeneca, Amgen, Diaachi Sankyo, Merck, LOXO, Sanofi, Curie Therapeutics, Fusion Pharma; Financial Interests, Institutional, Funding: Janssen, AbbVie/Stemcentrx, Bristol Myers Squibb,; Financial Interests, Institutional, Research Grant: Diaachi Sankyo, Circle Pharma; Financial Interests, Personal and Institutional, Steering Committee Member: Novartis. All other authors have declared no conflicts of interest.