1182P - Determination of tumor PSMA expression in prostate cancer from blood using a novel epigenomic liquid biopsy platform

Background

177Lu-PSMA-617 is an FDA-approved radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Treatment eligibility requires a PSMA PET scan to confirm tumor PSMA expression. With therapeutic strategies in development targeting an array of cell surface proteins, there is an emerging unmet need to quantify tumor drug target expression minimally invasively. We performed comprehensive epigenomic profiling on 1 mL of plasma and demonstrated an accurate minimally invasive readout of tumor PSMA expression in mCRPC.

Methods

We collected plasma at the time of PSMA PET scan in men with mCRPC and analyzed the PET images to quantify total tumor SUV_mean, SUV_max, and tumor volume (PSMA-avid disease with voxel SUV>3). We profiled genome-wide epigenomic signals across histone modifications associated with active enhancers, promoters and DNA methylation on these plasma samples and healthy controls. We identified genes associated with greater gene-regulatory activation (GRA) signal in men with mCPRC, and evaluated the association of this signal with PSMA PET features.

Results

We present results for the initial patients (n=12) and controls (n=14) from a larger cohort. Differential analysis between mCRPC and control plasma identified greater GRA signal in mCRPC at the transcription start site (TSS) of several genes known to be highly expressed in mCRPC, such as AR and HOXB13 (FDR-adjusted p < 0.05). GRA signal at the TSS of FOLH1, the gene that encodes PSMA, was elevated in the mCRPC samples compared to controls (p < 0.05). PSMA tumor load (tumor SUVmean * tumor volume) was strongly correlated with FOLH1, and not other relevant prostate cancer genes. After adjusting for cfDNA tumor fraction, FOLH1 GRA signal strongly correlated with PSMA PET SUV_max (p < 0.05) with a trend towards correlation with PSMA PET SUV_mean (p < 0.1).

Conclusions

These data suggest that comprehensive epigenomic cfDNA profiling provides an accurate surrogate of tumor PSMA expression in men with mCRPC. Pending ongoing validation in a larger cohort, these results highlight the potential of epigenomic cfDNA profiling as a real-time, non-invasive readout of tumor drug target expression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

J.E. Berchuck.

Funding

Precede Biosciences.

Disclosure

P. Ravi: Financial Interests, Institutional, Funding: Bayer, Lilly, Telix. A. D'Ippolito: Financial Interests, Institutional, Full or part-time Employment: Precede Biosciences; Financial Interests, Institutional, Stocks/Shares: Precede Biosciences, Syros Pharmaceuticals. J. Wurster: Financial Interests, Institutional, Full or part-time Employment: Precede Biosciences; Financial Interests, Personal, Stocks/Shares: Precede Biosciences. T. Tamakloe: Financial Interests, Institutional, Full or part-time Employment: Precede Biosciences; Financial Interests, Institutional, Stocks/Shares: Precede Biosciences. S. Kieft: Financial Interests, Institutional, Full or part-time Employment: Precede Biosciences; Financial Interests, Institutional, Stocks/Shares: Precede Biosciences, Beam Therapeutics. J. Guess: Financial Interests, Personal, Full or part-time Employment: Precede Biosciences Inc.; Financial Interests, Personal, Stocks/Shares: Precede Biosciences Inc. C. OBrien: Financial Interests, Personal, Stocks/Shares: Precede Biosciences; Financial Interests, Personal, Full or part-time Employment: Precede Biosciences. M. Coyne: Financial Interests, Institutional, Full or part-time Employment, Stock holder: Precede Biosciences; Financial Interests, Institutional, Stocks/Shares: Precede Biosciences. A. Gorthi: Financial Interests, Institutional, Full or part-time Employment: Precede Biosciences, Inc; Financial Interests, Institutional, Stocks/Shares: Precede Biosciences, Inc. C. Painter: Financial Interests, Personal, Full or part-time Employment, VP External Research: Precede Biosciences; Financial Interests, Personal, Stocks/Shares: Precede Biosciences. M. Freedman: Financial Interests, Personal, Other, co-founder, shareholder, and consultant: Precede Biosciences; Financial Interests, Personal, Other, moderator for The Third Transatlantic Exchange in Oncology: Liquid Biopsy as an Emerging Approach in Precision Cancer Medicine: L'Institut Servier; Financial Interests, Personal, Stocks/Shares, I hold equity: Precede Biosciences. M. Eaton: Financial Interests, Personal, Full or part-time Employment: Precede Biosciences; Financial Interests, Personal, Stocks/Shares: Precede Biosciences. J.C. Barrett: Financial Interests, Personal, Full or part-time Employment: AstraZeneca, Precede Biosciences; Financial Interests, Personal, Member of Board of Directors: Saga Diagnostics; Financial Interests, Personal, Stocks/Shares: Precede Biosciencea, AstraZeneca, Corsita, Nexosomes; Financial Interests, Personal, Advisory Role: Akoya, Leica, Agilent, Multiplex, Bain Capital, ExAI. H. Jacene: Financial Interests, Personal, Invited Speaker: Munrol, ITM, intouchCONGRESS, Blue Earth Diagnostics; Financial Interests, Personal, Other, Consulting: Spectrum Dynamics; Financial Interests, Personal, Other, Section Editor, American Journal of Radiology, compensated position: American Roentgen Ray Society; Financial Interests, Personal, Other, committee member: NCI Imaging Steering Committee; Financial Interests, Personal, Royalties, book royalties: Cambridge Publishing; Financial Interests, Institutional, Local PI, research support to institution: Blue Earth Diagnostics, Lantheus; Non-Financial Interests, Principal Investigator, Study Co-Chair of EA1183 and EA1211: ECOG-ACRIN; Non-Financial Interests, Member of Board of Directors: Society of Nuclear Medicine and Molecular Imaging; Non-Financial Interests, Member of Board of Directors, Nuclear Medicine and PET/CT: Intersocietal Accreditation Council. J.E. Berchuck: Financial Interests, Personal, Invited Speaker, Speaker honoraria: Guardant Health; Financial Interests, Personal, Advisory Board, Consulting fees: Genome Medical, Oncotect, Precede Biosciences, TracerDx; Financial Interests, Personal, Writing Engagement, Scientific Writer: Digital Science Press; Financial Interests, Personal, Advisory Board, Consulting Fees: Guardant Health; Financial Interests, Personal, Stocks/Shares, Company Equity: Cityblock Health, Genome Medical, Oncotect, Precede Biosciences, TracerDx; Financial Interests, Institutional, Advisory Board, Institutional patent filed on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis and licensed by Precede Biosciences; Financial Interests, Personal, Coordinating PI: Precede Biosciences. All other authors have declared no conflicts of interest.