Molecular Hallmarks of Prostate-specific Membrane Antigen in Treatment-naïve Prostate Cancer

Adam B Weiner; Raag Agrawal; Nicholas K Wang; Ida Sonni; Eric V Li; Jaron Arbet; J J H Zhang; James A Proudfoot; Boon Hao Hong; Elai Davicioni; Nathanael Kane; Luca F Valle; Amar U Kishan; Alan Dal Pra; Pirus Ghadjar; Christopher J Sweeney; Nicholas G Nickols; R Jeffrey Karnes; John Shen; Matthew B Rettig; Johannes Czernin; Ashely E Ross; Melvin Lee Kiang Chua; Edward M Schaeffer; Jeremie Calais; Paul C Boutros; Robert E Reiter

doi:10.1016/j.eururo.2024.09.005

Molecular Hallmarks of Prostate-specific Membrane Antigen in Treatment-naïve Prostate Cancer

Eur Urol. 2024 Dec;86(6):579-587. doi: 10.1016/j.eururo.2024.09.005. Epub 2024 Sep 17.

Authors

Adam B Weiner¹, Raag Agrawal², Nicholas K Wang³, Ida Sonni⁴, Eric V Li⁵, Jaron Arbet⁶, J J H Zhang⁷, James A Proudfoot⁸, Boon Hao Hong⁹, Elai Davicioni⁸, Nathanael Kane¹⁰, Luca F Valle¹⁰, Amar U Kishan¹¹, Alan Dal Pra¹², Pirus Ghadjar¹³, Christopher J Sweeney¹⁴, Nicholas G Nickols¹⁰, R Jeffrey Karnes¹⁵, John Shen¹⁶, Matthew B Rettig¹⁶, Johannes Czernin¹⁷, Ashely E Ross⁵, Melvin Lee Kiang Chua¹⁸, Edward M Schaeffer⁵, Jeremie Calais¹⁷, Paul C Boutros⁶, Robert E Reiter¹⁹

Affiliations

¹ Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].
² Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
³ Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁴ Department of Radiological Sciences, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Department of Clinical and Experimental Medicine, University Magna Graecia, Catanzaro, Italy.
⁵ Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁶ Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁷ Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁸ Veracyte, Inc, San Diego, CA, USA.
⁹ Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
¹⁰ Department of Radiation Oncology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Radiation Oncology Service, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
¹¹ Department of Radiation Oncology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹² Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
¹³ Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia.
¹⁵ Department of Urology, Mayo Clinic, Rochester, MN, USA.
¹⁶ Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁷ Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁸ Divisions of Radiation Oncology and Medical Sciences, National Cancer Centre, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore.
¹⁹ Department of Urology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA.

Abstract

Background and objective: We characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer.

Methods: We first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts. We validated those associations in independent cohorts (18 total; 5684 tumor samples) to characterize the pathways and treatment responses associated with PSMA.

Key findings and limitations: PSMA RNA abundance correlates moderately with SUVmax (ρ = 0.41). In independent cohorts, androgen receptor signaling is more active in tumors with high PSMA. Accordingly, patients with high PSMA tumors experienced longer cancer-specific survival when managed with androgen deprivation therapy for biochemical recurrence (adjusted hazard ratio [AHR] 0.54 [0.34-0.87]; n = 174). PSMA low tumors possess molecular markers of resistance to radiotherapy. Consistent with this, patients with high PSMA tumors experience longer time to recurrence following primary radiotherapy (AHR 0.50 [0.28-0.90]; n = 248). In the SAKK09/10 trial (n = 224), patients with high PSMA tumors who were managed with salvage radiotherapy experienced longer time to progression in the 64-Gy arm (restricted mean survival time [RMST] +7.60 [0.05-15.16]), but this effect was mitigated in the 70-Gy arm (RMST 3.52 [-3.30 to 10.33]). Limitations include using PSMA RNA as a surrogate for PET SUVmax.

Conclusions and clinical implications: PSMA levels in treatment-naïve prostate cancer differentiate tumor biology and treatment susceptibilities. These results warrant validation using PET metrics to substantiate management decisions based on imaging.

Keywords: Biomarkers; Gene expression; Gene expression profiling; Humans; Prognosis; Prostatic neoplasms/genetics; Prostatic neoplasms/pathology; Tumor.

MeSH terms

Aged
Antigens, Surface* / genetics
Antigens, Surface* / metabolism
Biomarkers, Tumor / genetics
Glutamate Carboxypeptidase II* / genetics
Glutamate Carboxypeptidase II* / metabolism
Humans
Male
Middle Aged
Positron-Emission Tomography
Prostatic Neoplasms* / diagnostic imaging
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology
Prostatic Neoplasms* / therapy

Substances

FOLH1 protein, human
Glutamate Carboxypeptidase II
Antigens, Surface
Biomarkers, Tumor

Abstract

MeSH terms

Substances

Grants and funding