A Comparative Review of PSA, PSMA PET, and PCA3 Biomarkers in Prostate Cancer Diagnosis: Effectiveness, Cost, and Safety Analysis
ABSTRACT
Background: Prostate cancer is the third most common urological cancer among men in Indonesia, with an incidence rate of 14.8 per 100,000 population in 2012. PSA has been a cornerstone of diagnosis, however its low specificity in distinguishing prostate cancer from other urological malignancies, is followed by study of other biomarkers such as PSMA and PCA3. PSMA and PCA3, either as a single marker or in combination with PSA, has the potential to enhance diagnostic accuracy, aid in risk assessment, and support treatment decision-making.
Results : The overall diagnostic accuracy, as indicated by the AUC integrating sensitivity and specificity, shows that PCA3 and PSMA have higher AUC values compared to PSA. Combining PSA with PSMA, PCA3, or both demonstrated promising potential for prostate cancer diagnosis when compared to PSA alone. PSA shows slightly higher sensitivity, supporting its role as a screening tool, while PSMA PET offers better specificity than conventional imaging for detecting advanced prostate cancer, albeit at a higher cost. Meanwhile, PCA3, a urinary biomarker, surpasses PSA in specificity, effectively reducing unnecessary biopsies with a safer, non-invasive approach.
Summary : PSA remains the standard diagnostic biomarker for prostate cancer screening. Its low specificity may result in unnecessary biopsies. Other biomarkers like PSMA and PCA3 may be more appropriate for specific patient situations than PSA, with PCA3 being the least invasive procedure and PSMA PET being the most expensive. A multimodal approach combining PSA with PSMA or PCA3 shows significantly higher accuracy than PSA alone, improving diagnostic chances and reducing the risk of overdiagnosis.
Wasim S, Lee SY, Kim J. Complexities of Prostate Cancer. Vol. 23, International Journal of Molecular Sciences. MDPI; 2022.
Mochtar CA, Atmoko W, Umbas R, Hamid ARAH. Prostate cancer detection rate in Indonesian men. Asian Journal of Surgery. 2018 Mar 1;41(2):163–9.
The American Cancer Society medical and editorial content team. What Is Prostate Cancer? About Prostate Cancer. 2024 Nov.
Salagierski M, Schalken JA. Molecular Diagnosis of Prostate Cancer: PCA3 and TMPRSS2:ERG Gene Fusion. Journal of Urology. 2012 Mar;187(3):795–801.
MedlinePlus. medlineplus.gov. 2020. Prostate cancer: MedlinePlus Genetics. Available from: https://medlineplus.gov/genetics/condition/prostate-cancer/#causes
Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules. 2022 Sep 5;27(17):5730.
Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification of a human prostate specific antigen. Investigative urology. 1979 Sep;17(2):159–63.
Mahmoud MM, Hamid FFA, Abdelgawad I, Ismail A, Malash I, Ibrahim DM. Diagnostic Efficacy of PSMA and PSCA mRNAs Combined to PSA in Prostate Cancer Patients. Asian Pacific Journal of Cancer Prevention. 2023;24(1):223–9.
Descotes JL. Diagnosis of prostate cancer. Asian J Urol. 2019 Apr;6(2):129–36.
Ross T, Ahmed K, Raison N, Challacombe B, Dasgupta P. Clarifying the PSA grey zone: The management of patients with a borderline PSA. Vol. 70, International Journal of Clinical Practice. Blackwell Publishing Ltd; 2016. p. 950–9.
Houshmand S, Lawhn-Heath C, Behr S. PSMA PET imaging in the diagnosis and management of prostate cancer. Abdominal Radiology. 2023 Jul 26;48(12):3610–23.
Leslie SW, Soon-Sutton TL, Skelton WP. Prostate Cancer. Treasure Island (FL): StatPearls Publishing; 2024.
Lemos AEG, Matos A da R, Ferreira LB, Gimba ERP. The long non-coding RNA PCA3 : an update of its functions and clinical applications as a biomarker in prostate cancer. Oncotarget. 2019 Nov 12;10(61):6589–603.
Catalona WJ, Hudson MA, Scardino PT, Richie JP, Ahmann FR, Flanigan RC, et al. Selection of Optimal Prostate Specific Antigen Cutoffs for Early Detection of Prostate Cancer: Receiver Operating Characteristic Curves. The Journal of Urology. 1994 Dec 1;152(6):2037–42.
National Cancer Institute. U.S. Department of Health and Human Services. 2024. Prostate-Specific Antigen (PSA) Test.
LeBeau AM, Kostova M, Craik CS, Denmeade SR. Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer. Biological Chemistry. 2010 Apr 1;391(4).
Chang SS. Overview of Prostate-Specific Membrane Antigen. Rev Urol. 2004;6(Suppl 10(Suppl 10)):S13–8.
Satapathy S, Singh H, Kumar R, Mittal BR. Diagnostic accuracy of 68Ga-PSMA PET/CT for initial detection in patients with suspected prostate cancer: A systematic review and meta-analysis. Vol. 216, American Journal of Roentgenology. American Roentgen Ray Society; 2021. p. 599–607.
Chow KM, So WZ, Lee HJ, Lee A, Yap DWT, Takwoingi Y, et al. Head-to-head Comparison of the Diagnostic Accuracy of Prostate-specific Membrane Antigen Positron Emission Tomography and Conventional Imaging Modalities for Initial Staging of Intermediate- to High-risk Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2023 Jul;84(1):36–48.
Vinsensia M, Chyoke PL, Hadaschik B, Holland-Letz T, Moltz J, Kopka K, et al. 68 Ga-PSMA PET/CT and Volumetric Morphology of PET-Positive Lymph Nodes Stratified by Tumor Differentiation of Prostate Cancer. Journal of Nuclear Medicine. 2017 Dec;58(12):1949–55.
Jilg CA, Drendel V, Rischke HC, Beck TI, Reichel K, Krönig M, et al. Detection Rate of 18 F-Choline PET/CT and 68 Ga-PSMA-HBED-CC PET/CT for Prostate Cancer Lymph Node Metastases with Direct Link from PET to Histopathology: Dependence on the Size of Tumor Deposits in Lymph Nodes. Journal of Nuclear Medicine. 2019 Jul;60(7):971–7.
Zhou J, Gou Z, Wu R, Yuan Y, Yu G, Zhao Y. Comparison of PSMA-PET/CT, choline-PET/CT, NaF-PET/CT, MRI, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a systematic review and meta-analysis. Skeletal Radiol. 2019 Dec 24;48(12):1915–24.
Loeb S, Partin AW. Review of the literature: PCA3 for prostate cancer risk assessment and prognostication. Rev Urol. 2011;13(4):191–5.
Wang Y, Liu XJ, Yao XD. Function of PCA3 in prostate tissue and clinical research progress on developing a PCA3 score. Chin J Cancer Res. 2014;26(4):493–500.
Marks LS, Bostwick DG. Prostate Cancer Specificity of PCA3 Gene Testing: Examples from Clinical Practice. Rev Urol. 2008;10(3):175–81.
Nabok A, Abu-Ali H, Takita S, Smith DP. Electrochemical Detection of Prostate Cancer Biomarker PCA3 Using Specific RNA-Based Aptamer Labelled with Ferrocene. Chemosensors. 2021 Mar 24;9(4):59.
McDunn JE, Li Z, Adam KP, Neri BP, Wolfert RL, Milburn M v., et al. Metabolomic signatures of aggressive prostate cancer. Prostate. 2013;73(14):1547–60.
Saylor PJ, Karoly ED, Smith MR. Prospective Study of Changes in the Metabolomic Profiles of Men during Their First Three Months of Androgen Deprivation Therapy for Prostate Cancer. Clinical Cancer Research. 2012 Jul 1;18(13):3677–85.
Jung K, Reszka R, Kamlage B, Bethan B, Stephan C, Lein M, et al. Tissue metabolite profiling identifies differentiating and prognostic biomarkers for prostate carcinoma. International Journal of Cancer. 2013 Dec 15;133(12):2914–24.
Kami K, Fujimori T, Sato H, Sato M, Yamamoto H, Ohashi Y, et al. Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry. Metabolomics. 2013 Apr 1;9(2):444–53.
Gan J, Zeng X, Wang X, Wu Y, Lei P, Wang Z, et al. Effective Diagnosis of Prostate Cancer Based on mRNAs From Urinary Exosomes. Frontiers in Medicine. 2022 Mar 23;9.
Rigau M, Ortega I, Mir MC, Ballesteros C, Garcia M, Llauradó M, et al. A Three‐Gene panel on urine increases PSA specificity in the detection of prostate cancer. The Prostate. 2011 Dec 25;71(16):1736–45.
Tales VN, Antognelli C, del Buono C, Stracci F, Serva MR, Cottini E, et al. Diagnostic potential in prostate cancer of a panel of urinary molecular tumor markers. Cancer Biomarkers. 2009 Dec 22;5(6):241–51.
Cao L, Lee CH, Ning J, Handy BC, Wagar EA, Meng QH. Combination of prostate cancer antigen 3 and prostate-specific antigen improves diagnostic accuracy in men at risk of prostate cancer. Archives of Pathology and Laboratory Medicine. 2018 Sep 1;142(9):1106–12.
Ramos CG, Valdevenito R, Vergara I, Anabalon P, Sanchez C, Fulla J. PCA3 sensitivity and specificity for prostate cancer detection in patients with abnormal PSA and/or suspicious digital rectal examination. First Latin American experience. Urologic Oncology: Seminars and Original Investigations. 2013 Nov;31(8):1522–6.
Bravaccini S, Puccetti M, Bocchini M, Ravaioli S, Celli M, Scarpi E, et al. PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. Scientific Reports. 2018 Mar 9;8(1):4254.
Kaittanis C, Andreou C, Hieronymus H, Mao N, Foss CA, Eiber M, et al. Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors. Journal of Experimental Medicine. 2018 Jan 1;215(1):159–75.
Refaat Ahmed S, Ibrahim Elattar N, Mohamed Maarouf A, Moustafa Ahmed A. Serum and Urinary Prostatic Cancer Antigen 3 as Diagnostic Biomarkers for Prostate Cancer Corresponding author*. 2024;30(6). Available from: https://doi.org/10.21608/zumj.2024.234154.2873
Borbiev T, Kohaar I, Petrovics G. Clinical Biofluid Assays for Prostate Cancer. Cancers (Basel). 2023 Dec 28;16(1):165.
Cornu J, Cancel‐Tassin G, Egrot C, Gaffory C, Haab F, Cussenot O. Urine TMPRSS2:ERG fusion transcript integrated with PCA3 score, genotyping, and biological features are correlated to the results of prostatic biopsies in men at risk of prostate cancer. The Prostate. 2013 Feb 15;73(3):242–9.
Salagierski M, Schalken JA. PCA3 and TMPRSS2-ERG: Promising Biomarkers in Prostate Cancer Diagnosis. Cancers. 2010 Jul 6;2(3):1432–40.
Salami SS, Schmidt F, Laxman B, Regan MM, Rickman DS, Scherr D, et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urologic Oncology: Seminars and Original Investigations. 2013 Jul;31(5):566–71.
Yin L, Rao P, Elson P, Wang J, Ittmann M, Heston WDW. Role of TMPRSS2-ERG Gene Fusion in Negative Regulation of PSMA Expression. PLoS One. 2011 Jun 24;6(6):e21319.
Hugosson J, Månsson M, Wallström J, Axcrona U, Carlsson S V., Egevad L, et al. Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only. New England Journal of Medicine. 2022 Dec 8;387(23):2126–37.
Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up. JNCI Journal of the National Cancer Institute. 2012 Jan 18;104(2):125–32.
Martin RM, Donovan JL, Turner EL, Metcalfe C, Young GJ, Walsh EI, et al. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality. JAMA. 2018 Mar 6;319(9):883.
Surasi DS, Eiber M, Maurer T, Preston MA, Helfand BT, Josephson D, et al. Diagnostic Performance and Safety of Positron Emission Tomography with 18F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE). Eur Urol. 2023 Oct;84(4):361–70.
Chevalme YM, Boudali L, Gauthé M, Rousseau C, Skanjeti A, Merlin C, et al. Survey by the French Medicine Agency (ANSM) of the imaging protocol, detection rate, and safety of 68Ga-PSMA-11 PET/CT in the biochemical recurrence of prostate cancer in case of negative or equivocal 18F-fluorocholine PET/CT: 1084 examinations. Eur J Nucl Med Mol Imaging. 2021 Aug 8;48(9):2935–50.
Siriwardana A, Thompson J, van Leeuwen PJ, Doig S, Kalsbeek A, Emmett L, et al. Initial multicentre experience of 68 gallium‐PSMA PET/CT guided robot‐assisted salvage lymphadenectomy: acceptable safety profile but oncological benefit appears limited. BJU Int. 2017 Nov 20;120(5):673–81.
Klein Nulent TJW, van Es RJJ, Willems SM, Braat ArthurJAT, Devriese LA, de Bree R, et al. First experiences with 177Lu-PSMA-617 therapy for recurrent or metastatic salivary gland cancer. EJNMMI Res. 2021 Dec 14;11(1):126.
Ceci F, Rovera G, Iorio GC, Guarneri A, Chiofalo V, Passera R, et al. Event-free survival after 68 Ga-PSMA-11 PET/CT in recurrent hormone-sensitive prostate cancer (HSPC) patients eligible for salvage therapy. Eur J Nucl Med Mol Imaging. 2022 Jul 26;49(9):3257–68.
von Eyben R, Kapp DS, Hoffmann MA, Soydal C, Uprimny C, Virgolini I, et al. A Risk Model for Patients with PSA-Only Recurrence (Biochemical Recurrence) Based on PSA and PSMA PET/CT: An Individual Patient Data Meta-Analysis. Cancers (Basel). 2022 Nov 7;14(21):5461.
Birnbaum JK, Feng Z, Gulati R, Fan J, Lotan Y, Wei JT, et al. Projecting Benefits and Harms of Novel Cancer Screening Biomarkers: A Study of PCA3 and Prostate Cancer. Cancer Epidemiology, Biomarkers & Prevention. 2015 Apr 1;24(4):677–82.
Pinkhasov GI, Lin Y, Palmerola R, Smith P, Mahon F, Kaag MG, et al. Complications following prostate needle biopsy requiring hospital admission or emergency department visits – experience from 1000 consecutive cases. BJU International. 2012 Aug 7;110(3):369–74.
Ma X, Wang R, Long JB, Ross JS, Soulos PR, Yu JB, et al. The cost implications of prostate cancer screening in the Medicare population. Cancer. 2014 Jan 1;120(1):96–102.
Lao C, Brown C, Obertova Z, Edlin R, Rouse P, Hodgson F, et al. The costs of identifying undiagnosed prostate cancer in asymptomatic men in New Zealand general practice. Family Practice. 2013 Dec 1;30(6):641–7.
Martin AJ, Lord SJ, Verry HE, Stockler MR, Emery JD. Risk assessment to guide prostate cancer screening decisions: a cost‐effectiveness analysis. Medical Journal of Australia. 2013 Jun 3;198(10):546–50.
Song R, Jeet V, Sharma R, Hoyle M, Parkinson B. Cost-Effectiveness Analysis of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) for the Primary Staging of Prostate Cancer in Australia. Pharmacoeconomics. 2022 Aug 27;40(8):807–21.
Szczesniewski JJ, Tellez Fouz C, García Tello A, de la Rubia Marcos M, García Alonso MP, Llanes González L. Cost analysis of next-generation imaging in high-risk prostate cancer staging. Actas Urológicas Españolas (English Edition). 2024 May;48(4):328–34.
Subramanian K, Martinez J, Huicochea Castellanos S, Ivanidze J, Nagar H, Nicholson S, et al. Complex implementation factors demonstrated when evaluating cost-effectiveness and monitoring racial disparities associated with [18F]DCFPyL PET/CT in prostate cancer men. Sci Rep. 2023 May 23;13(1):8321.
de Rooij M, Crienen S, Witjes JA, Barentsz JO, Rovers MM, Grutters JPC. Cost-effectiveness of Magnetic Resonance (MR) Imaging and MR-guided Targeted Biopsy Versus Systematic Transrectal Ultrasound–Guided Biopsy in Diagnosing Prostate Cancer: A Modelling Study from a Health Care Perspective. Eur Urol. 2014 Sep;66(3):430–6.
Schwenck J, Olthof SC, Pfannenberg C, Reischl G, Wegener D, Marzec J, et al. Intention-to-Treat Analysis of 68 Ga-PSMA and 11 C-Choline PET/CT Versus CT for Prostate Cancer Recurrence After Surgery. Journal of Nuclear Medicine. 2019 Oct;60(10):1359–65.
Tien T, Gkougkousis E, Allchorne P, Green JSA. The Use of Healthcare Services by Prostate Cancer Patients in the Last 12 Months of Life: How Do We Improve the Quality of Care During This Period? J Palliat Care. 2021 Apr 26;36(2):93–7.
Kirby R, Fitzpatrick JM. Optimising repeat prostate biopsy decisions and procedures. BJU Int. 2012 Jun 22;109(12):1750–4.
Nicholson A, Mahon J, Boland A, Beale S, Dwan K, Fleeman N, et al. The clinical effectiveness and cost-effectiveness of the PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation. Health Technol Assess (Rockv). 2015 Oct;19(87):1–192.
Department of Health NHS England. Reference costs 2012 to 2013. 2013.
Cardiff (UK): National Collaborating Centre for Cancer (UK) [Internet]. 2014. Prostate Cancer: Diagnosis and Treatment. Available from: https://pubmed.ncbi.nlm.nih.gov/25340246/
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