BACKGROUND: PSMA-targeted radioligand therapies (PSMA RLT) are an effective and safe option for metastatic castration-resistant prostate cancer, but responsive subtypes and their biomarkers are not fully defined. METHODS: Plasma samples for cell-free DNA (cfDNA) analysis were collected from 17 patients undergoing [¹⁷⁷Lu]Lu-PSMA-I&T. CfDNA underwent whole-genome sequencing to establish copy number variation (CNV) profiles and circulating-tumor DNA (ctDNA) levels and compared between prostate-specific antigen (PSA) response- and 1-year overall survival (1YOS) groups. RESULTS: Non-responders exhibited higher degrees of cfDNA CNV burden (P = 0.048) and higher ctDNA levels (P = 0.036) than responders. Both markers allowed for the differentiation of responses (AUC: 0.792, 0.806) and 1YOS (AUC: 0.778, 0.847). CONCLUSION: Unresponsive patients exhibited higher levels of cfDNA genomic instability and ctDNA levels, warranting genome-wide CNV profiling studies next to targeted approaches for mechanistic radiobiological insights and their value as response biomarkers for PSMA RLTs.

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Division of Nuclear Medicine Medical University of Vienna Währinger Gürtel 18 20 Vienna 1090 Austria

Department of Pathology Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology and Andrology University Hospital Krems Krems Austria

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology University of Texas Southwestern Medical Center Dallas USA

Department of Urology Weill Cornell Medical College New York USA

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

IT Service and Strategic Information Management Medical University Vienna Vienna Austria

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

See more in PubMed

Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic Castration-Resistant prostate Cancer. N Engl J Med. 2021;385:1091–103. PubMed DOI PMC

Buteau JP, Martin AJ, Emmett L, Iravani A, Sandhu S, Joshua AM, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus Cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23:1389–97. PubMed DOI

Gafita A, Calais J, Grogan TR, Hadaschik B, Wang H, Weber M, et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. Lancet Oncol. 2021;22:1115–25. PubMed DOI

Ahmadzadehfar H, Seifert R, Afshar-Oromieh A, Kratochwil C, Rahbar K. Prostate cancer theranostics with 177Lu-PSMA. Semin Nucl Med. 2024;54:581–90. PubMed DOI

Crumbaker M, Goldstein LD, Murray DH, Tao J, Pathmanandavel S, Boulter N, et al. Circulating tumour DNA biomarkers associated with outcomes in metastatic prostate cancer treated with lutetium-177-PSMA-617. Eur Urol Open Sci. 2023;57:30–6. PubMed DOI PMC

De Bono JS, Morris MJ, Sartor O, Wei XX, Fizazi K, Herrmann K, et al. Baseline ctdna analyses and associations with outcomes in taxane-naive patients with mCRPC treated with

Raychaudhuri R, Mo G, Tuchayi AM, Graham L, Gulati R, Pritchard CC, et al. Genomic correlates of prostate-specific membrane antigen expression and response to 177Lu-PSMA-617: A retrospective multicenter cohort study. JCO Precis Oncol. 2024;8:e2300634. PubMed DOI

Fettke H, Kostos L, Buteau J, Steen JA, Medhurst E, Haskali MB, et al. Abstract 5614: genomic aberrations in Circulating tumor DNA (ctDNA) and clinical outcomes from [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC). Cancer Res. 2023;83:5614–5614. DOI

Sartor O, Ledet E, Huang M, Schwartz J, Lieberman A, Lewis B et al. Prediction of Resistance to 177Lu-PSMA Therapy by Assessment of Baseline Circulating Tumor DNA Biomarkers. J Nucl Med [Internet]. 2023; Available from: https://doi.org/10.2967/jnumed.123.266167

Lanka SM, Jang A, Sweeney PL, Gupta K, Caputo S, Casado C, et al. Evaluation of ctdna in patients treated with lutetium-177-PSMA-617. J Clin Oncol. 2023;41:243–243. DOI

Vanwelkenhuyzen J, Van Bos E, Van Bruwaene S, Lesage K, Maes A, Üstmert S, et al. AR and PI3K genomic profiling of cell-free DNA can identify poor responders to lutetium-177-PSMA among patients with metastatic castration-resistant prostate cancer. Eur Urol Open Sci. 2023;53:63–6. PubMed DOI PMC

Ulz P, Belic J, Graf R, Auer M, Lafer I, Fischereder K et al. Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer. Nat Commun [Internet]. 2016;7. Available from: https://doi.org/10.1038/ncomms12008

Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–77. PubMed DOI PMC

Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y, et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci U S A. 2014;111:11139–44. PubMed DOI PMC

Sumanasuriya S, Seed G, Parr H, Christova R, Pope L, Bertan C, et al. Elucidating prostate Cancer behaviour during treatment via Low-pass Whole-genome sequencing of Circulating tumour DNA. Eur Urol. 2021;80:243–53. PubMed DOI PMC

Nørgaard M, Bjerre MT, Fredsøe J, Vang S, Jensen JB, De Laere B, et al. Prognostic value of Low-Pass whole genome sequencing of Circulating tumor DNA in metastatic Castration-Resistant prostate Cancer. Clin Chem. 2023;69:386–98. PubMed DOI

Kluge K, Einspieler H, Haberl D, Spielvogel C, Amereller D, Egger G, et al. Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET/CT and Circulating tumor DNA in prostate cancer-a cross-sectional study. Eur J Nucl Med Mol Imaging. 2024;51:2833–42. PubMed DOI PMC

Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG, Parsons HA, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun. 2017;8:1324. PubMed DOI PMC

Mitchell T, Neal DE. The genomic evolution of human prostate cancer [Internet]. British Journal of Cancer. Nature Publishing Group; 2015. pp. 193–8. Available from: https://doi.org/10.1038/bjc.2015.234

Pös O, Radvanszky J, Buglyó G, Pös Z, Rusnakova D, Nagy B, et al. DNA copy number variation: main characteristics, evolutionary significance, and pathological aspects. Biomed J. 2021;44:548–59. PubMed DOI PMC

Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009;10:551–64. PubMed DOI PMC

Kratochwil C, Giesel FL, Heussel CP, Kazdal D, Endris V, Nientiedt C, et al. Patients resistant against PSMA-targeting α-radiation therapy often harbor mutations in DNA damage-repair-associated genes. J Nucl Med. 2020;61:683–8. PubMed DOI

Hasenleithner SO, Speicher MR. A clinician’s handbook for using ctdna throughout the patient journey. Mol Cancer. 2022;21:81. PubMed DOI PMC