Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer

Nicolette M. Fonseca(University of British Columbia), Corinne Maurice‐Dror, Cameron Herberts(University of British Columbia), Wilson Tu(University of British Columbia), William R. S. Fan, Andrew J. Murtha(University of British Columbia), Catarina Kollmannsberger, Edmond M. Kwan(University of British Columbia), Karan Parekh(University of British Columbia), Elena Schönlau(University of British Columbia), Cecily Q. Bernales(University of British Columbia), Gráinne Donnellan(University of British Columbia), Sarah W.S. Ng(University of British Columbia), Takayuki Sumiyoshi(University of British Columbia), Joanna Vergidis, Krista Noonan, Daygen L. Finch, Muhammad Zulfiqar, Stacy Miller, Sunil Parimi, Jean‐Michel Lavoie, Edward Hardy(Vernon Jubilee Hospital), Maryam Soleimani, Lucia Nappi(University of British Columbia), Bernhard J. Eigl, Christian Kollmannsberger, Sinja Taavitsainen(Tampere University), Matti Nykter(Tampere University), Sofie H. Tolmeijer(University of British Columbia), Emmy Boerrigter(Radboud University Nijmegen), Niven Mehra(Radboud University Nijmegen), Nielka P. van Erp(Radboud University Nijmegen), Bram De Laere(Karolinska Institutet), Johan Lindberg(Karolinska Institutet), Henrik Grönberg(Karolinska Institutet), Daniel Khalaf, Matti Annala(University of British Columbia), Kim N.(BC Cancer Agency), Alexander W. Wyatt(University of British Columbia)
Nature Communications
February 28, 2024
10.1038/s41467-024-45475-w
Cited by 114Open Access
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Abstract

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

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