Circulating tumour DNA and extrachromosomal DNA in prostate and bladder cancer: biology, clinical applications and future perspectives.

Abstract

Purpose: To critically appraise circulating tumour DNA (ctDNA) and extrachromosomal DNA (ecDNA) in prostate and bladder cancer, and to define what evidence links the two.

Methods: Narrative review of search period July-September 2026, supplemented by reference-list and citation screening, covering ctDNA and ecDNA biology, detection and clinical application in prostate and urothelial cancer. The ctDNA-ecDNA interface was appraised using a five-tier evidentiary framework (copy-number gain; structural rearrangement; amplicon-graph reconstruction; phasing/optical mapping; orthogonal validation).

Results: In bladder cancer, the phase 3 IMvigor011 trial validated ctDNA-guided adjuvant atezolizumab (disease-free survival [DFS] HR 0.64; overall survival [OS] HR 0.59), while persistently ctDNA-negative patients had 2-year DFS/OS of 88.4%/97.1% without adjuvant therapy. In prostate cancer, ctDNA positivity and androgen-receptor alterations are strongly prognostic (median OS 29.0 vs. 47.4 months; HR 2.0), but no prospective ctDNA-guided interventional trial exists. ecDNA is present in approximately 36% of urothelial carcinomas and drives oncogene amplification, heterogeneity, immune evasion and resistance. Evidence linking the two is indirect and asymmetric: prostate cancer offers stronger longitudinal ctDNA evidence via plasma AR-ecDNA proxy signatures, whereas bladder cancer shows stronger structural evidence from urinary sediment; no structurally validated blood ecDNA has been reported. This evidence derives predominantly from metastatic cohorts (mCRPC, post-cystectomy bladder cancer), with no established role in earlier-stage or minimal-residual-disease settings.

Conclusion: ctDNA is clinically actionable in bladder cancer and prognostic in advanced prostate cancer, whereas ecDNA remains an investigational driver. Structural confirmation of ecDNA in blood, assay standardisation and prospective biomarker-stratified trials are the priorities for the field.