What question did this study set out to answer?

This study aims to determine if longitudinal ctDNA testing can identify patients with high-risk NMIBC who are at increased risk of upstaging and recurrence.

July 4, 2026Open Access

Longitudinal circulating tumour DNA identifies patients at high risk of upstaging and recurrence in non‐muscle‐invasive bladder cancer

Key Points

This study aims to determine if longitudinal ctDNA testing can identify patients with high-risk NMIBC who are at increased risk of upstaging and recurrence.
Cohort study of 52 high-risk NMIBC patients undergoing serial plasma ctDNA testing.
ctDNA was tested at initial presentation and approximately every 3 months during treatment and follow-up.
Whole-exome sequencing was performed on a subset of tumours to evaluate genomic alterations.
33% of patients showed detectable ctDNA, with significant clinical upstaging in 59% of ctDNA-positive patients vs 14% of ctDNA-negative patients (P=0.002).
Among cystectomy patients, 78% of ctDNA-positive patients experienced pathological upstaging compared to 8% of ctDNA-negative patients (P=0.002).
Distant recurrence was observed in 18% of ctDNA-positive patients, while none of the ctDNA-negative patients experienced recurrence.

Abstract

OBJECTIVES: To evaluate whether longitudinal tumour-informed circulating tumour DNA (ctDNA) testing identifies patients at increased risk of upstaging and recurrence in high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A cohort of 52 patients with high-risk NMIBC underwent serial plasma ctDNA testing using a personalised tumour-informed assay. The ctDNA was obtained at initial presentation and at approximately 3-month surveillance intervals during appropriate routine clinical NMIBC therapy and follow-up. A subset of tumours underwent tumour-normal whole-exome sequencing to evaluate genomic alterations associated with ctDNA detection and clinical progression. RESULTS: Circulating tumour DNA was detectable in 17 of 52 patients (33%), including eight of 29 who were Bacillus Calmette-Guérin (BCG)-naïve (28%) and nine of 23 who were BCG-exposed/BCG-unresponsive patients (39%). Most patients received intravesical therapy, including BCG or salvage intravesical chemotherapy, and a subset underwent radical cystectomy. Clinical upstaging occurred in 10 of 17 ctDNA-positive patients vs five of 35 ctDNA-negative patients (59% vs 14%, P = 0.002). Among the 21 patients undergoing cystectomy, pathological upstaging occurred in seven of nine ctDNA-positive patients and one of 12 ctDNA-negative patients (78% vs 8%, P = 0.002). Distant recurrence occurred in three of 17 (18%) ctDNA-positive patients and in none of ctDNA-negative patients. TP53 alterations were enriched in ctDNA-positive tumours, whereas fibroblast growth factor receptor (FGFR3) alterations were more frequent in ctDNA-negative tumours. Limitations include the small cohort and limited follow-up. CONCLUSION: Longitudinal ctDNA testing in high-risk NMIBC identifies a subgroup with higher risk of clinical and pathological upstaging and distant recurrence, often without corresponding cystoscopic or radiographic evidence. ctDNA-positivity reflects aggressive tumour biology and may help identify patients unlikely to benefit from continued intravesical salvage therapy. These findings support further evaluation of ctDNA as a potential risk stratification tool and motivate prospective studies of ctDNA-guided management.

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