Positive ctDNA predicts metastatic progression in MIBC after trimodality therapy

Plasma circulating tumour DNA (ctDNA) can act as a biomarker for the early detection of metastatic progression in patients with muscle-invasive bladder cancer (MIBC) treated with bladder-sparing trimodality therapy (TMT), suggests a study.

“Plasma ctDNA identified metastatic progression with high sensitivity and specificity and a substantial positive lead time compared with radiographic imaging,” the investigators said.

Thirty-two patients with at least one post-TMT ctDNA measurement prior to disease recurrence were included in this retrospective analysis. They were stratified as post-TMT ctDNA (+) or (‒) and assessed for metastasis-free survival (MFS) and recurrence-free survival (RFS) using Kaplan-Meier and Cox regression methods. The median follow-up was 181 days after the first post-TMT ctDNA measurement.

Of the patients, four (12.5 percent) were ctDNA (+) and 28 (87.5 percent) were ctDNA (‒). Three of the ctDNA (+) patients developed radiographic evidence of metastasis, while all ctDNA (‒) patients did not. [J Urol 2026;215:305-315]

At 6 months after TMT ctDNA surveillance, ctDNA (+) detected all metastatic progression accurately, with a sensitivity of 100 percent and a specificity of 93 percent. In addition, ctDNA-based detection preceded clinical identification of metastasis, with a median lead time of 138 days.

Furthermore, ctDNA (+) status significantly correlated with worse MFS (p<0.0001) and RFS (p<0.0001). Univariate analysis also revealed that ctDNA (+) status was the only variable that significantly predicted worse RFS (hazard ratio, 3.53, 95 percent confidence interval, 1.11‒11.53; p=0.03).

“Based on our findings, a potential workflow for ctDNA-guided post-TMT surveillance can be proposed,” the investigators said.

“For ctDNA (+) patients, surveillance intensification by shortening the interval of imaging or changing the imaging approach (ie, switch from CT to positron emission tomography) may provide an opportunity for earlier detection of metastatic progression, which can be salvaged by metastasis-directed therapy (eg, ablative radiation, surgery) or earlier initiation of systemic therapy,” they added.

On the other hand, those with ctDNA (‒) status for a sustained period may undergo imaging surveillance with reduced intensiveness due to their low risk of micrometastatic spread and continuation with complementary ctDNA monitoring, according to the investigators.

“This could represent a path to reduce radiation exposure from diagnostic imaging and lessen the economic burden of bladder cancer care,” they added. [Eur Urol 2014;66:253-262]

Therapy escalation

Ongoing prospective trials (ie, IMvigor011 and MODERN) are examining how postcystectomy ctDNA can guide therapy escalation with immunotherapy. [Future Oncol 2023;19:509-515; Transl Oncol 2023;37:101763]

“Given the equipoise in outcomes between extirpative surgery and TMT, it may be assumed that adjuvant therapy escalation with immunotherapy in post-TMT patients with positive ctDNA would have similar benefits as those in the IMvigor010 subset,” the investigators said.

“Thus, future translational studies evaluating ctDNA in this cohort will be of benefit to understand how ctDNA-based adjuvant therapy intensification may be applied in TMT,” they added.

Future studies may explore the suitability of TMT in patients planned for cystectomy but with clearance of their ctDNA following neoadjuvant systemic therapy or determine whether pre- and post-TMT ctDNA dynamics should guide adjuvant therapy, according to the investigators.