Circulating tumor DNA informs response-adapted bladder preservation in muscle invasive bladder cancer: an integrated analysis of the RETAIN trials

Circulating tumor DNA informs response-adapted bladder preservation in muscle invasive bladder cancer: an integrated analysis of the RETAIN trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Circulating tumor DNA informs response-adapted bladder preservation in muscle invasive bladder cancer: an integrated analysis of the RETAIN trials Pooja Ghatalia, Eric Ross, Li Zhang, Alexander MacFarlane, Matthew Zibelman, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9181680/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Muscle-invasive bladder cancer (MIBC) is traditionally managed with neoadjuvant chemotherapy followed by radical cystectomy. Although bladder preservation offers substantial quality-of-life advantages, clinically validated biomarkers to guide organ-sparing strategies are lacking. Here, we report results from RETAIN-2, a phase II trial evaluating neoadjuvant AMVAC plus nivolumab followed by response-adapted management, alongside an integrated tumor-informed circulating tumor DNA (ctDNA) analysis spanning 111 patients across RETAIN-1 and RETAIN-2. Whereas prior ctDNA studies in MIBC have been limited to cystectomy- or chemoradiation-based paradigms and largely limited to binary assessment at discrete timepoints, this integrated analysis uniquely captures longitudinal ctDNA dynamics in patients forgoing any immediate definitive local therapy, representing the largest prospective ctDNA dataset in any bladder-preservation trial. RETAIN-2 met its primary endpoint, with 70% of patients metastasis-free at 2 years. The Kaplan–Meier analysis estimated 2-year MFS was 83.5% and 68% of active surveillance patients remained metastasis-free with intact, non-irradiated bladders. Baseline and post-treatment ctDNA positivity were strongly associated with inferior metastasis-free and overall survival. Critically, ctDNA-negative patients managed with active surveillance had outcomes comparable to those undergoing cystectomy (24-month MFS 91% vs. 84%; OS 97% vs. 89%), providing the first prospective evidence that ctDNA negativity can identify patients who safely avoid radical cystectomy without compromising metastatic control. Importantly, plasma ctDNA reflected systemic metastatic risk rather than intravesical disease burden, underscoring the need for complementary bladder-directed surveillance. These results establish ctDNA as a clinically actionable biomarker for response-adapted organ preservation in MIBC. Trial registration number: NCT02710734 Health sciences/Medical research/Biomarkers/Diagnostic markers Biological sciences/Cancer Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTablesandFigures.docx Supplementary Tables and Figures RETAIN2protocol.pdf Clinical Trial Protocol Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9181680","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":613337791,"identity":"f7290981-6406-4588-8a53-f7d0abf4092d","order_by":0,"name":"Pooja 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