Longitudinal analysis of circulating tumor DNA in localized and metastatic urothelial cancer.
Authors: Adanma Ayanambakkam, Anh B. Lam, Niveditha Popuri, Laxmi Alekhya Mitta, Chao Xu, Sanjay Patel, Michael Cookson, Kelly Lynn Stratton, Minh Duc Phan, Shandy Gosnell, Amber Dawn Kraft Tarantini, Vineetha Finny, Jessica Elliott, Alicia Tyler-Dixon, Jessica Mayberry, Ryan David Nipp, Abdul Rafeh Naqash, Abhishek Tripathi, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

4587 Background: Circulating tumor DNA (ctDNA)-based minimal residual disease has been established as a prognostic biomarker in advanced urothelial carcinoma (UC). Despite the confirmed utility of ctDNA in muscle-invasive non-metastatic UC (nmUC), validation in patients with metastatic UC (mUC) remains unexplored. This study aims to prospectively assess the utility of ctDNA in nmUC and mUC Methods: This prospective study analyzed the results of longitudinal ctDNA testing in a single academic center of patients with UC. A personalized, tumor-informed, multiple PCR-NGS assay (Signatera, Natera, Inc) was used for the detection and quantification of ctDNA. A total of 203 samples were analyzed (median: 3 samples/patient) with a median follow up (mFU) from first ctDNA of 12months. nmUC and mUC patients with &gt;1 ctDNA sample were included for analysis. Disease progression was assessed by clinical/radiographic exams. ctDNA dynamics were categorized based on clearance (ctDNA-), residual (ctDNA+), ≥50% quantitative reduction (≥50%ctDNAr), and &lt;50% quantitative reduction (&lt;50%ctDNAr), at any time point after treatment. We used Cox regression analysis to examine associations between ctDNA and the median time to progression (mTTP). Results: 67 patients (77% male, median age: 70 years,) with nmUC (n=31,46%) and mUC (n=36,54%) were included for analysis. Quantitative reduction in ctDNA samples aligned with radiographic responses in 98.5% (n=200) of samples analyzed. nmUC patients were treated with chemotherapy, immune checkpoint inhibitors (ICPI), and radiation. In nmUC, 74% (n=23) were ctDNA-, and all these patients remained progression free at the time of data analysis (mFU:13 months). Conversely, all ctDNA+ patients (n=8) experienced progression (mTTP:3 months). Among the 38.7% (n=12) of patients who pursued bladder preservation strategies, all ctDNA- patients (n=9) remained progression free (mFU:16 months), while all ctDNA+ patients (n=3) experienced progression (mTTP 3months). In mUC, patients were treated with chemotherapy, ICPI, and enfortumab vedotin. In mUC 86% (n=31) achieved ≥50%ctDNAr and 56% (n=20) achieved ctDNA- status. 23/31 (74%) patients with &gt;50%ctDNAr remained progression free at analysis (mFU:11mo) and mTTP in 8/31 patients was 9.5months. Notably, 5/9 patients with ≥50%ctDNAr who underwent treatment breaks due to adverse events remained progression free (median treatment break: 7 months, mFU:19 months). Patients with ≥50%ctDNAr and ctDNA-had significantly improved mTTP when compared to patients with &lt;50%ctDNAr (HR 0.18, p=0.02 and HR 0.11, p=0.009 respectively). Conclusions: Our findings underscore the potential for personalized assessment of tumor-informed ctDNA dynamics as a promising prognostic biomarker in patients with both localized and metastatic UC. Further prospective studies are necessary to validate utility for ctDNA guided treatment de-escalation in mUC.