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

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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 >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 <50% quantitative reduction (<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 >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 <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.