Circulating tumor DNA as an early response indicator in anal squamous cell carcinoma treated with chemoradiation.

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3518 Background: Definitive chemoradiation (CRT) is a highly effective, organ-preserving treatment for localized anal squamous cell carcinoma (ASCC). However, a subset of patients experience locoregional failure, leading to unfavorable oncologic outcomes despite salvage surgery. Circulating tumor DNA (ctDNA) has emerged as a promising tool for monitoring treatment efficacy and predicting prognosis; however, there is a paucity of studies evaluating the baseline detectability and kinetics of tumor-informed ctDNA assays in ASCC. Methods: Patients with ASCC ( N =88) undergoing definitive CRT provided prospective consent for longitudinal ctDNA monitoring using a personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc.). ctDNA testing was assessed at three key time points: pre-treatment (any time before CRT to within 5 days after initiation), mid-treatment (from >5 days after initiation to <7 days before completion), and post-treatment (>7 days before completion to 42 days after CRT). Surveillance testing continued every three months. Changes in ctDNA levels were analyzed in relation to clinical outcomes. Locoregional failure (LRF) was assessed using competing risk regression, stratified by ctDNA status (positive vs. negative). ctDNA results were also correlated with progression-free survival (PFS). Results: Pre-treatment ctDNA was detected in 79% of patients, with 92% achieving ctDNA-negativity at post-treatment (Table 1). Over a median follow-up of 18 months (IQR 11–26), 7 patients experienced LRF, and 5 experienced distant failure. The cumulative LRF incidence was 0% among patients with ctDNA negativity by mid-treatment. Conversely, 26% of patients with ctDNA positivity at mid-treatment and 61% of patients with ctDNA positivity at post-treatment experienced LRF, respectively. Estimated one-year PFS was 100% for patients who achieved ctDNA negativity by mid-treatment. In contrast, patients who remained ctDNA-positive at mid-treatment and post-treatment had estimated one-year PFS rates of 81% and 44%, respectively, from the date of the corresponding ctDNA test. Among patients who achieved ctDNA negativity but subsequently developed molecular recurrence during the surveillance period ( N =7), all developed disease recurrence. Molecular recurrence predated clinical or radiographic evidence of recurrence in all instances. Conclusions: This tumor-informed ctDNA assay demonstrates high baseline detectability and rapid clearance during CRT, with molecular clearance correlating with favorable outcomes in ASCC. Notably, ctDNA-based detection of molecular recurrence consistently precedes conventional clinical and radiographic indicators of disease recurrence. Further validation in large, prospective cohorts is warranted. Pre -Treatment Mid -Treatment Post- Treatment Positive 61 (79%) 29 (47%) 6 (8%) Negative 16 (21%) 33 (53%) 67 (92%) Unknown 11 26 15

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