228 - Circulating Tumor DNA Positivity after Chemoradiation Marks an Imminent High-Risk State in Anal Squamous Cell Carcinoma
Presenter(s)
E. K. Liu1, C. Kostrzewa2, R. Ravella1, F. J. Arturi1, A. Adames1, D. A. Roth O’Brien1, A. Tin3, N. Schauer4, R. Lentz4, V. M. Williams1, J. J. Cuaron1, M. Zinovoy1, M. Reyngold1, M. Weiser5, J. Garcia-Aguilar5, C. H. Crane1, A. Cercek6, R. Tuli7, M. Gönen2, and P. B. Romesser1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 3Natera, Austin, TX, 4Natera, Inc., Austin, TX, 5Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 7USF Health Morsani College of Medicine, Tampa, FL
Purpose/Objective(s): Circulating tumor DNA (ctDNA) measured during and after chemoradiation (CRT) for anal squamous cell carcinoma (ASCC) serves as an early, treatment-responsive biomarker with potential to identify patients at risk of failure. We hypothesized that ctDNA detection after CRT defines a high-risk state preceding rapid clinical progression.
Materials/Methods: Patients with ASCC treated with definitive-intent CRT at two institutions underwent serial ctDNA monitoring using a clinically validated, personalized, tumor-informed 16-plex PCR-NGS sequencing assay (SignateraTM, Natera, Inc). Longitudinal plasma samples for ctDNA testing were collected during CRT and post-treatment (on or after the last day of CRT). Patients were clinically restaged 3-4 months after CRT using digital rectal exam, endoscopy, MRI, and annual cross-sectional imaging. Patients who were ctDNA positive underwent heightened surveillance (directed clinical examination and expedited cross-sectional imaging). Progression-free survival (PFS) and overall survival (OS) were calculated from time of ctDNA detectability and end of CRT, with ctDNA modeled as a baseline and time-varying covariate, respectively. Multi-state modeling was used to evaluate the relationships between treatment end, positive ctDNA test, and progression.
Results:
A total of 1,270 plasma samples from 151 patients were analyzed. Median follow-up was 23 months (range 3-60). Twenty-three (15%) patients had positive post-treatment ctDNA, including 6 patients in the immediate post-CRT window (£42 days from CRT completion) and 17 patients during surveillance (>42 days). The overall probability of a positive test by 12 months post-CRT is 14% (95% confidence interval [CI] 8-20). Treatment failure events were reported in all patients during follow-up: 13 locoregional, 8 distant, and 1 combined failure. Among patients with post-treatment ctDNA positivity, 12-month PFS and OS from the time of ctDNA positivity was 23.5% and 84%, respectively. Median lead-time to radiographic/clinical progression was 2.5 months (95% CI 1.8-12.3). Positive post-treatment ctDNA increased the risk of death 8-fold (hazard ratio [HR] = 7.98, 95% CI 2.2-29, p = 0.002). In patients without positive ctDNA post-treatment, 18-month PFS was 97% (95% CI 92-99). In patients with positive ctDNA at 12 months after CRT, PFS at 18 months was 29% (95% CI 15-56). ctDNA detection at a level greater than 0.1 mean tumor molecules (MTM)/mL was associated with shorter-lead time and time to progression (HR = 8.2, 95% CI 1.1-62, p = 0.04).Conclusion: ctDNA positivity after the completion of definitive intent CRT for ASCC identifies a distinct high-risk state in ASCC characterized by high risk of progression. These findings support ctDNA as an early biomarker to identify patients who may benefit from intensified surveillance or clinical trials assessing risk-adapted therapeutic intervention.