Longitudinal monitoring for post-surgical molecular residual disease in patients with stage I–IIIB melanoma using a whole-genome sequencing–based ctDNA assay.

Abstract

9577 Background: Circulating tumor DNA (ctDNA) is a novel biomarker for detecting molecular residual disease (MRD) and monitoring recurrence risk in melanoma. Personalized, tumor-informed ctDNA assays may enable highly sensitive and specific longitudinal detection of disease burden following curative-intent surgery. Here, we evaluate the prognostic value of whole-genome sequencing (WGS)-based ctDNA detection in patients with resected stage I–IIIB melanoma. Methods: This was a retrospective analysis of residual samples from a deidentified real-world dataset. Clinicopathologic information was collected from Natera’s commercial database under an IRB-approved protocol (#20-049-ALL). Patients with stage I-IIIB melanoma who underwent surgery between March 2018 to May 2023 were included. Whole genome-based ctDNA assays (Signatera Genome, Natera, Inc.) were designed from the respective patients’ matched tumor and normal WGS data. ctDNA was subsequently tracked in the patients’ longitudinal blood samples, which were collected postoperatively until recurrence/end of follow-up. The correlation between ctDNA status post-definitive treatment and recurrence-free survival (RFS) was assessed using Cox regression analysis with a time-dependent covariate and the Kaplan-Meier method. Results: A total of 103 patients with stage I-IIIB melanoma and residual material available for testing were included with a median of 6 tests per patient (range: 1–23) and a median of 91 days between ctDNA tests. Median follow-up was 25.1 months (range: 8.5–73.4). Stage distribution was: 1.9% (2/103) IA, 3.9% (4/103) IB, 7.8% (8/103) IIA, 39.8% (41/103) IIB, 20.4% (21/103) IIC, 8.7% (9/103) IIIA, and 17.5% (18/103) IIIB, and 38 patients received adjuvant treatment, with the majority 87% (33/38) receiving immunotherapy only. ctDNA results during the post-operative treatment window were available for 95 patients. Among the 15 patients who experienced recurrence after completion of definitive treatment, 12 (80%) were ctDNA-positive prior to or within 2-weeks of clinical recurrence (range: 99 days pre - 12 days post-imaging). Among patients who did not experience recurrence, 97.5% (78/80) were serially ctDNA-negative. ctDNA positivity at any time during post–definitive treatment was associated with significantly shorter RFS compared with persistent ctDNA-negativity (HR 55.3; 95% CI 18.7–163.3; p < 0.0001). Analyses are ongoing to characterize ctDNA dynamics (including quantification) and clinical outcomes in an expanded cohort. Conclusions: This analysis demonstrates the prognostic value of longitudinal post-operative ctDNA monitoring for the detection of recurrence in patients with stage I–IIIB melanoma using a WGS-based, personalized, tumor-informed assay with implications for optimizing surveillance and improving clinical outcomes.