Whole Genome Sequencing-based tumor-informed circulating tumor DNA monitoring for early detection of recurrence in patients with solid tumors.

Abstract

Background: Circulating tumor DNA (ctDNA) assays can transform patient management by enabling molecular residual disease (MRD) detection, prognosis prediction, and treatment monitoring. Here, we report clinical performance of Signatera™ Genome, a whole genome sequencing (WGS)-based ctDNA assay, in a diverse pan-cancer cohort at landmark and longitudinal settings post-definitive treatment.

Methods: We performed a retrospective analysis of 386 patients with one of the following cancers: breast, colorectal, non-small cell lung, melanoma, or renal cell carcinoma. Signatera™ Genome assays, designed with high-quality variants selected from the matched tumor and normal WGS data, were used to detect ctDNA in the associated patients' longitudinal plasma samples collected post-operatively. The correlation between ctDNA-based MRD status and systemic, distant recurrence-free survival (systemic DRFS) was assessed using Cox regression analysis.

Results: In the pan-cancer cohort, landmark analysis at 3 months post-surgery revealed that patients with MRD-positivity had significantly inferior systemic DRFS compared to ctDNA-negative patients (HR: 23.7, p < 0.0001). Additionally, ∼30% improvement in 24-month systemic DRFS was observed among adjuvant-treated MRD-positive patients, whereas MRD-negative patients derived no clear benefit from adjuvant therapy. In the longitudinal setting, MRD positivity anytime post-definitive treatment surveillance significantly correlated with shorter systemic DRFS compared to serial MRD negativity (HR: 104.7, p < 0.0001). Tumor-specific analyses yielded similar findings. Notably, 62% (72/116) of patients had ctDNA detected in the ultra-sensitive range of < 100 ppm.

Conclusions: Our findings underscore the robust clinical performance of the Signatera Genome assay for MRD detection across solid tumors. Its broad applicability and high specificity support its integration into clinical practice and prospective trials.