Signatera Genome Assay Demonstrates Strong Prognostic Value in Early-Stage Resectable NSCLC

The tumor-informed whole genome-based circulating tumor DNA (ctDNA) assay Signatera Genome demonstrated strong prognostic value for predicting recurrence and guiding therapeutic strategies in patients with early-stage resectable non–small cell lung cancer (NSCLC), according to data presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer.1

Findings showed a strong correlation between ctDNA negativity during the post-surgical molecular residual disease (MRD) window, defined as 3 months post-surgery and prior to adjuvant treatment initiation, as well as improved recurrence-free survival (RFS) and overall survival (OS; P < .0001). The hazard ratios for RFS in the overall patient population and among patients with extracranial relapse were 10.0 (95% CI, 3.9-28.0; P < .001) and 17.0 (95% CI, 5.4-57.0; P < .001).

Conversely, post-definitive treatment ctDNA positivity was strongly associated with reduced RFS across all subtypes (HR, 88.3; 95% CI, 34.8-224.0; P < .0001), including adenocarcinoma (P = .004).

Longitudinal ctDNA testing after completion of definitive therapy detected extracranial relapses with 89.3% sensitivity in all patients. Further detailed analysis of relapses detected post-definitive treatment showed high sensitivity across stages and histologies. Across all stages of adenocarcinoma (n = 19), the assay demonstrated 90% sensitivity; when further broken down by disease stage, sensitivity rates were 100%, 80%, 50%, and 100%for patients with stage IA (n = 9), IB (n = 5), II (n = 2), and III (n = 3) adenocarcinoma, respectively. For those with non-adenocarcinoma across various stages (n = 13), the sensitivity rate was 77%.

“These data demonstrate the value of serial ctDNA testing with Signatera Genome as a prognostic biomarker for RFS in patients with early-stage resectable NSCLC,” Gaston Becherano, MD, a postdoctoral research fellow at Baylor Scott & White Research Institute in Dallas, stated in a presentation of the data.

What Was the Rationale for Investigating the Value of ctDNA Results in Patients With NSCLC?

ctDNA is recognized as a clinically validated biomarker for detecting MRD in NSCLC. Despite often presenting with limited radiographic burden, early-stage, resectable NSCLC demonstrates aggressive biological characteristics, evidenced by a recurrence rate of up to approximately 27% for stage I disease.2 This aggressive nature highlights a critical need for sensitive assays capable of informing prognosis and guiding therapeutic strategies.1 Consequently, Becherano and colleagues conducted a study evaluating the clinical performance of the Signatera Genome assay to determine its prognostic value for risk stratification within this patient population.

What Was the Design of the Study Investigating the Signatera Genome Assay in Patients With Early-Stage NSCLC?

The main study cohort included patients with available ctDNA test results (n = 216), with 197 patients included in the final analyses after exclusions for incomplete clinical information (n = 3), lack of ctDNA test prior to RFS event and/or inclusion criteria not being met (n = 6), multiple primary tumors (n = 7), or less than 3 months of follow-up post-operation (n = 3).

Two main analyses were conducted. The MRD landmark analysis (n = 126) comprised patients with a post-operative ctDNA test performed within 3 months of surgery and prior to adjuvant treatment. The post-definitive treatment analysis (n = 184) included patients after completion of adjuvant therapy(if given) or surgery (if no adjuvant treatment), up to an RFS event.

What Were the Baseline Characteristics of Patients With NSCLC in Whom the Signatera Genome Assay Was Studied?

There were 612 and 856 total ctDNA timepoints in the MRD (n = 126) and post-definitive treatment groups (n = 184), respectively. The median numbers of ctDNA timepoints were 5 (range, 1-11) and 4 (range 1-18) in these respective groups. Of note, the longitudinal serial ctDNA analysis employed a time-dependent variable in a Cox regression analysis.

The median age was 69 years in both the MRD cohort (range, 30-88) and the post-definitive treatment cohort (range, 25-88). Most patients were female (61.9% and 57.1%, respectively) and had adenocarcinoma histology (76.2%; 73.9%). Stage IA disease was most prevalent (54.8%; 60.3%), followed by stage IB (19.0%; 20.7%), stage IIB (11.1%; 10.9%), stage III (11.1%; 6.0%) and stage IIA (4.0%; 2.2%). The median follow-up was 18.8 months for the MRD cohort and 20.5 months for the post-definitive treatment cohort. Adjuvant treatment was administered to 27.8% of patients in the MRD cohort.

What Are the Next Steps for Evaluating the Utility of ctDNA Results in NSCLC?

Given the small number of patients in the MRD ctDNA-positive group who received adjuvant treatment (n = 9), investigators noted that further validation in an expanded cohort is needed to assess ctDNA dynamics in response to adjuvant treatment.

Disclosures: Dr Becheranos hared no disclosures.

References

1. Becherano G, et al. Clinical performance of a tumor informed whole genome based ctDNA assay for predicting recurrence in early-stage resectable NSCLC. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract MA03.02.
2. Okami J, Shintani Y, Okumura M, et al. Demographics, safety and quality, and prognostic information in both the seventh and eighth editions of the TNM Classification in 18,973 surgical cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010. J Thorac Oncol. 2019;14(2):212-222. doi:10.1016/j.jtho.2018.10.002