Circulating tumor DNA as a prognostic biomarker for long-term survival in de-novo oligometastatic non-small cell lung cancer.

Abstract

e20535 Background: For patients with de-novo oligometastatic non-small cell lung cancer (NSCLC), combining local ablative therapy (LAT) with systemic treatment may offer extended survival. However, the imaging-based definition of oligometastatic disease (OMD) includes both patients with limited metastatic potential and favorable response to systemic treatment, as well as those harboring occult micrometastases prone to rapid progression. Prognostic biomarkers are thus critical to guide local and systemic treatment approaches. Although circulating tumor DNA (ctDNA) represents a promising biomarker, early studies have limited follow-up. Therefore, we investigated the prognostic value of ctDNA for long-term survival beyond 5 years in this patient population. Methods: This prospective study included patients with plasma liquid biopsy performed at the time of metastatic NSCLC diagnosis, treated between 2014 and 2019. ctDNA was analyzed using the validated ResBio ctDx-Lung assay, which targets up to 23 genes and enables the sensitive detection of variant allele frequencies (VAF) >0.1%. Patients ≤5 disease sites on imaging were classified as having OMD, other as polymetastatic disease (PMD). Results: Among 623 patients, 103 (16.5%) had OMD, and 520 (83.5%) had PMD. Overall, ctDNA was detected in 405 patients (65.0%). Patients with OMD were less likely to have ctDNA detected (39.8% vs. 70.0%; p<0.001), and had a significantly lower median VAF (1.1% vs. 2.9%; p=0.012) if ctDNA was detected. The median age was 67 years (range: 27–93). Driver mutations were detected in tumor tissue of 412 (66.1%) patients, most commonly in EGFR (n=171, 27.4%) and KRAS (n=127, 20.4%). Immune checkpoint inhibitors were given in 301 (48.3%), and targeted therapy in 282 (45.3%). Among patients with OMD, 48 (46.6%) received LAT of metastases and primary tumor at diagnosis. After a median follow-up of 68.6 months, 478 deaths were recorded. Median overall survival (OS) was significantly longer in patients with OMD compared to those with PMD (30.8 vs. 16.4 months, p<0.0001). The 5-year OS rate was 31.1% (95% CI: 23.0–42.0) for OMD and 15.0% (95% CI: 12.0–18.8) for patients with PMD. On univariate Cox regression, OMD (HR: 0.57, p<0.001) and driver mutations in tissue (HR: 0.81, p=0.034) correlated with improved OS, whereas ctDNA detection (HR: 1.94, p<0.001) and higher VAF (HR: 1.01, p=0.017) were associated with worse OS. Multivariate Cox regression confirmed the significant association of ctDNA detection (HR: 1.88, p<0.001), OMD (HR: 0.69, p=0.005) and driver mutations (0.77, p=0.008) with OS. Conclusions: Long-term survival beyond 5 years was observed in more than 30% of patients with NSCLC and OMD, with ctDNA detection and maximum VAF demonstrating prognostic value. Integration of ctDNA with radiographic stratification could enhance patient selection for combined local and systemic treatment approaches.