Circulating Tumor DNA as a Biomarker in Oligometastatic Non-small Cell Lung Cancer

Abstract

Selected patients with oligometastatic non-small cell lung cancer (NSCLC) benefit from aggressive local consolidative therapy. We explore the clinical utility of liquid biopsy for circulating tumor DNA (ctDNA) as a biomarker for patients with oligometastatic NSCLC. Patients with metastatic lung cancer underwent liquid biopsy with plasma next-generation sequencing of ctDNA at diagnosis or disease progression using a validated ctDNA assay targeting 23 genes. Oligometastatic state was defined < 5 sites of metastatic disease at initial diagnostic imaging or progression of < 5 sites of disease. Driver alterations were defined by the National Comprehensive Cancer Network guidelines to include EGFR, ALK, ROS1, KRAS, BRAF, MET, RET, HER2, or NTRK. ctDNA detection rates were compared based on clinical and treatment characteristics using Fisher’s exact test. Survival was evaluated using Kaplan-Meier analysis from the time of local consolidative radiation therapy. Among 820 patients with advanced NSCLC, 109 patients (13%) had oligometastatic disease and 711 patients (87%) had polymetastatic disease. Among the oligometastatic cohort, 73 patients (67%) were oligometastatic at initial diagnosis whereas 36 patients (33%) were oligoprogressive. Oligometastatic disease was associated with a lower rate of ctDNA detection compared to polymetastatic disease (52/109, 48% vs 478/711, 67%; p < 0.001). The rate of ctDNA detection was higher among oligometastatic patients with extrathoracic metastases compared to patients with disease confined to lungs, pleura, and/or thoracic lymph nodes (43/79, 54% vs 9/30, 30%, p = 0.031). ctDNA detection among oligometastatic patients was not associated with the presence of brain metastases (p = 0.2), liver metastases (p = 0.6), or prior smoking history (p = 0.7). Among patients with oligometastatic disease, 47% (51/109) underwent consolidative radiation therapy including stereotactic body ablative therapy and conventionally fractionated radiation therapy. Detection of a driver alteration in ctDNA was associated with decreased progression-free survival (HR 2.62, 95% CI 1.27 – 5.43, p = 0.009) following consolidative radiation therapy. In the setting of advanced NSCLC cancer, the rate of ctDNA detection varies according to the number of disease sites and anatomic distribution of disease. ctDNA shows potential as a biomarker for identification of oligometastatic NSCLC patients likely to benefit from local consolidative therapy.