Abstract 5583: Pre-radiotherapy ctDNA risk-stratifies non-small cell lung cancer patients with oligometastatic disease
Authors: Semenkovich Nicholas P. , Wang Yun E. , Chaudhuri Aadel A. 
Published: April 2023

Abstract
Background: Oligometastatic non-small cell lung cancer (NSCLC) patients may uniquely benefit from personalized therapies via liquid biopsy. Widespread metastatic disease is incurable, yet some patients with oligometastatic disease experience prolonged progression-free survival when treated with aggressive local stereotactic body radiotherapy (RT). Distinguishing patients who would benefit from aggressive RT from those who would benefit from systemic therapies remains a challenge. We hypothesized that pre-RT ctDNA can be used to risk-stratify those with oligometastatic NSCLC and enable earlier personalized approaches when considering systemic therapy versus aggressive local RT.
Methods: A retrospective multi-institutional cohort of 1,487 patients (median age: 65 years, 53% female [n=784], 47% male [n=703]) who were diagnosed with oligometastatic NSCLC was selected. Each patient underwent liquid biopsy ctDNA analysis using the Tempus xF assay (v2) at least once, with a subset of patients undergoing serial sampling at 2-8 timepoints for a total of 1,880 ctDNA assays. 309 of the patients (20%) underwent RT after liquid biopsy was obtained and oligometastatic NSCLC was diagnosed. Outcomes for overall survival (OS) and progression-free survival (PFS) were defined with respect to the initiation time of RT (i.e., time from RT to death, time from RT to progressive disease).
Results: Across all ctDNA assays, 3,520 pathogenic or likely pathogenic (P/LP) variants were identified (1.8 variants/sample, mean). Among patients with a liquid biopsy obtained prior to RT, 48% (n=151) experienced progressive disease and 11% (n=34) died during the study period. Focusing on patients with ctDNA obtained pre-RT, P/LP variants were detected in 74% (n=230) while 26% (n=79) had zero variants detected. Of those with detectable variants, 76% (n=175) had 1-3 variants, while 24% (n=55) had ≥4 P/LP variants detected in ctDNA. Both overall survival and progression-free survival were significantly worse in patients with detectable ctDNA from pre-RT liquid biopsy compared to those without (median OS 16.8 months vs. 25 months; p=0.027, HR=1.65; median PFS 5.4 months vs. 8.8 months; p=0.021, HR=1.57). Remarkably, survival correlated inversely with the number of detected variants from pre-RT liquid biopsies; when patients were stratified by variant quantity, both OS and PFS were significant (OS p=0.045, PFS p=0.003; stratified by 0, 1-3, and ≥4 variants). This finding was also significant in a multivariate Cox proportional hazards analysis (OS HR=1.15, CI 1.04-1.24; PFS HR=1.16, CI 1.06-1.25), but was not significant for parameters such as age at diagnosis or squamous histology.
Conclusions: These data suggest that a ctDNA-informed approach may be a powerful pre-RT biomarker to help risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for RT versus systemic therapy.
Citation Format: Nicholas P. Semenkovich, Yun E. Wang, Aadel A. Chaudhuri. Pre-radiotherapy ctDNA risk-stratifies non-small cell lung cancer patients with oligometastatic disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5583.