Circulating Tumor DNA Dynamics Predict Prognosis of Locally Advanced Non-Small Cell Lung Cancer Patients Treated With Definitive Chemoradiotherapy

Abstract

Locally advanced non-small cell lung cancer (LA-NSCLC) has strong tumor heterogeneity. Postradiotherapy concentration of circulating tumor DNA (ctDNA) has been demonstrated a promising prognostic biomarker of LA-NSCLC and might be helpful in assisting consolidation decision-making. However, it is widely acknowledged that many biomarkers are specific to certain patient populations. Therefore, we performed this prospective study in Chinese patients with LA-NSCLC to evaluate the prognostic role of ctDNA.We consecutively enrolled patients with unresectable LA-NSCLC. Plasma samples were prospectively collected at different time point if obtained (1) baseline (pretreatment), (2) the fourth week during radiotherapy (RT), and (3) one-month post RT. All plasma specimens were subjected to next-generation sequencing panel of 474 cancer-related genes. Plasma samples with at least 1 variant detected were defined as ctDNA+. A landmark analysis was used to assess predictive value of ctDNA clearance at the time point of one-month post RT. Nonparametric test was used to compare ctDNA concentrations among groups. The Kaplan-Meier method was used to estimate survival distributions, Cox model to estimate hazard ratios and confidence intervals, and log-rank test to estimate P value.A total of 35 patients treated with definitive chemoradiotherapy (CRT) were enrolled. The median follow-up from diagnosis was 16 months. At baseline timepoint, 21 patients with ctDNA+ and 14 patients with ctDNA-. For ctDNA+ patients, ctDNA concentration (ng/ml) was significantly higher with increasing clinical stage (stage IIIA vs stage IIIB vs stage IIIC, 0.345 vs 0.580 vs 3.630, P = 0.007). Both progression free survival (PFS) and overall survival (OS) was not significantly different between ctDNA- and ctDNA+ group at baseline timepoint. However, at the time point of one-month post RT, patients with ctDNA- had significantly higher PFS (median: NA vs 7 months; HR 0.205, 95% CI: 0.066∼0.637; P = 0.002) and OS (HR 0.065, 95% CI: 0.008∼0.541; P = 0.001). Kinetic changes in ctDNA concentrations were analyzed in 16 pts with matching baseline and one-month post RT specimens. Of these 16 cases with detectable ctDNA at baseline, 50% (8/16) became undetectable at one-month post RT ("ctDNA clearance"), all these 8 patients were alive and nonrecurrent during the following-up. ctDNA clearance was associated with significantly higher PFS (P = 0.003) and OS (P = 0.016) compared with ctDNA residual patients.For LA-NSCLC receiving CRT, ctDNA concentration was significantly higher with increasing clinical stage (IIIA vs IIIB vs IIIC). Baseline ctDNA+/- seemed not a prognosis factor, whereas ctDNA- or ctDNA clearance at the time of one-month post RT was associated with significantly superior PFS and OS. More enrolled patients are needed to update and validate these results.NCT04014465.