Abstract B20: Prolonged time to clearance of circulating-tumor DNA from patients with limited-stage small-cell lung cancer is associated with inferior progression-free and overall survival
Authors: Cann Christopher , Kopparapu Prasad , Yan Yingjun , Muterspaugh Anel , Chen Heidi , Zhao Zhiguo , York Sally , Horn Leora , Ancell Kristen , Wyman Kenneth , Bertucci Caterina , Shaffer Tristan , Hodson Lauren , Garg Kavita , Hosseini Seyed Ali , Lim Lee , Lovly Christine M. , Iams Wade 
Published: June 2020

Abstract
Introduction: Despite recent incremental advances, patients with small-cell lung cancer (SCLC) continue to have a poor prognosis, with a median overall survival (OS) of 12-20 months in limited-stage disease (LS-SCLC) and approximately 12 months in extensive-stage disease (ES-SCLC). In an attempt to improve the detection and monitoring of SCLC, assays of circulating tumor DNA (ctDNA) via blood-based next-generation sequencing (NGS) have been validated. In this study, we used a blood-based 14 gene SCLC ctDNA NGS panel to evaluate the prognostic significance of the diagnostic maximum ctDNA variant allele frequency (VAF), diagnostic mean ctDNA VAF, and time to ctDNA clearance while on first-line therapy.
Design: In our previous work, we developed a ctDNA assay to sequence 14 genes (TP53, RB1, BRAF, KIT, NOTCH1-4, PIK3CA, PTEN, FGFR1, MYC, MYCL1, and MYCN) that are commonly mutated in SCLC. A total of 104 plasma samples were analyzed from a cohort of 14 patients with LS-SCLC who completed definitive chemoradiation (n=13) or surgical resection (n=1) and had an end-of-treatment blood collection within nine weeks (mean 10.5 days, range 0-63 days) of completion of definitive initial therapy. We used a Cox Proportional Hazards model to estimate the hazard ratio (HR) for progression-free survival (PFS) or death based on the diagnostic maximum ctDNA VAF, diagnostic mean ctDNA VAF, and time to ctDNA clearance on first-line therapy.
Results: In our 14-patient cohort, we did not observe any association between progression or death and maximum diagnostic ctDNA VAF (PFS HR: 1.01, CI 0.97-1.05; OS HR: 1, CI 0.95-1.04) or mean diagnostic ctDNA VAF (PFS HR: 1.01, CI 0.94-1.08; OS HR: 0.99, CI 0.91-1.07). Of the specific mutations representing the maximum diagnostic ctDNA VAF, TP53 represented 14.2% (n=2), while the remaining included RB1 associated mutations (n=5), PIK3CA (n=1), MYCL1 amplification (n=1), or no ctDNA at diagnosis (n=5). Among patients with clearance of ctDNA during first-line therapy (n=9), delayed time to ctDNA clearance was associated with inferior PFS (HR 1.1, CI 1.01-1.19) and OS (HR 1.07, CI 1.01-1.15), with median time to clearance of 63 days (range 29-92 days). Notably, 3 patients cleared ctDNA on their first on-treatment draw at approximately 30 days (29, days, 29 days, and 32 days). These patients have had no evidence of relapse and all remain alive since the start of first-line treatment (1467, 965, and 383 days of follow-up). Of the patients who had disease recurrence, the median time to clearance on first-line therapy was 65 days and median time to progression was 249 days, with all but 1 patient succumbing to their disease (median OS 437 days).
Conclusion: In patients with LS-SCLC, prolonged time to ctDNA clearance during first-line therapy is associated with inferior PFS and OS. Larger patient cohorts are needed to validate this finding.
Citation Format: Christopher Cann, Prasad Kopparapu, Yingjun Yan, Anel Muterspaugh, Heidi Chen, Zhiguo Zhao, Sally York, Leora Horn, Kristen Ancell, Kenneth Wyman, Caterina Bertucci, Tristan Shaffer, Lauren Hodson, Kavita Garg, Seyed Ali Hosseini, Lee Lim, Christine M. Lovly, Wade Iams. Prolonged time to clearance of circulating-tumor DNA from patients with limited-stage small-cell lung cancer is associated with inferior progression-free and overall survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B20.