Abstract 5606: Dynamics of sequence and structural cell-free DNA landscapes in small-cell lung cancer during systemic therapy
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo 
Published: June 2023

Abstract
Background: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis and may not always undergo biopsies for molecular testing, necessitating real-time non-invasive biomarkers of early therapeutic response to ultimately enable timely intervention and improve patient outcomes.
Methods: We performed targeted error-correction sequencing on serial plasma cell-free DNA (n=139) and matched white blood cell (WBC; n=32) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n=16) or immunotherapy-containing (n=17) regimens. Tumor-derived sequence mutations and plasma aneuploidy were tracked longitudinally using a tumor-agnostic WBC DNA-informed approach and combined to evaluate changes in total cell-free tumor load (cfTL). Dynamic changes in cfTL were monitored for each patient to determine circulating tumor DNA (ctDNA) molecular response during therapy.
Results: Longitudinal assessment of cfTL dynamics allowed for the evaluation of molecular response in all patients studied. Overall, 9 patients were classified as molecular responders based on sustained complete elimination of cfTL. For 14 patients, we observed initial molecular responses, followed by cfTL recrudescence. In a subset of 10 patients we observed a distinct pattern of molecular progression characterized by cfTL persistence across all timepoints analyzed. Patients with sustained molecular responses attained longer overall (OS; log-rank p=0.0006) and progression-free (PFS; log-rank p&lt;0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging. Importantly, ctDNA molecular response remained the most significant predictor of OS (molecular response vs molecular progression HR=0.09, 95% CI=0.02-0.42, p=0.002; molecular response f/b recrudescence vs molecular progression HR=0.14, 95% CI=0.04-0.48, p=0.002) and PFS (molecular response vs molecular progression HR=0.02, 95% CI=0.00-0.16, p&lt;0.001; molecular response f/b recrudescence vs molecular progression HR=0.05, 95% CI=0.01-0.26, p&lt;0.001) after adjustment for clinical covariates in a multivariate cox proportional hazards regression model. Analysis of landmark OS and PFS endpoints revealed that molecular responses more accurately predicted OS at 12 (AUC 78.1% vs 73.3%) and 64 months (AUC 87.3% vs 67.6%) and PFS at 3 (AUC 91.7% vs 82.0%) and 12 months (AUC 83.5% vs 78.8%) compared to conventional imaging.
Conclusions: Longitudinal tracking of sequence and structural ctDNA features provide an accurate and rapid approach to track changes in tumor burden and prognosticate outcomes during systemic therapy in patients with SCLC. These findings suggest that therapeutic response monitoring based on combined molecular response criteria may be used to provide guidance on clinical decision making for patients with SCLC.
Citation Format: Lavanya Sivapalan, Wade T. Iams, Zineb Belcaid, Susan C. Scott, Noushin Niknafs, Archana Balan, James R. White, Prasad Kopparapu, Christopher Cann, Blair V. Landon, Gavin Pereira, Victor E. Velculescu, Christine L. Hann, Christine M. Lovly, Valsamo Anagnostou. Dynamics of sequence and structural cell-free DNA landscapes in small-cell lung cancer during systemic therapy. [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 5606.