Dynamic Surveillance of Minimal Residual Disease via a Tumor-Informed Circulating Tumor DNA Assay for Outcome Prediction in Small-Cell Lung Cancer: A Prospective Pilot Study

Background: Small-cell lung cancer (SCLC) represents an aggressive malignancy associated with a poor prognosis, underscoring the critical demand for enhanced monitoring methodologies. Circulating tumor DNA (ctDNA) constitutes a promising non-invasive biomarker; however, reports employing highly sensitive, tumor-informed assays in SCLC remain scarce. This investigation aimed to assess the clinical utility of a personalized ctDNA monitoring strategy for predicting therapeutic outcomes and resistance in SCLC patients. Methods: This prospective, observational study enrolled patients diagnosed with unresectable SCLC. Whole exome sequencing was conducted on baseline tumor specimens to design customized 16-plex multiplex PCR panels. Serial blood samples were obtained at baseline, at six-week intervals during treatment, and upon disease progression. Detection of ctDNA-based minimal residual disease (MRD) was performed using a tumor-informed assay (Huajianwei® bespoke MRD) with ultra-deep sequencing. Results: Among seven evaluable patients, the baseline ctDNA-MRD positivity rate was 100%. A significant positive correlation was observed between baseline ctDNA levels and radiographic tumor burden (r = 0.821, P = 0.034). Longitudinal analysis indicated that patients exhibiting an early decline in MRD levels (n=5) demonstrated a trend toward superior progression-free survival (PFS) compared to those with an MRD increase (n=2) (P = 0.0665, hazard ratio (HR) = 0.24 (95% CI: 0.02 - 3.19)). Notably, elevation in MRD preceded radiographic progression by as much as 135 days in certain instances. Conclusions: Tumor-informed ctDNA-MRD monitoring effectively mirrors tumor burden and offers early prediction of treatment response and clinical outcomes in SCLC. ctDNA kinetics may serve as a crucial prognostic indicator, presenting the potential to inform personalized management approaches and facilitate earlier therapeutic interventions compared to conventional imaging techniques.