Abstract 1987: Circulating tumor cell-based molecular responses stratify EGFR-TKI efficacy in EGFR-mutant lung cancer patients

Abstract Background: Liquid biopsy offers a minimally invasive alternative to tissue biopsy, enabling therapeutic monitoring, precision medicine-based treatment decisions, and detection of tumor heterogeneity. Circulating tumor cell (CTC) analysis is a promising minimally invasive biomarker for monitoring treatment response and stratifying prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Meanwhile, detection of CTCs in peripheral blood is challenging due to their rarity and the limitations of both marker-dependent and marker-independent isolation techniques, which may compromise sensitivity and specificity. Continuous Centrifugal Microfluidics - Circulating Tumor Cell Disc (CCM-CTCD) enriches heterogeneous CTCs through automated microfluidic extraction and leukocyte depletion without interrupting centrifugation. Method: In this study, 77 EGFR-mutant NSCLC patients treated with EGFR-TKIs were enrolled. CTCs were isolated using CCM-CTCD before and after EGFR-TKI treatment and compared with plasma cfDNA and tissue biopsy for EGFR mutation analysis. CK-positive, CD45-negative CTCs were isolated and visualized using immunofluorescence staining. Patients were categorized as CTC molecular responders or non-responders based on a ≥30% reduction in CTC count from baseline. Progression-free survival (PFS) and tumor burden changes were evaluated. Results: The CCM-CTCD method showed concordance with Cobas® liquid biopsy but demonstrated superior sensitivity in detecting EGFR mutations. Mutational discordance between tissue, plasma cfDNA, and CTCs highlighted tumor heterogeneity. CTC molecular responders had significantly longer median PFS (46.3 vs. 12.2 months) and greater tumor burden reduction (-39.2% vs. -32.2%, p = 0.025) compared to non-responders. Multivariable analysis revealed that CTC molecular response was an independent predictor of improved PFS (HR 0.45, p = 0.023). Additionally, a non-significant trend was observed toward shorter PFS in patients receiving later-line treatments compared to first-line (HR 1.30, p = 0.523), first- or second-generation EGFR-TKIs compared to third-generation EGFR-TKIs (HR 1.59, p = 0.196), and in those with a history of smoking (HR 1.45, p = 0.300). CTC profiling was found to complement traditional methods for identifying genomic alterations and predicting early progression. Conclusion: CTC analysis using CCM-CTCD demonstrates potential as a reliable tool for predicting treatment response and stratifying prognosis in EGFR-mutant NSCLC. Stratifying patients based on CTC molecular response may guide treatment intensification strategies, offering a pathway for risk-adapted precision oncology. Prospective studies are warranted to validate these findings and optimize therapeutic decision-making. Citation Format: Seoyoung Lee, Chaeyeon Kim, Chang Gon Kim, Min Hee Hong, Mina Han, Wonrak Son,Gamin Kim, Minseok Kim, Hye Ryun Kim. Circulating tumor cell-based molecular responses stratify EGFR-TKI efficacy in EGFR-mutant lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1987.