Abstract 5100: A next-generation extracellular vesicle and particle-based liquid biopsy for early lung cancer detection

Abstract Background: Early detection of lung cancer (LC) remains a critical unmet need, as most patients are diagnosed at advanced stages when treatment is less effective. The current standard of care for detection, computed tomography lung screening (CTLS), is constrained by limited uptake, emphasizing the need for a more universally accessible approach. Circulating extracellular vesicles and particles (EVPs) offer a minimally invasive source of tumor-derived biomarkers reflective of underlying tumor biology. We developed an EVP-based liquid biopsy assay for LC detection that aims to achieve high sensitivity through detection of vesicles and particles released abundantly by tumor cells and high specificity by assessing multiple cancer-associated biomarkers colocalized on the same EVP surface. Methods: The LC Test, consisting of a predefined biomarker panel and classifier was locked following a training study. A blinded case-control study was conducted using plasma samples from individuals enrolled in a routine LC screening program and from those enrolled in a lung cancer study in those who never smoked. The study included two arms: 1) High-risk participants with a history of tobacco use without evidence of lung cancer (n = 75; 37 Lung-RADS 1, 38 Lung-RADS 2) and participants with lung adenocarcinoma (LUAD) (n = 20; median tumor diameter 1.8 cm), and small-cell carcinoma (SCLC; n=5), and 2) participants who never smoked without evidence of lung cancer (n = 74) and with LUAD (n = 26; median tumor diameter 2.3 cm), and squamous cell carcinoma (LUSC; n= 1). The design enabled evaluation of assay performance for the detection of LCs arising in high and average risk individuals, with strong representation of early-stage disease (71% Stage I/II). Results: Using a pre-specified locked classifier with specificity set to 90%, the LC Test achieved an overall sensitivity of 47.8% for LUAD and 35.3% for Stage I/II disease in high-risk participants. For SCLC, overall sensitivity was 60%. Among those who never smoked, the assay demonstrated 50% overall sensitivity and 31.3% sensitivity for Stage I/II LUAD. The biomarker panel test score correlated with predicted tumor size at blood draw (R = 0.60; p = 0.0048). The smallest detected tumor measured 0.8 cm in diameter. Conclusions: The LC Test enables sensitive and specific detection of early-stage LC in both high-risk individuals undergoing screening and those who never smoked, with incidentally or clinically detected disease. Assay performance approaches that of CTLS, supporting its potential as a minimally invasive complement or, in select settings, as an alternative for imaging-based screening. These findings warrant further evaluation of the LC Test in larger clinical studies. Citation Format: Toumy Guettouche, Caroline Schissel, Daniel P. Salem, Troy B. Hawkins, Aaron Chevalier, Ibukunoluwapo O. Zabrowski, Brittany Grimes, Timothy Santos-Heiman, Nina Insixiengmay, Gabrielle N. Barcaskey, Katherine S. Yang, MacKenzie S. King, Mahmoud M. Bassam, Michael J. Smith, Anish Panda, Travis B. Sullivan, Prasanth Reddy, Dawn R. Mattoon, Kimberly M. Rieger-Christ. A next-generation extracellular vesicle and particle-based liquid biopsy for early lung cancer detection abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5100.