Abstract 1961: Analysis of lung cancer clinical characteristics using cell-free DNA fragmentomes

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Abstract Liquid biopsy approaches provide an opportunity for both cancer detection and clinical assessment in a non-invasive manner. Here we apply a blood-based lung cancer screening test to 578 individuals diagnosed with lung cancer through a real-world diagnostic prospective trial (LEMA, NCT02894853). Pre-treatment plasma samples were processed through the DELFI assay, a validated cell-free DNA (cfDNA) test based on a locked machine learning analysis of genome-wide fragmentation patterns. Clinical data, including tumor stage (I=165, II=60, III=147, IV=206), histologic subtypes, lymph node invasion, comorbidities, medications, smoking history, treatment type and overall-survival data were collected from all patients. Tissue molecular profiling was performed to identify actionable alterations in driver oncogenes. Genome-wide cell-free DNA fragmentome analyses revealed that LEMA patients had similar chromosomal gains (1q, 3q, 5p, 8q) and losses (3p, 4q, 5q, 10q, 13q) to lung cancer patients collected in TCGA (LUAD and LUSC) and L101 trial (NCT04825834), suggesting the landscape of cfDNA alterations are consistent with other lung cancer studies in Europe and the United States. DELFI fragmentation scores were significantly different amongst both tumor stage (p<0.0001, kruskal-wallis) and lymph node invasion (p<0.0001, kruskal-wallis), exhibiting progressively higher scores with increasing disease burden. Lung adenocarcinoma displayed lower DELFI scores compared to squamous cell carcinomas, while small-cell lung cancer cases presented the highest scores among all lung cancer subtypes. Stage III patients not eligible for surgery with curative intent (n=96) had significantly higher DELFI scores compared to surgery-eligible stage III patients (p=0.02, Wilcox rank-sum).Localized cancer cases (I-III) experiencing cancer relapse after complete surgical resection also showed significantly higher DELFI scores compared to patients who did not experience relapse (p<0.01, log-rank). Metastatic cancer patients, treated with chemotherapy, immunotherapy or targeted therapy had a median overall survival of 8.7 months. For all these treatment types, patients with low DELFI score at baseline (below the median) had longer overall-survival (OS) compared to patients with high DELFI score (above the median p<0.01, log-rank). Neither systemic comorbidities nor medications were found to significantly alter DELFI scores amongst groups (q>0.05, Wilcox rank-sum) and cancer cases driven by oncogenic alterations showed equivalent DELFI scores to cases without any driver mutation detected by tissue profiling. Overall, this study reveals that DELFI fragmentomes can be used as prognostic biomarkers, similarly in lung cancer patients from US and European populations. DELFI scores increase with stage and tumor burden, predict survival, and are not altered by mutational status, comorbidities, or medications. Citation Format: Milou Schuurbiers, Zachary L. Skidmore, Paul van der Leest, Jamie E. Medina, Garrett Graham, Tony Wu, Jacob Carey, Alessandro Leal, Bryan Chesnick, Kim Monkhorst, Nicholas Dracopoli, Robert B. Scharpf, Victor E. Velculescu, Daan van den Broek, Michel van den Heuvel, Lorenzo Rinaldi. Analysis of lung cancer clinical characteristics using cell-free DNA fragmentomes [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 1961.

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