Abstract 4548: The association between tissue genomic alterations and ctDNA shedding in non small cell lung cancer

Abstract Introduction: Tumor burden, stage and metastatic extent are associated with the presence of circulating tumor DNA (ctDNA). However, the association between genomic alterations and the presence of ctDNA remains unclear. Methods: We retrospectively analyzed patients with non-small cell lung cancer (NSCLC) with available Next-Generation Sequencing (NGS) analysis on both tissue and blood treated at the University of Chicago. NGS on tissue biopsies was conducted using the internal Oncoplus assay (168 genes). NGS on blood samples was conducted using the Guardant360 assay. Plasma ctDNA concentration was measured by the Variant Allele Frequency (VAF). Spearman rank correlation coefficient was used to assess the relationship between increasing number of mutations and VAF. Wilcoxon rank-sum test was used to compare the distribution of VAF between subgroups. Results: A total of 221 patients were identified. Adenocarcinoma was the predominant histological subtype, accounting for 89.6% (n=199) of cases. The cohort was predominantly Caucasian (55.4%) and female (66.2%). The median age at diagnosis was 65 years. At the time of index liquid biopsy, 85.1% of patients had metastatic disease. Among the 221 patients, 129 (58.6%) harbored actionable mutations, with EGFR exon 19 or 21 mutations being the most prevalent (n=80, 36.2%). This study found a weak but significant association between VAF and mutation count in the tissue biopsy: for total mutations including both significant alterations and variants of unknown significance (r = 0.146, p=0.032) and for significant mutations only (r = 0.160, p=0.018). These associations were stronger in the KRAS G12C mutated sub-cohort for both total (r=0.471, p=0.036) and significant mutations (r=0.573, p=0.008). Significantly higher ctDNA VAF was observed in TP53 (p=0.006) and STK11 (p=0.05) mutant tumors. Conclusions: Our results showed a correlation between increasing number of alterations and ctDNA shedding. The association was stronger for KRAS G12C mutated tumors. The relationship between genetic changes and ctDNA release is supported by the increased ctDNA VAF seen in TP53 and STK11 mutant tumors. Citation Format: Robert Cameron, Anna Di Lello, Faith Abodunrin, Sulin Wu, Alessandra Esposito, Apameh Pezeshk, Valter Torri, Christine Bestvina, Marina Garassino. The association between tissue genomic alterations and ctDNA shedding in non small cell lung cancer [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 4548.