Abstract 5902: Quantification of the effect of early-stage cancer on cell-free DNA levels in plasma

Abstract Elevated cell-free DNA (cfDNA) levels are often observed in cancer patients. However, the exact effect of cancer on cfDNA concentration is not fully understood. In order to obtain insight into cfDNA dynamics in the presence of early-stage cancer, we analyze a rich, previously published dataset of cfDNA in healthy individuals and patients with stage I-III lung, breast, colorectal, pancreatic, ovarian, esophageal, stomach and liver cancer. We find that, despite the high variance of cfDNA levels among both healthy individuals and cancer patients, early-stage cancer exhibits a systemic effect resulting in a multiplicative, cancer-type specific increase in cfDNA concentration originating from healthy tissue. For each cancer type, we also observe similar multiplicative increases in the concentration of mutant DNA fragments detected in plasma that do not originate from tumor, providing additional validation that increased cfDNA levels in early-stage cancer originate from healthy tissue and not from the tumor. The magnitude of the multiplicative increase in cfDNA differs greatly between the cancer types considered, ranging from a ∼1.3-fold increase in lung cancer, to a ∼12-fold increase in patients with liver cancer. To determine the mechanism responsible for the increase in cfDNA levels, we employ an additional dataset that reports the cfDNA composition regarding its tissue of origin, in healthy individuals and patients with pancreatic and ovarian cancer. We find that elevated cfDNA levels in cancer patients do not originate from a proportional increase in cfDNA shedding, but from impaired clearance of cfDNA. The impaired cfDNA clearance could stem either from a direct decrease in cfDNA clearance rate in the presence of cancer, or can be due to a saturation effect in the cfDNA clearance mechanism, triggered by smaller increases in cfDNA shedding due to cancer. Our results contribute to the development of quantitative understanding of cfDNA dynamics in the presence of cancer. Citation Format: Konstantinos Mamis, Ivana Bozic. Quantification of the effect of early-stage cancer on cell-free DNA levels in plasma [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 5902.