Palumbo, Lucia (2025) Evaluation cell-free tumour DNA (cftDNA) in the clinical management of colorectal lesions. [Tesi di dottorato]

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Abstract

Background: Colorectal cancer screening programs are effective in reducing incidence and mortality. In Europe, the routinely available test for screening program is FIT and FIT positive (+) patients are referred to colonoscopy. However, about 75.0% of these patients are negative suffering for a not optimized clinical management. Moreover, a not negligible percentage of false positive results dramatically impact on the stratification of high-risk patients increasing the series of patients elected to non-informative colonoscopy. On this basis, the implementation of liquid biopsy in selecting advanced tumour patients for the best therapeutical option has revolutionized the clinical practice. Particularly, peripheral blood become an essential test integrating triage of FIT+ patients may optimize the administration of these patients. To date, liquid biopsy emerges as a dynamic, less invasive and clinically reliable biological source of nucleic acids. Among several analytes isolated by peripheral blood circulating tumour DNA (ctDNA), a component of cell-free DNA (cfDNA), is the target of molecular testing. Of note, cfDNA is a useful diagnostic and prognostic tool in a variety of clinical settings. Given these advantages, liquid biopsy may play a key role in the clinical management of pre-cancerous lesions in FIT+ patients. Here, fragmentomic analysis of liquid biopsy samples has been evaluated to successfully distinguish between pre-cancerous and benign lesions. In addition, the potential impact of “co-founders” impacting on ctDNA relapsing in torrent blood was also investigated. Methods: The investigation of the potential impact of “co-founders” was approached on n= 637 FIT+ patients of the screening program organized by ASL-NA-3-SUD (Naples, Italy). For the evaluation of cfDNA fragments, n=711 FIT+ patients were enrolled in the study. For fragmentation analysis, the QuantiDNA™ assay was used and the performance of QuantiDNA™ test and non-inferiority of an alternative approach (AAP) were assessed too. Results: Evaluating the impact of potential co-founders in n=637 FIT+ patients a single and multiple logistic regression yielded similar results. Crude sensitivity was 75.9% versus adjusted sensitivity of 74.1%, relative risk 0.9761 (0.8516 to 1.1188), risk difference 0.0181 (−0.0835 to 0.1199) and OR 0.9079 (0.5264 to 1.5658). Potential confounding effect from other source of cfDNA plays a pivotal role in the clinical stratification of FIT+ patients. Concerning the evaluation of cfDNA by using QuantiDNA™ assay compared to AAP, the odds ratio was 1.76 (p-value= 0.009). The detection rate of AAP was 15.9% for colorectal neoplasia, 13.0% for advanced adenoma, and 3.0% for CRC. The risk difference between AAP and SOC was -5.07% (95% C.I -9.23, -0.90) for colorectal neoplasia, - 4.02% (95% C.I. -7.89, -0.16) for advanced adenomas, and -1.04% (95% C.I. -3.16, 1.07) for CRC. This data suggests the non-inferiority of QuantiDNA™ assay compared to AAP for the detection and evaluation of cfDNA.

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