Augustus, Elien

Abstract: In order to provide cancer patients with a personalized treatment, molecular understanding of the tumor is indispensable. Today, tissue biopsies are often used to characterize the tumor. However, tissue biopsies face some limitations. Circulating cell-free DNA (cfDNA) in liquid biopsies might overcome these issues. Analyzing cfDNA is a cost-effective, minimal invasive technique that enables repetitive sampling and gives real-time information on the tumor characteristics. The first objective of this thesis was to establish some standardized guidelines on the use of urine samples for cfDNA analysis in the management of cancer patients. We collected urine samples from 39 healthy volunteers and 14 cancer patients. Based on our results, we advise to: (i) isolate cfDNA from the whole urine sample; (ii) store fresh urine samples at 4\ub0C and centrifuge them with a two-step centrifugation protocol as soon as possible after sample collection; (iii) supplement urine samples with a preservative in case the samples cannot be processed immediately after collection, store these samples at room temperature and centrifuge them with a short one-step centrifugation protocol at high speed. The second objective was to investigate the prognostic value of cfDNA in 10 non-small cell lung cancer (NSCLC) patients receiving immunotherapy. We found that NSCLC patients without detectable levels mutated cfDNA in their liquid biopsy samples, had a better clinical outcome compared to patients with detectable levels. We also compared the performance of next-generation sequencing (NGS) for genomic alterations in tissue samples with liquid biopsy samples. We were able to detect gene amplifications in the blood-derived cfDNA of the included NSCLC patients. Furthermore, we identified a resistance mechanism against alectinib in a blood sample of one NSCLC patient. The third objective was to study the role of liquid biopsy for the follow-up of PDAC patients. We studied the cfDNA derived from matched plasma and urine samples of 47 pancreatic ductal adenocarcinoma (PDAC) patients who underwent surgery and 26 metastatic PDAC patients. According to our results, plasma might be a more suitable body fluid than urine when evaluating the levels cfDNA to monitor PDAC patients. Secondly, our data show that the sensitivity of a liquid biopsy test can be increased by combining multiple tumor markers. We also found that cfDNA analysis enables the detection of disease progression in patients whose total tumor volume (primary tumor and metastases) increases. However, the detection of small primary tumors or new metastases can be challenging when using liquid biopsy

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Analysis of blood and urine nucleic acids : the value of liquid biopsy to improve diagnosis, follow-up and monitoring of treatment response of lung cancer and pancreatic cancer patients

Analysis of blood and urine nucleic acids : the value of liquid biopsy to improve diagnosis, follow-up and monitoring of treatment response of lung cancer and pancreatic cancer patients

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Institutional Repository Universiteit Antwerpen