Novel tissue- and blood-based biomarkers in Barrett’s Esophagus and esophageal adenocarcinoma
Esophageal cancer is one of the most aggressive tumors ranked as the seventh most common cancer worldwide and sixth in cancer-related mortality overall. The overall 5-year survival in the high-income countries for patients diagnosed with esophageal cancer is less than 20%. The first part of my thesis (chapter 3) focusses on the histopathologic finding of central fibrosis in lymph nodes after chemoradiation in esophageal cancer patients. The aim was to investigate the prognostic value of the number of lymph nodes with central fibrosis in patients with ypTN0 staged disease. I confirmed that in addition to the response by the primary tumor, the regression signs in lymph nodes after neoadjuvant chemoradiation is of great prognostic relevance for patients with advanced esophageal cancer. In the second part of this thesis an exploration was done of liquid biopsies in esophageal adenocarcinoma and its precursor lesion, Barrett’s Esophagus. I focussed on innovative research fields that showed promise for biomarker search in esophageal cancer like transcriptome mapping of circulating tumor nucleic acids and circulating tumor cells (CTCs). A prospective robust biobank of liquid and linked tissue biopsies of patients with esophageal adenocarcinoma was key. Consequently, a high quality multicentric biobank for EAC was founded which is discussed in chapter 4. In chapter 5, an explorative study is described, performing comprehensive exRNA profiling in matched tissue- and plasma samples from patients diagnosed with esophageal adenocarcinoma, high-grade dysplastic Barrett’s Esophagus and non-dysplastic Barrett’s Esophagus. The aim of this explorative study was to discover novel biomarkers for Barrett’s Esophagus and esophageal adenocarcinoma and disease mechanisms of esophageal adenocarcinoma. With this study, a unique dataset of both miRNA and mRNA data of matching disease and healthy tissue samples was generated which is unprecedented for EAC in the current literature. However, this proof-of-concept study could not identify significant candidate non-invasive biomarkers for screening and diagnosis in BE and EAC. Despite inherent phenotypic heterogeneity and differences in cell surface marker expression, most CTC isolation technologies typically use epitope-dependent selection. This necessitates the optimization of epitope-independent CTC methods, enabling the capture of heterogenous CTCs. The aim was to compare a size-dependent and a marker-dependent CTC-isolation method, using spiked esophageal malignant cells in healthy donor blood and blood from patients diagnosed with esophageal adenocarcinoma (chapter 6). An epitope-independent isolation workflow showed consistent and reliable results but did not isolate the same number of CTCs out of whole blood compared to the golden standard. In conclusion, this thesis emphasizes the importance and potential of novel tissue-and blood-based biomarkers in Barrett’s Esophagus and esophageal adenocarcinoma to improve and guide oncologic treatment. Future research should expand their scope on biomarker search for Barrett Esophagus and esophageal adenocarcinoma to patient liquids like blood, plasma, saliva, cytology brushes or exhaled volatile compounds in breath because of their non-invasive character. Special attention should be paid to standardising and benchmarking pre-analytical variables in biobanking for liquids to improve comparability of biodata between research groups.
Medicine and Health Sciences, Esophageal cancer, Barrett's esophagus, liquid biopsies, circulating biomarkers, circulating tumor cells
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Ghent University. Faculty of Medicine and Health Sciences