Khan, MS;
(2013)
Circulating Tumour Cells and Biomarkers in Neuroendocrine Tumours.
Doctoral thesis , UCL (University College London).
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Abstract
Neuroendocrine tumours(NETs) are heterogeneous with respect to biological behavior. Consequently, prognosis is variable and biomarkers predicting survival or tumour progression are required to inform clinical management. The best available biomarker, histological grade, is assigned using Ki-67 or mitotic count. Agreement between these two indices is implied but analysis of 131 pancreatic and 136 midgut NETs suggested discordances of 44% and 38% respectively. Ki-67 was the superior prognostic marker, making the additional value of mitotic count questionable. Detection of Circulating Tumour Cells(CTCs) using the Cellsearch™ platform requires expression of epithelial cell adhesion molecule(EpCAM). I demonstrated EpCAM expression by immunohistochemistry and detected CTCs in patients with metastatic NETs. In 175 patients, ≥1 CTC was detected in 51%(midgut) and 36%(pancreatic). ≥1 CTC was an independent poor prognostic factor, offering better prognostic value than grade or chromogranin A(CgA). Changes in CTCs 3-5 weeks after commencing therapy were predictive of response and survival, suggesting CTCs could provide an early assessment. Using chip-based capillary-electrophoresis, higher concentrations of circulating free DNA(cfDNA) were found in 88 patients with NETs compared to healthy controls with a correlation between cfDNA quantity and CTCs. Since cfDNA was detected in 25% of cases, more sensitive methods of detection are required before studies are conducted to validate cfDNA as a biomarker and to analyse mutations. The hypervascular nature of NETs suggested that circulating endothelial cells(CECs) might be informative. Using immunomagnetic separation and CD105 phenotyping, CECs were demonstrated in 55 patients. Although not significantly elevated, there was a wider range of CECs in NETs compared to controls. Further studies investigating changes with anti-angiogenic therapy could prove valuable. My research suggests circulating biomarkers, specifically CTCs, provide additional and better prognostic information than grade. Furthermore, detection of CTCs and cfDNA in NETs may allow future studies into molecular analysis, which may enhance understanding of NET pathogenesis.
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