Evaluation of Biomarkers in Ovarian Cancer.

Epithelial Ovarian Cancer (EOC) remains the most lethal of gynaecological cancers with 4295 deaths in 2010 in the UK. There is ongoing research for novel biomarkers as these are needed to improve the management of this disease which is characterised by development of drug resistance. Previous work suggested that cell cycle dysregulation is associated with anticancer drug resistance. Both p57kip2 and cyclinE as key players in cell cycle, were considered as potential markers of chemoresponse and disease progression in EOC in the present thesis. In order to evaluate the utility of biomarkers (p57kip2 and Cyclin E), immunohistochemistry (IHC) was used to assess the expression levels in tissue sections from a cohort of 250 women with a confirmed diagnosis of EOC. This included the establishment of a robust scoring system for the assessment of expression levels of either p57kip2 or cyclin E. In addition, the study involved the setting up of an extensive database of clinico-pathological data for each patient. With appropriate statistical management of the data, associations between expression levels of p57kip2 and cyclin E in relation to disease stage, histological type, prognosis and survival were made to enable the assessment of each parameter as a potential biomarker in EOC. The study observed that high cyclin E levels were associated with poor prognosis in agreement with the literature for other tumour types; however, this did not reach levels of statistical significance to enable predictive modelling. Importantly, the data obtained for p57kip2 revealed that high expression was associated with lower grade, earlier FIGO stage and better prognosis, reaching high levels of statistical significance. Predictive modelling using clinicopathological data and expression levels was used to compute survival and this model is currently being tested and validated (in further work beyond the scope of this thesis). In Stage I EOC where the role of adjuvant chemotherapy on survival remains unclear, p57kip2 expression may help to influence decision making and larger studies are required to explore this further. This study encompassed the largest cohort of EOC patients for the assessment of either cyclin E or p57kip2, according to current literature