HGSOC subtypes and treatment interaction : implications for clinical implementation of the PrOTYPE classifier

High-grade serous ovarian cancer (HGSOC) represents approximately 70% of cases of ovarian carcinoma. Investigation into its molecular features led to the discovery of four subtypes of HGSOC, which differ from each other in their gene expression, cellular composition and survival outcomes. However, methods of whole-genome expression clustering have limited the reproducibility of existing subtype-specific research findings as well as being unsuitable for use in individual cases, such as in a clinical setting. PrOTYPE has been developed as a clinical-grade tool for determining the subtype of HGSOC tumours according to expression of a select panel of genes. To investigate the potential utility of determining HGSOC subtype using PrOTYPE in the clinical decision-making process, this thesis has two aims: 1) explore subtype-specific differences in survival outcomes of HGSOC patients treated with the anti-angiogenic drug bevacizumab, to determine whether subtype could be used to inform treatment decisions, and 2) evaluate the subtypes of paired samples collected before and after treatment to platinum and taxane chemotherapy to determine whether exposure to chemotherapy induces changes in subtype. In Aim 1, I found that cases belonging to the immunoreactive C2.IMM subtype generally had improved overall and progression-free survival when treated with bevacizumab. Results also suggested that the C5.PRO subtype may be associated with poorer survival when treated with bevacizumab compared to if treated with platinum and taxane chemotherapy alone. However, these findings could not be validated in independent cohorts; stratification of patients by subtype-specific treatment response in a clinical setting would require further investigation before being implemented. Additionally, a search for novel genes associated with differential treatment outcomes with bevacizumab identified several genes that may be useful in future research on targeted approaches to bevacizumab treatment. In Aim 2, I found that change in subtype from before to after exposure to neoadjuvant chemotherapy occurred in the majority (11/16) of the cases studied; this indicates that pre-chemotherapy subtype cannot be determined from post-chemotherapy samples. Clinical and prognostic significance of HGSOC subtype after chemotherapy remains an area for future investigation. Subtyping using PrOTYPE could be used in the clinical context to guide treatment decisions and evaluate patient prognosis.Medicine, Faculty ofObstetrics and Gynaecology, Department ofGraduat