Milea Timbergen

11 are currently awaited 45 . If positive, these results will lead to the first officially approved drug for DTF tumours. Despite all these positive scientific advances, determination of the true therapeutic value of the most above-mentioned treatments remains challenging, as many trials only included progressive, inoperable, refractory DTF tumours. In this thesis, we focus on three aspects of DTF. Several studies identified a prognostic role for the CTNNB1 mutation but so far, no biological differences have been found. The first part therefor focusses on the molecular origin and biology of DTF. In this part, we aim to explain the observed clinical behaviour of the different mutations types by identification of biological differences. Due to the rarity of DTF, uniform imaging protocols are lacking, and diagnosis can be challenging. Treatment decisions are depending on symptoms and tumour site and up till now, the CTNNB1 mutation is not incorporated in the clinical decision- making. The second part, deals with simplifying the diagnostic process by the use of radiomics. Furthermore, it focusses on two commonly used treatments: active surveillance and surgery. With low mortality rates and irrelevance of traditional oncology endpoints, the search for novel endpoints in clinical trials continues. The third part encompasses health- related quality of life (HRQoL) describing the disease from a patients’ perspective. Insight into common DTF-related HRQoL-problems will lead to the development of a DTF-specific HRQoL-tool and HRQoL can be used as an endpoint in clinical trials. Part I – Genetics and Molecular Biology Mutations in the CTNNB1 gene cause accumulation of β-catenin in the nucleus and consequently aberrant Wingless (Wnt)/β-catenin signalling 15 . Knowledge about the influence of other signalling pathways in the pathogenesis of DTF is limited. In Chapter 2 , we reviewed the current available literature regarding DTF and common cell signalling pathways such as JAK/STAT, Notch, PI3 kinase/AKT, mTOR, Hedgehog, the oestrogen pathway, and the growth regulatory pathway. Additionally, we described the current evidence for the use of therapies targeting the aforementioned signalling pathways. As the Wnt/β-catenin signalling pathway is one of the most important oncogenic pathways, we aimed to gain more insight into the Wnt/β-catenin signalling pathway in the setting of DTF. Several studies indicate that there is a difference in the clinical behaviour between the different CTNNB1 mutation types (T41A, S45F, and S45P) and wild-type DTF 12, 49-51 . 1