Milea Timbergen

316 General Discussion The knowledge about desmoid-type fibromatosis (DTF) has grown significantly over the past decades. Various, often patient-initiated, projects have led to more awareness for this rare disease. Today the research community still faces many challenges in DTF research; gathering knowledge about tumour genetics, biology, growth behaviour, and risk prediction. The efficacy of existing treatments are evaluated and the search for novel therapeutic targets continues. Lastly, the impact of the disease on patients’ health-related quality of life (HRQoL) is increasingly acknowledged and incorporated in both research and clinical decision-making. The aim of this thesis was to describe the many faces of desmoid-type fibromatosis, to contribute to the current knowledge of this peculiar disease. Genetics and Molecular Biology DTF is rare with an incidence of 5 patients per million people per year in the Netherlands 1 . Several treatments options are currently available including active surveillance, surgery, and several systemic treatments 2 . In Chapter 2 , we evaluate existing biological evidence for the activity of common cell-signalling pathways in DTF including Wnt/β-catenin, JAK/ STAT, Notch, PI3 kinase/AKT, mTOR, Hedgehog, the oestrogen pathway, and the growth regulatory pathway in order to identify potential therapeutic opportunities. Furthermore, we summarized the results of completed clinical trials studying targeted drug regimens in the DTF setting. The evidence for most of these treatment regimens are based on small sized, retrospective cohort studies with heterogeneous study populations, and the biological rationale for the use of these targeted therapies is often limited. The variable efficacy of systemic treatments in DTF may also be caused by the absence of recommendations on the sequence of systemic treatments in international treatment guidelines 3 . This leaves room for individual physicians to follow their preferred indication for starting systemic treatment and their drugs of choice 4 . Thus many current treatments, administered to DTF patients lack the solid evidence base for efficacy that is preferred. Nevertheless, initiation of systemic treatments in a stepwise fashion, starting with the least toxic agent, is recommended 3 . The current systemic regimens include traditional chemotherapy such as methotrexate alone 5 or combined with vinblastine/vinorelbine 6 , anthracycline-containing regimens (i.e., dacarbazin and/or (liposomal pegylated) doxorubicin) 5, 7 , but also targeted therapies. The later encompasses non-steroidal anti-inflammatory drugs, such as celecoxib or sulindac, alone 8 or in combination with selective oestrogen receptor modulators (i.e., tamoxifen, toremifene, or raloxifene 9-13 ), and tyrosin kinase inhibitors (i.e., imatinib, nilotinib, and 11