Milea Timbergen

198 Discussion This meta-analysis uniquely combined the IPD of seven studies to determine the effect of the CTNNB1 mutation type on recurrence rate in a cohort of surgically-treated DTF patients, who did not receive any additional perioperative therapy for their primary tumour. Although active surveillance is advocated in asymptomatic patients, a substantial number of patients still receive surgical treatment for their DTF during their course of disease 10, 36 . Reported recurrence rates after surgical treatment remain high, between 20% and 68%, and highlight the need for prognostic factors to predict recurrence, to inform patients and to explore strategies to reduce recurrence risk in high risk groups 14, 24, 30, 37-39 . Tumour site, age at onset, and CTNNB1 mutation type are most frequently mentioned as important prognostic factors 14, 40 . Although several studies have reported that CTNNB1 mutation type had no prognostic value for recurrence compared to WT DTF, others have identified a correlation between the CTNNB1 S45F mutation and a higher risk of recurrence 15, 20, 24, 25, 41, 42 . This study showed that CTNNB1 mutation type is indeed relevant for recurrence, and the observed risk of recurrence was highest for S45F tumours, although the association was not statistically significant (p = 0.082). We also found that tumour size is a mediator for recurrence rate. The findings of this study are remarkable since none of the included studies found a significant correlation between recurrence and tumour size, and did not identify size as a prognostic marker recurrence 20, 22, 41-43 . However, others did report that tumour size is an independent predictor of recurrence (Crago et al., p = 0.004) or event free survival (Huang et al., p = 0.006), but they did not adjust for CTNNB1 mutation type 44, 45 . Other larger series, not included in this meta-analysis because they did not meet our inclusion criteria or used overlapping patient cohorts, did not find a correlation between tumour size and progression free survival 31 , time to recurrence 19 , mutation type 34 , and progression or recurrence 30 . Although the variable tumour size is prone to inter-observer and intra-observer variability, the current multivariable model suggests that both tumour size and mutation type should be considered as predictors for recurrence in patients with primary, extra-abdominal, surgically treated DTF. Tumour site, especially the extremity, is reported as a significant prognostic factor for recurrence in the univariable analysis of multiple studies. However, this statement often does not hold in the multivariable analysis 19, 24, 37, 45 . These conflicting results could be explained by the fact that most of these studies comprise relatively small case series or cohort studies and include patients who received neoadjuvant/adjuvant chemotherapy, or radiotherapy, which influences the recurrence rates and impairs the assessments of the true prognostic value of these parameters 46 . The current study shows that a tumour located in one of the 7