Prognostic impact and causality of age on oncological outcomes in women with endometrial cancer: a multimethod analysis of the randomised PORTEC-1, -2 and -3 trials

BackgroundNumerous studies have shown that elderly women with endometrial cancer (EC) have a higher risk of recurrence and cancer-related death. It is, however, unclear whether aging is a causal prognostic factor, or whether other risk factors become increasingly common with age. We address to this with a unique multi-method study design using state of the art statistical and causal inference techniques on datasets of three large randomised trials. MethodsData of 1801 women participating in the randomised PORTEC-1, -2 and -3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk EC, 427 high-intermediate risk EC patients and 660 high-risk EC patients. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable a deep learning Causal Inference model called AutoCI was used. FindingsMedian follow-up was 12{middle dot}3 years for PORTEC-1, 10{middle dot}5 years for PORTEC-2 and 6{middle dot}1 years for PORTEC-3. Both overall recurrence and EC-specific deaths significantly increased with age. Moreover, elderly women had a higher incidence of deep myometrial invasion, serous tumour histology and p53abn tumours. Age was an independent risk factor for both overall recurrence (HR 1{middle dot}02 per year, 95%CI 1{middle dot}01-1{middle dot}04; p=0{middle dot}0012) and EC-specific death (HR 1{middle dot}03 per year, 95%CI 1{middle dot}01-1{middle dot}05; p=0{middle dot}0012), and was identified as a significant causal variable. InterpretationThis study shows that advanced age is associated with more aggressive tumour features, and independently and causally related to worse oncological outcomes. Therefore, treatment for endometrial cancer in elderly women should not be de-escalated based on their age alone. FundingThe PORTEC-1, -2 and -3 trials and the associated translational studies are supported by the Dutch Cancer Society.