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

Background Numerous 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. Methods Data 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. Findings Median follow-up was 12·3 years for PORTEC-1, 10·5 years for PORTEC-2 and 6·1 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 1·02 per year, 95%CI 1·01-1·04; p=0·0012) and EC-specific death (HR 1·03 per year, 95%CI 1·01-1·05; p=0·0012), and was identified as a significant causal variable. Interpretation This 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. Funding The PORTEC-1, -2 and -3 trials and the associated translational studies are supported by the Dutch Cancer Society.