Association of Age with Outcomes in Adrenocortical Carcinoma: A Combined Cancer Registry and Multi-Omic Analysis

Background: Given the higher incidence of adrenocortical carcinoma in peri-menopausal women, this study investigates the associations between sex, age, and ACC prognosis. Methods: We analyzed the National Cancer Database (NCDB) for adult patients with ACC (n = 2384) from 2004 to 2022. Overall survival (OS) was the primary endpoint. Patients were stratified by sex and menopausal status (pre- and post-menopausal age of ≤45 and ≥55, respectively). Data from The Cancer Genome Atlas (TCGA) cohort (n = 92) were analyzed to examine clinical characteristics, genetics, transcriptomics, and methylation profiles of primary ACC samples by age group. Results: The analysis of the NCDB cohort revealed that younger men and pre-menopausal women had significantly longer OS compared to older groups. However, age was the only independent variable associated with OS. Using 50 years as the optimal age cutoff, we found no differences in clinical characteristics, rates of pathogenic driver mutations, methylation or gene expression profiles, or enriched molecular pathways in the TCGA ACC cohort by age group. Conclusions: While age ≥50 years is an independent factor associated with shorter OS in ACC, no differences in clinical characteristics or multi-omic profiles were observed by age. These findings suggest that age-related prognosis may be influenced by other factors such as microenvironmental changes or epigenetics.