A Multi-Cohort Analysis of Age-Associated Clinical and Transcriptomic Differences in Breast Cancer

Breast cancer incidence increases with age, but the molecular features of cancers arising in older patients remain poorly characterized. We examined the age-associated differences in clinicopathologic characteristics, transcriptional pathways, and tumour microenvironment signatures using clinical and gene-expression data from three large cohorts. Patients were grouped as younger than 45, 45–64, or 65 years and older; the oldest group was further divided into 65–74, 75–84, and 85 years and older. Among the included 6323 patients, those younger than 45 had a higher proportion of hormone-receptor negative subtypes and grade 3 tumours with enrichment of proliferation-related pathways. Comparisons between patients aged 65–74 and 75–84 did not show a consistent shift towards markers of less aggressive tumour biology. Instead, metabolic-related differences such as in oxidative phosphorylation, glycolysis, and mechanistic target of rapamycin complex 1 signalling were noted. Immune cell signature differences were most evident in younger hormone-receptor positive tumours. These findings overall support evaluating tumour biology instead of chronological age in guiding future treatment strategies and research.