Abstract
BACKGROUND: Age is one of the strongest risk factors for breast cancer. Measures of biological age based on DNA methylation have gained popularity for their strong association with risk of many diseases, including cancer, which may help to identify high-risk subgroups for targeted prevention. METHODS: We carried out a systematic review of prospective studies that examined the association of methylation-based markers of ageing with risk of invasive breast cancer in healthy (breast cancer-free) women, published up to May 2023. The search of three databases (MEDLINE, EMBASE and Web of Science) identified 2913 individual abstracts eligible for screening. Risk of bias assessment was conducted using ROBINS-E. RESULTS: Ten prospective studies met the eligibility criteria, and these were heterogeneous in design and findings. The most frequently assessed epigenetic ageing measures were Horvath's first-generation clock, PhenoAge and GrimAge. Four studies reported mainly positive associations, five null associations and one reported a negative association. These associations were generally weak and the results were not consistent across epigenetic ageing measures. CONCLUSION: The summarised evidence is insufficient to support a role for current epigenetic ageing measures to stratify breast cancer risk. PROSPERO Registration: This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023417559).