Early signatures of breast cancer up to seven years prior to clinical diagnosis in plasma cell-free DNA methylomes

Abstract Limited studies to date have investigated the detectability of cell-free DNA (cfDNA) markers in asymptomatic individuals prior to a cancer diagnosis. Here, we performed cfDNA methylation profiling in blood of individuals up to seven years prior to a breast cancer diagnosis in addition to matched cancer-free controls (n=150). We identified cfDNA differentially methylated signatures that discriminated cancer-free controls from pre-diagnosis breast cancer cases over five years prior to diagnosis and demonstrate that these markers were reflective of methylation profiles in breast cancer tissue. We report classification of a range of pre-diagnosis breast cancer cases detected at Stage I (area under the receiver operating characteristic curve (AUC) of 0.771), and in cases with a negative mammogram screening within a year of blood collection (AUC of 0.852). This study provides evidence that cfDNA methylation markers indicative of breast cancers can be detected in blood among asymptomatic individuals prior to clinical detection.