Localized breast cancer (LBC) embraces multiple genetic mutagenic events during the tumour development. Each mutation, at both gene copy number variant (CNV) and singlenucleotide variant (SNV) levels, may generate distinct cellular subclones within the same tumour, resulting in intra-tumoral heterogeneity (ITH). Although ITH is a risk factor for therapy resistance and relapse, its intrinsic nature at the single-cell level remains obscure. Here, we investigate the genetic mechanism underlying ITH in a cohort of hormone receptor-positive/ HER2- negative (HR + /HER2 – ) LBC.