The study aims to comprehensively characterize the genomic and transcriptomic profiles of ER-positive HER2-negative breast cancer (BC) and their evolution under the pressure of modern targeted therapies. Here, we will integrate multi-omics data from 3 methods including whole exome sequencing (WES), CUTseq, and RNA sequencing (RNA-seq) to investigate 181 ER-positive BC with ~543 tumor samples longitudinally collected from the randomized phase 2 PREDIX Luminal B trial (ClinicalTrials.gov Identifier: NCT02603679). The association between recurrent somatic variants and objective response rate (ORR) based on mammography will be assessed for paclitaxel versus the combination of endocrine treatment and Cyclin D 4/6 inhibitor palbociclib, respectively. Treatment response will also be assessed based on the residual cancer burden index from histopathology. Likewise, other genomic profiling such as mutation signatures, tumor mutation burden, and copy number scores as well as transcriptomic characteristics like intrinsic subtypes, pathway scores and immune cell deconvolution will be calculated, whose predictive values on targeted therapies will be evaluated.