Recent advancements in genomic technologies have become critical tools for deciphering the genetic complexities of cancer tissues, enabling precision medicine strategies aimed at improving patient clinical outcomes. Here we performed a comprehensive analysis of clinically annotated whole genome and whole transcriptome sequences from 1,364 breast cancer cases. Our investigation provides the most detailed genomic landscapes of breast cancer to date, which allowed us to comprehensively correlate genomic changes with clinical characteristics. Our findings include, but not limited to, (1) whole-genome-based homologous recombination deficiency profiles effectively predict responses to adjuvant chemotherapy and first-line CDK4/6 inhibitor treatment, (2) focal ERBB2 amplifications, often arising via extrachromosomal DNA mechanisms, are strongly associated with a positive response to neoadjuvant chemotherapy. Additionally, our study identified (3) recurrent copy number amplifications linked to patient survival, and (4) whole-genome-based intratumoral heterogeneity profiles that can predict patient survival as well as response to anti-HER2 therapies. Our work underscores the power of highly-annotated whole-genome and transcriptome sequencing of a population-scale cancer cohorts for uncovering clinically relevant genomic mutations and novel molecular targets, thereby advancing precision oncology strategies for breast cancer.