Despite remarkable progress in medium-term overall survival benefit in the adjuvant, neoadjuvant and metastatic settings, with multiple recent targeted drug approvals, acquired resistance, late relapse, and cancer-related death rates remain challenging. Integrated technological systems have been developed to overcome these unmet needs. The characterization of structural and functional noncoding genome elements through next-generation sequencing (NGS) systems, Hi-C and CRISPR/Cas9, as well as computational models, allows for whole genome and transcriptome analysis. Rapid progress in large-scale single-biopsy genome analysis has identified several novel breast cancer driver genes and oncotargets. The exploration of spatiotemporal tumor evolution has returned exciting while inconclusive data on dynamic intratumor heterogeneity (ITH) through multiregional NGS and single-cell DNA/RNA sequencing and circulating genomic subclones (cGSs) by serial circulating cell-free DNA NGS to predict and overcome intrinsic and acquired therapeutic resistance. This review discusses reliable breast cancer genome analysis data and focuses on two major crucial perspectives. The validation of ITH, cGSs, and intrapatient genetic/genomic heterogeneity as predictive biomarkers, as well as the valid discovery of novel oncotargets within patient-centric genomic trials, encouraging early drug development, could optimize primary and secondary therapeutic decision-making. A longer-term goal is to identify the individualized landscape of both coding and noncoding key Med Res Rev. 2019;39:1205-1227. wileyonlinelibrary.com/journal/med © 2018 Wiley Periodicals, Inc. | 1205 mutations. This progress will enable the understanding of molecular mechanisms perturbating regulatory networks, shaping the pharmaceutical controllability of deregulated transcriptional biocircuits. K E Y W O R D S biomarkers, breast cancer, drugs, intrapatient heterogeneity, next-generation sequencing systems, precision therapy, regulatory networks 1 | INTRODUCTION Over the past decade, Modern Oncology and Pharmacology have been based on linear static experimentation, singlebiopsy tumor analysis, and single-gene transcription. 1 Although breast cancer represents a prime paradigm of advancing progress in targeted and personalized treatment, reflected by improved oncological outcomes, a significant proportion of patients remains at risk of late relapse and death. 2 Currently, conventional research, as well as commercial and funding interest are focused on the concept of static interpatient genetic heterogeneity as an already fruitful approach. 3 Whether scientific perspectives should shift toward promising comprehensive dynamic structural intrapatient genomic heterogeneity, 4-6 as well as temporal regulatory networks controlling gene expression in the human genome 7-9 and nonlinear transcription-based drug development, 10 is currently under debate. Remarkable progress in the integration of next-generation sequencing (NGS) technologies and breakthrough NGS systems into patient-deriv...
