The steady, incremental improvements in outcomes for both early-stage and advanced breast cancer patients are, in large part, attributable to the success of novel systemic therapies. In this review, we discuss key conceptual paradigms that have underpinned this success including (1) targeting the driver: the identification and targeting of major oncoproteins in breast cancers; (2) targeting the lineage pathway: inhibition of those pathways that drive normal mammary epithelial cell proliferation that retain importance in cancer; (3) targeting precisely: the application of molecular classifiers to refine therapy selection for specific cancers, and of antibody-drug conjugates to pinpoint tumor and tumor promoting cells for eradication; and (4) exploiting synthetic lethality: leveraging unique vulnerabilities that cancer-specific molecular alterations induce. We describe promising examples of novel therapies that have been discovered within each of these paradigms and suggest how future drug development efforts might benefit from the continued application of these principles.
