Next-generation sequencing has sparked the exploration of cancer genomes, with the aim of discovering the genetic etiology of the disease and proposing rationally designed therapeutic interventions. Driver gene alterations have been comprehensively charted, but the improvement of cancer patient management somewhat lags behind these basic breakthroughs. Recently, large-scale sequencing that focused on metastasis, the main cause of cancer-related deaths, has shed new light on the driving forces at work during disease progression, particularly in breast cancer. Despite a fairly stable pool of driver genetic alterations between early and late disease, a number of therapeutically targetable mutations have been found enriched in metastatic samples. The molecular processes fueling disease progression have been delineated in recent studies and the clonal composition of breast cancer samples can be examined in detail. Here we discuss how these findings may be combined to improve the diagnosis of breast cancer to better select patients at risk, and to identify targeted agents to treat advanced diseases and to design therapeutic strategies exploiting vulnerabilities of cancer cells rooted in their ability to evolve and drive disease progression.
©2020 American Association for Cancer Research.