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We all learned the classic stepwise, monoclonal progression of cancer, yet we regularly see real-world examples that defy this logic. This review in NEJM highlights two Nature articles (1, 2) that compare the evolution of cells at the primary tumor versus sites of metastases in HER2(+) breast cancer. Interestingly, malignant cells at distant sites appear to gain metastatic ability early in tumor development and then leave for locations better suited for their original phenotypes (e.g., RANK expression in the marrow) as opposed to gaining those phenotypes once reaching a new destination. These subpopulations then evolve in parallel with—or divergently from—the primary tumor so may respond (or not) to therapy in different ways. Now how’s that for an evolving understanding of cancer.