Mutability Dependence of Breast Cancer Metastasis and Latency to Recurrence

To evaluate the functional relevance of mutations newly detected in breast cancer metastases, we analyzed genomic data from 662 paired and ~6,000 unpaired primary and metastatic tumors. These analyses indicate that metastasis-specific mutations are frequently acquired post-dissemination, with a disproportionate contribution from APOBEC-mediated mutagenesis. Metastasis-specific mutations converged on a set of pathways that were highly recurrent, distinct from those altered in primary tumors, and dependent on metastatic site. 95% of patients harbored metastasis-specific mutations within a minimum set of 10 pathways. Remarkably, more than half the variation in metastatic latency across patients was explained by the relative timing of mutation acquisition within implicated pathways before versus after dissemination. These findings support a "mutability-dependent" model of metastasis in which functionally consequential mutations accumulate after primary tumor dissemination and contribute to metastatic outgrowth, with latency reflecting the time required for DTCs to acquire the remaining driver mutations needed to achieve metastatic competence.