Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed whole-exome sequencing data from 457 paired primary tumor and metastatic samples from 136 breast, colorectal and lung cancer patients, including untreated (n=99) and treated (n=100) metastases. Treated metastases often harbored private ‘driver’ mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in untreated lymph node metastases (n=17/29, 59%) and distant metastases (n=20/70, 29%), but less frequent in treated distant metastases (n=9/94, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which we estimated occurred 2–4 years prior to diagnosis across these cancers. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumorigenesis and that metastasis-private mutations are not drivers of cancer spread but instead associated with drug resistance.