Highlights
•Metastases mostly disseminate late from primary breast tumors, keeping most drivers
•Drivers at relapse sample from a wider range of cancer genes than in primary tumors
•Mutations in SWI-SNF complex and inactivated JAK-STAT signaling enriched at relapse
•Mutational processes similar in primary and relapse; radiotherapy can damage genome
Summary
Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. These include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2-STAT3 pathways.
Significance
These findings have implications for personalized therapy of breast cancer. The late dissemination of cells that seed metastasis or local relapse suggests that the primary tumor genome can proxy for the genome of disseminated cells at the time of first diagnosis, supporting the use of genome sequencing to aid decisions about adjuvant therapy for primary breast cancer. Biopsy and sequencing of metastases may be helpful in some patients because most distant metastases have acquired additional driver mutations not seen in the primary; these often involve potentially actionable genes and cellular pathways. Sequencing local recurrences can distinguish a genuine relapse from a second primary cancer, two scenarios with very different care pathways.
