The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer. [Display omitted] •Genomic and transcriptomic landscapes for 10 lethal breast cancers•Within a patient, metastases group in limited clades with shared genomic ancestry•Tumor immune microenvironments across metastases are not uniform•Phylogenetic trees are correlated with TIL-TCR trees across metastases De Mattos-Arruda et al. profiled multiple metastases from autopsies of patients with therapy-resistant breast cancer, showing that multi-clonal spreading occurs in a small number of founder events. The analysis characterizes predicted neo-antigen landscapes, tumor microenvironments, and accumulation of HLA LOH. T cell immune responses appear to co-evolve with metastatic cancer genomes.