Abstract
SummaryThe 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.
Highlights
Large-scale studies reporting the genomic and transcriptomic characterization of breast cancer metastasis (Robinson et al, 2013) and whole-genome sequencing of matched primary tumors and metastases (Yates et al, 2017) have identified targets that are enriched in metastases compared with primary tumors
Intra-tumor genomic heterogeneity is seen in early breast cancers, highlighting that complex clonal architectures are already present in primary tumors (Nik-Zainal et al, 2016; Pereira et al, 2016; Shah et al, 2012; Yates et al, 2015)
The nature of the adaptive immune response, the status of immunoediting, and the diversity of the T cell receptor (TCR) repertoire have been analyzed in some early breast cancers (Munson et al, 2016; Park et al, 2016; Wang et al, 2017), but such information for metastatic lesions is lacking
Summary
Large-scale studies reporting the genomic and transcriptomic characterization of breast cancer metastasis (Robinson et al, 2013) and whole-genome sequencing of matched primary tumors and metastases (Yates et al, 2017) have identified targets that are enriched in metastases compared with primary tumors. These studies were generally limited to single metastatic sample
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