11 The heterogeneous genomic and immune landscapes of lethal metastatic breast cancer

Abstract

Introduction The heterogeneous fates of metastatic breast cancer (MBC) preclude our understanding of both resistance to therapy and escape from cancer immunoediting. Here, we performed a comprehensive molecular analysis of lethal MBC patients (pts), interrogating both the malignant and immune tumour microenvironment (TME) compartments, and T-cell receptor (TCR) repertoires, across multiple metastases (mets). Material and methods Multi-platform profiling of mets (n=182 mets to 22 organs, 5-36 mets/pt), primary tumours (n=6) and ctDNA from body fluids (4.7/pt) in 10 warm autopsies of MBC pts (5 ER+/HER2-, 3 ER+/HER2+, 1 ER-/HER2+, 1 ER-/HER2-), included exome seq (n=86), shallow whole genome seq (n=168), RNA seq (n=61), ultra-deep targeted seq (TS) (n=243), TCRseq (n=70) and IHC (n=102). Stateof-the-art bioinformatics was applied to integrate the data. Results and discussions Mutation (mut) burden landscapes varied between pts (11 579 mut, median 255.41 mut/pt) and across mets within each pt (median 122 mut/met; were greater than TCGA mut burden (median 63.5 mut/primary, p=4.927e-14). Landscape of mut and predicted neo-antigen were dominated by stem (present in all mets/pt) or clade (some mets/pt), but not private (one met/pt). TS data confirmed that all primary tumours contained the clonal ancestors of 10 pts, and characterised ctDNA bathing organs. Copy number alteration profiles were remarkably similar across mets in 9 of the 10 pts, except in a ER+/HER2-pt, whose mets shared a common ancestor (1q gain/16q loss), then early subclonal evolution occurred. Mets were grouped into phylogenic clades that shared common genomic ancestry and accumulated previously unknown mutation signatures. Mets evolved as communities of clones as a fraction of the metastatic stem and clade mutations were sub-clonal. Immune TME was either homogeneous in a particular metastatic clade, or different across mets to a particular organ. Stem and clade clonotypes prevailed across TCR landscape within each pt. TCR repertoires revealed adaptive immune responses to co-evolve with the metastatic genomes. Conclusion The genomic and immune landscapes demonstrate an unprecedented integrated view of the heterogeneous landscape of genomic aberrations, TME features and T-cell adaptive immune responses in lethal MBC.