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). State-of-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 sub-clonal 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.

Authors:

L De Mattos-Arruda, SJ Sammut, EM Ross, R Bashford-Rogers, E Greenstein, OM Rueda, S Nik-Zainal, F Markowetz, J Seoane, C Caldas

Journal:

ESMO Open

Citation info:

3:a5

Publication date:

1st Jun 2018

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