The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer

Abstract

Summary 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.

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…In many cases the growth pattern (histological type), the expression of phenotypic biomarkers and the molecular subtype of the primary tumour remains quite stable during progression of disease. Genomic data reveal a high concordance in the mutations and in particular copy number alterations between matched primary and metastatic tumours [71][72][73][74][75]. Thus, there is a clear clonal ancestry during progression, and the early molecular drivers of behaviour and phenotype (e.g., mutations in TP53, PIK3CA, CDH1, GATA3, amplification of MYC, CCND1, ERRB2/HER2) remain prevalent drivers in metastatic deposits [71][72][73][74][76][77][78][79][80].…”

“…Compared to early breast cancer, distant metastases tend to harbour a higher mutation burden and more frequent alterations to driver genes that may confer resistance to chemotherapy or targeted therapy, in particular endocrine therapy [74,75,[78][79][80]. Most notably, activating mutations in ESR1 and amplification of the ESR1 gene region (6q25.1) are rarely observed in primary disease, but are prominent and critical drivers of resistance observed in around 20% of metastases arising following endocrine therapy [73,74,[78][79][80]93,94].…”

“…Mutational signatures found in the primary tumour are also found in metastases; but as with individual gene mutations, the frequencies of individual mutation signatures may also change, with an enrichment in signatures associated with APOBEC enzymatic activity and homologous recombination deficiency being higher in metastases than in primary tumours [75,78,82]. Evidence suggests the acquisition of APOBEC signature maybe a driver of intra tumour heterogeneity and endocrine resistance [17,84,96,97].…”

“…The genomic analysis of matched primary and metastatic samples has revealed fascinating insight regarding the evolution of metastatic disease [73,75,[82][83][84]86,90,[98][99][100]. Such efforts reveal, for example, that driver mutations that are enriched in metastasis are indeed rarely found in the matched primary tumour, indicating they arose either in a small subclone not sampled when the primary tumour was sequenced, or they occurred during the metastatic process after cells had disseminated from the breast (i.e., treatment induced mutations) [39,73,79,80,82,101].…”

“…The genetic relationship between multiple metastases within a patient is exceedingly complex but accruing sequencing data and phylogenetic analysis suggests that all metastases within a patient are genetically related, arising from a common ancestral clone. However, subclonal divergence of metastases is invariably observed within patients: driver and non-driver gene mutations are heterogeneously accumulated in different metastases, subsets of metastases may therefore be more closely related to each other than they are to other metastases, and heterogenous tumour phenotypes (ER positive and ER negative) often coincide with this divergent history [75,84,90].…”