The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies

Abstract

Whole genome sequencing (WGS) of prospectively collected tissue biopsies of 442 metastatic breast cancer (mBC) patients reveals that, compared to primary BC, tumour mutational burden (TMB) doubled, relative contributions of mutational signatures shifted, and mutation frequency of six known driver genes increased in mBC. Significant associations with pre-treatment were observed as well. The contribution of mutational signature 17 was significantly enriched in patients pre-treated with 5-FU, taxanes, platinum and/or eribulin, whereas the here identified de novo mutational signature I was significantly associated with pre-treatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumours were identified exhibiting either homologous recombination deficiency (13%), high TMB (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides important novel insight into the biology of mBC and identifies clinically useful genomic features for future improvement of patient management.

Tumour-derived extracellular vesicles in blood of metastatic cancer patients associate with overall survival

“…[3][4][5] In addition, tumours evolve over time and treatments while developing drug-resistance mechanisms. 6 From these observations emerge the importance of a biopsy that could provide clinicians with realtime data to facilitate treatment decision-making. In theory, subsequent collections of solid biopsies from multiple sites could be a solution; however, in practice, not all sites are accessible by surgery and such a procedure is highly invasive leading to patient discomfort and health complications.…”

Prediction of breast cancer proteins using molecular descriptors and artificial neural networks: a focus on cancer immunotherapy proteins, metastasis driver proteins, and RNA-binding proteins

“…Patients do not die from their primary breast tumor but as a consequence of metastases. Due to tumor evolution and treatment pressure, the genomic alterations in metastatic BC can differ substantially from the primary tumor [79]. To date, the molecular and microenvironmental determinants of metastasis are largely unknown, as is the timing of systemic spread, hindering effective treatment and prevention efforts [13, 68, 80].…”

High ctDNA molecule numbers relate with poor outcome in advanced ER+, HER2− postmenopausal breast cancer patients treated with everolimus and exemestane

“…Last, our cohort of patients might have a different genomic make-up in metastases than that in primary breast cancer, as shown by the in silico analyses. In that respect, Angus et al (2019) have recently reported on the genomic landscape of MBC and showed more frequent mutations in ESR1, TP53, NF1, AKT1, KMT2C and PTEN in ER+/HER2-metastatic lesions than in primary breast carcinomas. Our targeted assay evaluated three of these genes (ESR1, TP53 and AKT1).…”