Journal Article

Genomic profile of advanced breast cancer in circulating tumour DNA

Reis-Filho, Jorge S., Turner, Nicholas C., Walsh-Crestani, Giselle, Lanman, Richard B., Bliss, Judith M., Wilkinson, Katie, Hrebien, Sarah, Banks, Kimberly C., Beaney, Matthew, Bye, Hannah, Wardley, Andrew M., Moretti, Laura, Baird, Richard D., Kingston, Belinda, Roylance, Rebecca, Hubank, Michael, Cutts, Rosalind J., Macpherson, Iain R., Kilburn, Lucy S., Garcia-Murillas, Isaac, Swift, Claire, Ring, Alistair, Kernaghan, Sarah, Faull, Iris

2021

Overview

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2− disease that associate with poor overall survival ( p  = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant ( p  = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA . In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities. Circulating tumour DNA can provide useful information on disease burden. Here, the authors analysed circulating tumour DNA from 800 patients from a breast cancer clinical trial and investigate the subclonal nature of the disease, and identify DNA mutations associated with resistance and poor survival.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 692/308/575 / 692/4028/67/1347 / 692/4028/67/68 / Aged / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomarkers, Tumor - genetics / Biopsy / Breast cancer / Breast Neoplasms - blood / Breast Neoplasms - genetics / Breast Neoplasms - therapy / Circulating Tumor DNA - genetics / Class I Phosphatidylinositol 3-Kinases - genetics / Clinical trials / Deoxyribonucleic acid / DNA / DNA sequencing / Drug Resistance, Neoplasm - genetics / ErbB-2 protein / ESR1 protein / Female / Fulvestrant / Genomics / Genomics - methods / Heterogeneity / Humanities and Social Sciences / Humans / Kinases / MAP kinase / Middle Aged / multidisciplinary / Mutagenesis / Mutation / Mutation hot spots / Patients / Progression-Free Survival / Receptor, ErbB-2 - genetics / Receptors, Estrogen - genetics / Science / Science (multidisciplinary) / Sequence Analysis, DNA / Survival / Tumors