Genomic profile of advanced breast cancer in circulating tumour DNA

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

doi:10.1038/s41467-021-22605-2

Abstract

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.

Highlights

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, these approaches are limited by geographical and temporal heterogeneity
Tumour autopsy studies have demonstrated the substantial prevalence of geographical heterogeneity, where individual metastases may have different genomic profiles[27], raising uncertainty over whether genomics studies based on single site biopsies have captured the full picture of advanced breast cancer genomics
Using the rich clinical data set associated with the clinical trial, we explore the clinical and pathological associations of advanced breast cancer genomics, and define the processes that generate the genomic diversity of metastatic breast cancer

Summary

Introduction

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, these approaches are limited by geographical and temporal heterogeneity. Tumour autopsy studies have demonstrated the substantial prevalence of geographical heterogeneity, where individual metastases may have different genomic profiles[27], raising uncertainty over whether genomics studies based on single site biopsies have captured the full picture of advanced breast cancer genomics. We define the genomic profile of metastatic breast cancer using ctDNA sequencing from patients within plasmaMATCH, a prospective platform trial leveraging ctDNA analysis in patients with metastatic breast cancer for which the primary outcomes have been published[28]. In this ad-hoc analysis we investigate how the profile of somatic genetic alterations in ctDNA differs from that obtained by tumour tissue sequencing. Using the rich clinical data set associated with the clinical trial, we explore the clinical and pathological associations of advanced breast cancer genomics, and define the processes that generate the genomic diversity of metastatic breast cancer

Methods

Results

Conclusion