Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

Muhammed Murtaza, Sarah-Jane Dawson, Katherine Pogrebniak, Oscar M Rueda, Elena Provenzano, John Grant, Suet-Feung Chin, Dana W Y Tsui, Francesco Marass, Davina Gale, H Raza Ali, Pankti Shah, Tania Contente-Cuomo, Hossein Farahani, Karey Shumansky, Zoya Kingsbury, Sean Humphray, David Bentley, Sohrab P Shah, Matthew Wallis, Nitzan Rosenfeld, Carlos Caldas, Nature communications 6, 8760 (2015)
Full text


Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.