The spatiotemporal evolution of lymph node spread in early breast cancer

Peter Barry, Alexandra Vatsiou, Inmaculada Spiteri, Daniel Nichol, George D. Cresswell, Ahmet Acar, Nicholas Trahearn, Sarah Hrebien, Isaac Garcia-Murillas, Kate Chkhaidze, Luca Ermini, Ian Said Huntingford, Hannah Cottom, Lila Zabaglo, Konrad Koelble, Saira Khalique, Jennifer E. Rusby, Francesca Muscara, Mitch Dowsett, Carlo C. MaleyRachael Natrajan, Yinyin Yuan, Gaia Schiavon, Nicholas Turner, Andrea Sottoriva*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)


Purpose: The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localized and systemic disease is key to understanding breast cancer progression; however, our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data are derived from primary tumors. Experimental Design: In 11 patients with treatment-na€ve node-positive early breast cancer without clinical evidence of distant metastasis, we investigated lymph node evolution using spatial multiregion sequencing (n ¼ 78 samples) of primary and lymph node deposits and genomic profiling of matched longitudinal circulating tumor DNA (ctDNA). Results: Linear evolution from primary to lymph node was rare (1/11), whereas the majority of cases displayed either early divergence between primary and nodes (4/11) or no detectable divergence (6/11), where both primary and nodal cells belonged to a single recent expansion of a metastatic clone. Divergence of metastatic subclones was driven in part by APOBEC. Longitudinal ctDNA samples from 2 of 7 subjects with evaluable plasma taken perioperatively reflected the two major evolutionary patterns and demonstrate that private mutations can be detected even from early metastatic nodal deposits. Moreover, node removal resulted in disappearance of private lymph node mutations in ctDNA. Conclusions: This study sheds new light on a crucial evolutionary step in the natural history of breast cancer, demonstrating early establishment of axillary lymph node metastasis in a substantial proportion of patients.

Original languageEnglish
Pages (from-to)4763-4770
Number of pages8
JournalClinical Cancer Research
Issue number19
Publication statusPublished - 1 Oct 2018
Externally publishedYes


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