Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion

Ana Lluch, Ana M. González-Angulo, David Casadevall, Agda K. Eterovic, Eduardo Martínez de Dueñas, Xiaofeng Zheng, Ángel Guerrero-Zotano, Shuying Liu, Ramón Pérez, Ken Chen, Jose Ignacio Chacón, Gordon B. Mills, Silvia Antolín, Isabel Blancas, Paula López-Serra, Eva Carrasco, Rosalía Caballero, Aleix Prat, Federico Rojo, Abel Gonzalez-PerezFunda Meric-Bernstam, Joan Albanell

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    2 Scopus citations

    Abstract

    Background: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples. Methods: A total of 57 paired primary and metastatic tumours from GEICAM/2009–03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion. Findings: CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3–29) and 9 (range, 1–38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor–positive and human epidermal growth factor 2 (HER2)–positive tumours (P = 0.006). Conclusions: Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution.

    Original languageEnglish (US)
    Pages (from-to)54-64
    Number of pages11
    JournalEuropean Journal of Cancer
    Volume120
    DOIs
    StatePublished - Oct 2019

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    Keywords

    • Bioinformatics
    • Breast cancer
    • Clinical subtype
    • Clonal remodelling
    • Heterogeneity
    • Intrinsic subtype
    • PAM50

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Lluch, A., González-Angulo, A. M., Casadevall, D., Eterovic, A. K., Martínez de Dueñas, E., Zheng, X., Guerrero-Zotano, Á., Liu, S., Pérez, R., Chen, K., Chacón, J. I., Mills, G. B., Antolín, S., Blancas, I., López-Serra, P., Carrasco, E., Caballero, R., Prat, A., Rojo, F., ... Albanell, J. (2019). Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. European Journal of Cancer, 120, 54-64. https://doi.org/10.1016/j.ejca.2019.07.003