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 Mills, Silvia Antolín, Isabel Blancas, Paula López-Serra, Eva Carrasco, Rosalía Caballero, Aleix Prat, Federico Rojo, Abel Gonzalez-Perez & 2 others Funda Meric-Bernstam, Joan Albanell

    Research output: Contribution to journalArticle

    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 1 2019

    Fingerprint

    Breast Neoplasms
    Neoplasm Metastasis
    Neoplasms
    Mutation
    Epidermal Growth Factor
    Paraffin
    Formaldehyde
    Hormones

    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., ... 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

    Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. / Lluch, Ana; González-Angulo, Ana M.; Casadevall, David; Eterovic, Agda K.; Martínez de Dueñas, Eduardo; Zheng, Xiaofeng; Guerrero-Zotano, Ángel; Liu, Shuying; Pérez, Ramón; Chen, Ken; Chacón, Jose Ignacio; Mills, Gordon; Antolín, Silvia; Blancas, Isabel; López-Serra, Paula; Carrasco, Eva; Caballero, Rosalía; Prat, Aleix; Rojo, Federico; Gonzalez-Perez, Abel; Meric-Bernstam, Funda; Albanell, Joan.

    In: European Journal of Cancer, Vol. 120, 01.10.2019, p. 54-64.

    Research output: Contribution to journalArticle

    Lluch, A, González-Angulo, AM, Casadevall, D, Eterovic, AK, Martínez de Dueñas, E, Zheng, X, Guerrero-Zotano, Á, Liu, S, Pérez, R, Chen, K, Chacón, JI, Mills, G, Antolín, S, Blancas, I, López-Serra, P, Carrasco, E, Caballero, R, Prat, A, Rojo, F, Gonzalez-Perez, A, Meric-Bernstam, F & Albanell, J 2019, 'Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion', European Journal of Cancer, vol. 120, pp. 54-64. https://doi.org/10.1016/j.ejca.2019.07.003
    Lluch A, González-Angulo AM, Casadevall D, Eterovic AK, Martínez de Dueñas E, Zheng X et al. Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. European Journal of Cancer. 2019 Oct 1;120:54-64. https://doi.org/10.1016/j.ejca.2019.07.003
    Lluch, Ana ; González-Angulo, Ana M. ; Casadevall, David ; Eterovic, Agda K. ; Martínez de Dueñas, Eduardo ; Zheng, Xiaofeng ; Guerrero-Zotano, Ángel ; Liu, Shuying ; Pérez, Ramón ; Chen, Ken ; Chacón, Jose Ignacio ; Mills, Gordon ; Antolín, Silvia ; Blancas, Isabel ; López-Serra, Paula ; Carrasco, Eva ; Caballero, Rosalía ; Prat, Aleix ; Rojo, Federico ; Gonzalez-Perez, Abel ; Meric-Bernstam, Funda ; Albanell, Joan. / Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. In: European Journal of Cancer. 2019 ; Vol. 120. pp. 54-64.
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    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.",
    keywords = "Bioinformatics, Breast cancer, Clinical subtype, Clonal remodelling, Heterogeneity, Intrinsic subtype, PAM50",
    author = "Ana Lluch and Gonz{\'a}lez-Angulo, {Ana M.} and David Casadevall and Eterovic, {Agda K.} and {Mart{\'i}nez de Due{\~n}as}, Eduardo and Xiaofeng Zheng and {\'A}ngel Guerrero-Zotano and Shuying Liu and Ram{\'o}n P{\'e}rez and Ken Chen and Chac{\'o}n, {Jose Ignacio} and Gordon Mills and Silvia Antol{\'i}n and Isabel Blancas and Paula L{\'o}pez-Serra and Eva Carrasco and Rosal{\'i}a Caballero and Aleix Prat and Federico Rojo and Abel Gonzalez-Perez and Funda Meric-Bernstam and Joan Albanell",
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    TY - JOUR

    T1 - Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion

    AU - Lluch, Ana

    AU - González-Angulo, Ana M.

    AU - Casadevall, David

    AU - Eterovic, Agda K.

    AU - Martínez de Dueñas, Eduardo

    AU - Zheng, Xiaofeng

    AU - Guerrero-Zotano, Ángel

    AU - Liu, Shuying

    AU - Pérez, Ramón

    AU - Chen, Ken

    AU - Chacón, Jose Ignacio

    AU - Mills, Gordon

    AU - Antolín, Silvia

    AU - Blancas, Isabel

    AU - López-Serra, Paula

    AU - Carrasco, Eva

    AU - Caballero, Rosalía

    AU - Prat, Aleix

    AU - Rojo, Federico

    AU - Gonzalez-Perez, Abel

    AU - Meric-Bernstam, Funda

    AU - Albanell, Joan

    PY - 2019/10/1

    Y1 - 2019/10/1

    N2 - 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.

    AB - 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.

    KW - Bioinformatics

    KW - Breast cancer

    KW - Clinical subtype

    KW - Clonal remodelling

    KW - Heterogeneity

    KW - Intrinsic subtype

    KW - PAM50

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    JO - European Journal of Cancer

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