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

Fecha de publicación: Fecha Ahead of Print:

Autores de INCLIVA

Participantes ajenos a INCLIVA

  • Gonzalez-Angulo, AM
  • Casadevall, D
  • Eterovic, AK
  • de Duenas, EM
  • Zheng, XF
  • Guerrero-Zotano, A
  • Liu, SY
  • Perez, R
  • Chen, K
  • Chacon, JI
  • Mills, GB
  • Antolin, S
  • Blancas, I
  • Lopez-Serra, P
  • Carrasco, E
  • Caballero, R
  • Prat, A
  • Rojo, F
  • Gonzalez-Perez, A
  • Meric-Bernstam, F
  • Albanell, J

Grupos y Plataformas de I+D+i

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 receptorepositive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). Conclusions(1): 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. (C) 2019 Elsevier Ltd. All rights reserved.

© 2019 Elsevier Ltd. All rights reserved.

Datos de la publicación

ISSN/ISSNe:
0959-8049, 1879-0852

EUROPEAN JOURNAL OF CANCER  ELSEVIER SCI LTD

Tipo:
Article
Páginas:
54-64
PubMed:
31491604

Citas Recibidas en Web of Science: 17

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Keywords

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

Campos de Estudio

Financiación

INSTITUTO SALUD CARLOS III (CB16/12/00481)
INSTITUTO SALUD CARLOS III (PI15/01617)
INSTITUTO SALUD CARLOS III (RD12/0036/0070)

Proyectos y Estudios Clínicos

RED TEMÁTICA DE INVESTIGACIÓN COOPERATIVA

Investigador Principal: ANA LLUCH HERNÁNDEZ

RD12/0036/0070 . INSTITUTO SALUD CARLOS III . 2014

Papel de la heterogeneidad tumoral y la reprogramación dinámica de la célula tumoral en la resistencia a anticuerpos anti-HER2 en cáncer de mama HER2 positivo

Investigador Principal: ANA LLUCH HERNÁNDEZ

PI15/01617 . INSTITUTO SALUD CARLOS III . 2016

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Investigador Principal: ANA LLUCH HERNÁNDEZ

CB16/12/00481 . INSTITUTO SALUD CARLOS III

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