Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion
Por:
Lluch A, Gonzalez-Angulo A, Casadevall D, Eterovic A, de Duenas E, Zheng X, Guerrero-Zotano A, Liu S, Perez R, Chen K, Chacon J, Mills G, Antolin S, Blancas I, Lopez-Serra P, Carrasco E, Caballero R, Prat A, Rojo F, Gonzalez-Perez A, Meric-Bernstam F, Albanell J
Publicada:
1 oct 2019
Resumen:
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.
Filiaciones:
Lluch A:
Hosp Clin Univ Valencia, Valencia, Spain
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
ISCIII, CIBERONC, Ctr Invest Biomed Red Oncol, Madrid, Spain
Univ Valencia, Valencia, Spain
Inst Invest Sanitaria INCLIVA, Valencia, Spain
Gonzalez-Angulo A:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Casadevall D:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
ISCIII, CIBERONC, Ctr Invest Biomed Red Oncol, Madrid, Spain
IMIM Hosp Mar Med Res Inst, Barcelona, Spain
Hosp del Mar, Med Oncol Dept, Barcelona, Spain
Eterovic A:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
de Duenas E:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Hosp Prov Castellon, Castellon de La Plana, Spain
Zheng X:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Guerrero-Zotano A:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Inst Valenciano Oncol, Valencia, Spain
Liu S:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Perez R:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Hosp Univ Quiron Madrid, Madrid, Spain
Chen K:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Chacon J:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Hosp Virgen Salud, Toledo, Spain
Mills G:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Univ Texas Austin, Dept Syst Biol, Austin, TX 78712 USA
Univ Texas Austin, Inst Personalized Canc Therapy, Austin, TX 78712 USA
Antolin S:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Complejo Hosp Univ A Coruna, La Coruna, Spain
Blancas I:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Hosp Clin San Cecilio, Granada, Spain
Lopez-Serra P:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Carrasco E:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Caballero R:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Prat A:
Hosp Clin Barcelona, Med Oncol Dept, Barcelona, Spain
Rojo F:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
ISCIII, CIBERONC, Ctr Invest Biomed Red Oncol, Madrid, Spain
Fdn Jimenez Diaz, Madrid, Spain
Gonzalez-Perez A:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
Inst Recerca Biomed Barcelona, Barcelona, Spain
Meric-Bernstam F:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Albanell J:
GEICAM Grp GEICAM Invest Canc Mama, Madrid, Spain
ISCIII, CIBERONC, Ctr Invest Biomed Red Oncol, Madrid, Spain
IMIM Hosp Mar Med Res Inst, Barcelona, Spain
Hosp del Mar, Med Oncol Dept, Barcelona, Spain
Univ Pompeu Fabra, Barcelona, Spain
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