Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. (October 2019)

• Record Type: Journal Article
• Authors: 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 B.; Antolín, Silvia; Blancas, Isabel; López-Serra, Paula; Carrasco, Eva; Caballero, Rosalía; Prat, Aleix; Rojo, Federico; Gonzalez-Perez, Abel; Meric-Bernstam, Funda; Albanell, Joan
• Is Part Of: European journal of cancer. Volume 120(2019)
• Page Start: 54
• Page End: 64
• Publication Date: 2019-10
• Subjects: Breast cancer -- Bioinformatics -- Clonal remodelling -- Clinical subtype -- Intrinsic subtype -- PAM50 -- Heterogeneity; BC Breast cancer -- CCF Cancer cell fraction -- CNA Copy number alteration -- CS Clinical subtype -- ER Oestrogen receptor -- HER2 Human epidermal growth factor receptor 2 -- HER2− Human epidermal growth factor receptor 2 negative -- HER2+ Human epidermal growth factor receptor 2 positive -- HR Hormone receptor -- HR− Hormone receptor negative -- HR+ Hormone receptor positive -- IS Intrinsic subtype -- PR Progesterone receptor -- TN Triple-negative -- VAF Variant allele frequency; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2019.07.003
• Languages: English
• ISSNs: 0959-8049

Abstract

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 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. Highlights: Cancer cell fraction of mutations increases between primary tumours and metastases. There is evidence for clonal remodelling during breast cancer progression. Clinical subtype conversion correlates with clonal heterogeneity in primary tumours.