edoc

Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases

De Mattos-Arruda, Leticia and Ng, Charlotte K. Y. and Piscuoglio, Salvatore and Gonzalez-Cao, Maria and Lim, Raymond S. and De Filippo, Maria R. and Fusco, Nicola and Schultheis, Anne M. and Ortiz, Carolina and Viteri, Santiago and Arias, Alexandra and Macedo, Gabriel S. and Oliveira, Mafalda and Gomez, Patricia and Teixidó, Cristina and Nuciforo, Paolo and Peg, Vicente and Saura, Cristina and Ramon y Cajal, Santiago and Casas, Francesc Tresserra and Weigelt, Britta and Cortes, Javier and Seoane, Joan and Reis-Filho, Jorge S.. (2018) Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases. Oncotarget, 9 (29). pp. 20617-20630.

[img] PDF - Published Version
Available under License CC BY (Attribution).

4Mb

Official URL: https://edoc.unibas.ch/68153/

Downloads: Statistics Overview

Abstract

Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes; FGFR2, PIK3CA; and; ATR; , homozygous deletion in; CDKN2A; and amplification in; KRAS; . Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including; ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1; and; TP53; . Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Piscuoglio, Salvatore
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Impact Journals
e-ISSN:1949-2553
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:28 Jan 2019 14:36
Deposited On:28 Jan 2019 14:36

Repository Staff Only: item control page