Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases
De Mattos-Arruda, Leticia (Memorial Sloan Kettering Cancer Center)
Ng, Charlotte K. Y. (Department of Biomedicine, University of Basel, Basel, Switzerland)
Piscuoglio, Salvatore (University Hospital Basel (Basilea, Suïssa))
Gonzalez-Cao, Maria (Grup Quirónsalud (Barcelona, Catalunya))
Lim, Raymond S. (Memorial Sloan Kettering Cancer Center)
De Filippo, Maria R. (Memorial Sloan Kettering Cancer Center)
Fusco, Nicola (Memorial Sloan Kettering Cancer Center)
Schultheis, Anne M. (Memorial Sloan Kettering Cancer Center)
Ortiz, Carolina (Vall d'Hebron Institut d'Oncologia)
Viteri, Santiago (Grup Quirónsalud (Barcelona, Catalunya))
Arias, Alexandra (Vall d'Hebron Institut d'Oncologia)
Macedo, Gabriel S. (Memorial Sloan Kettering Cancer Center)
Oliveira, Mafalda (Vall d'Hebron Institut d'Oncologia)
Gómez, Patricia (Vall d'Hebron Institut d'Oncologia)
Teixidó, Cristina (Grup Quirónsalud (Barcelona, Catalunya))
Nuciforo, Paolo (Vall d'Hebron Institut d'Oncologia)
Peg, Vicente (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Saura Manich, Cristina (Vall d'Hebron Institut d'Oncologia)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Tresserra Casas, Francesc (Grup Quirónsalud (Barcelona, Catalunya))
Weigelt, Britta (Memorial Sloan Kettering Cancer Center)
Cortés, Javier (Universitat Autònoma de Barcelona. Departament de Medicina)
Seoane Suárez, Joan (Institució Catalana de Recerca i Estudis Avançats)
Reis-Filho, Jorge S. (Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center)

Date:	2018
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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Metastatic breast cancer ; HER2-positive ; Brain metastasis ; Actionable genetic alterations ; Personalized medicine
Published in:	Oncotarget, Vol. 9 (april 2018) , p. 20617-20630, ISSN 1949-2553

DOI: 10.18632/oncotarget.25041
PMID: 29755676

14 p, 4.6 MB

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