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

   


Authors: De Mattos-Arruda, L.; Ng, C. K. Y.; Piscuoglio, S.; Gonzalez-Cao, M.; Lim, R. S.; De Filippo, M. R.; Fusco, N.; Schultheis, A. M.; Ortiz, C.; Viteri, S.; Arias, A.; Macedo, G. S.; Oliveira, M.; Gomez, P.; Teixidó, C.; Nuciforo, P.; Peg, V.; Saura, C.; Cajal, S. R.; Casas, F. T.; Weigelt, B.; Cortes, J.; Seoane, J.; Reis-Filho, J. S.
Article Title: Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases
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. © De Mattos-Arruda et al.
Keywords: brain metastasis; metastatic breast cancer; personalized medicine; her2-positive; actionable genetic alterations
Journal Title: Oncotarget
Volume: 9
Issue: 29
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2018-04-17
Start Page: 20617
End Page: 20630
Language: English
DOI: 10.18632/oncotarget.25041
PROVIDER: scopus
PMCID: PMC5945519
PUBMED: 29755676
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045521514&doi=10.18632%2foncotarget.25041&partnerID=40&md5=476d151de51843a79ea57936187b69d4
Notes: Article -- Export Date: 1 May 2018 -- Source: Scopus
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MSK Authors
  1. Britta Weigelt
    633 Weigelt
  2. Jorge Sergio Reis-Filho
    639 Reis-Filho
  3. Kiu Yan Charlotte Ng
    155 Ng
  4. Salvatore Piscuoglio
    130 Piscuoglio
  5. Raymond Sear Lim
    57 Lim
  6. Nicola Fusco
    30 Fusco
  7. Leticia De Mattos Arruda
    15 De Mattos Arruda
  8. Anne Maria Schultheis
    38 Schultheis
  9. Maria Rosaria De Filippo
    28 De Filippo
  10. Gabriel De Souza Macedo
    19 De Souza Macedo
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