TY - JOUR
T1 - Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases
AU - De Mattos-Arruda, Leticia
AU - Ng, Charlotte K.Y.
AU - Piscuoglio, Salvatore
AU - Gonzalez-Cao, Maria
AU - Lim, Raymond S.
AU - De Filippo, Maria R.
AU - Fusco, Nicola
AU - Schultheis, Anne M.
AU - Ortiz, Carolina
AU - Viteri, Santiago
AU - Arias, Alexandra
AU - Macedo, Gabriel S.
AU - Oliveira, Mafalda
AU - Gomez, Patricia
AU - Teixidó, Cristina
AU - Nuciforo, Paolo
AU - Peg, Vicente
AU - Saura, Cristina
AU - Cajal, Santiago Ramon y.
AU - Casas, Francesc Tresserra
AU - Weigelt, Britta
AU - Cortes, Javier
AU - Seoane, Joan
AU - Reis-Filho, Jorge S.
PY - 2018/4/17
Y1 - 2018/4/17
N2 - © De Mattos-Arruda et al. 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.
AB - © De Mattos-Arruda et al. 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.
KW - Actionable genetic alterations
KW - Brain metastasis
KW - HER2-positive
KW - Metastatic breast cancer
KW - Personalized medicine
UR - https://ddd.uab.cat/record/190818
U2 - https://doi.org/10.18632/oncotarget.25041
DO - https://doi.org/10.18632/oncotarget.25041
M3 - Article
VL - 9
SP - 20617
EP - 20630
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 29
ER -