Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases
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Leticia De Mattos-Arruda1,2,3,*, Charlotte K. Y. Ng1,4,5,*, Salvatore Piscuoglio1,4, Maria Gonzalez-Cao6, Raymond S. Lim1, Maria R. De Filippo1, Nicola Fusco1, Anne M. Schultheis1, Carolina Ortiz2, Santiago Viteri6, Alexandra Arias2, Gabriel S. Macedo1, Mafalda Oliveira2, Patricia Gomez2, Cristina Teixidó6, Paolo Nuciforo2, Vicente Peg7, Cristina Saura2, Santiago Ramon y Cajal7, Francesc Tresserra Casas6, Britta Weigelt1, Javier Cortes2,3,8, Joan Seoane2,3,9 and Jorge S. Reis-Filho1,10
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
2Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
3Universitat Autònoma de Barcelona, Barcelona, Spain
4Institute of Pathology, University Hospital Basel, Basel, Switzerland
5Department of Biomedicine, University of Basel, Basel, Switzerland
6Quirón Dexeus University Hospital, Barcelona, Spain
7Vall d'Hebron Institute of Research, Vall d'Hebron University Hospital, Barcelona, Spain
8Ramon y Cajal University Hospital, Madrid, Spain
9Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
10Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
*These authors contributed equally to this work
Leticia De Mattos-Arruda, email: firstname.lastname@example.org
Jorge S. Reis-Filho, email: email@example.com
Keywords: metastatic breast cancer; HER2-positive; brain metastasis; actionable genetic alterations; personalized medicine
Received: January 16, 2018 Accepted: March 12, 2018 Published: April 17, 2018
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.
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