title: Oncogenic alterations in ERBB2/HER2 represent potential therapeutic targets across tumors from diverse anatomic sites of origin.
abstract: BACKGROUND
  Targeted ERBB2/HER2 inhibitors are approved by the U.S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents. Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications.
  
  
  METHODS
  We explored the spectrum of activating ERBB2 alterations across a collection of ∼ 7,300 solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes.
  
  
  RESULTS
  Known oncogenic ERBB2 alterations were identified in tumors derived from 27 tissues, and ERBB2 amplification in breast, gastric, and gastroesophageal cancers accounted for only 30% of these alterations. Activating mutations in ERBB2 were identified in 131 samples (32.5%); amplification was observed in 246 samples (61%). Two samples (0.5%) harbored an ERBB2 rearrangement. Ten samples (2.5%) harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases.
  
  
  CONCLUSIONS
  Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Compared with current clinical standards, comprehensive genomic profiling of a more diverse set of tumor types may identify ∼ 3.5 times the number of patients who may benefit from ERBB2-targeted therapy.
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA jchmielecki@foundationmedicine.com pstephens@foundationmedicine.com.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Norma
authors.initials: N
authors.lastname: Palma
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA jchmielecki@foundationmedicine.com pstephens@foundationmedicine.com.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077341:Lapatinib; D009154:Mutation; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: Antibodies; High-throughput nucleotide sequencing; Humanized; Lapatinib; Monoclonal; Mutation; Pertuzumab; Trastuzumab