title: HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo- and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib.
abstract: Erb-b2 receptor tyrosine kinase (HER2) transmembrane domain (TMD) mutations (HER2V659E, HER2G660D) have previously been identified in lung adenocarcinomas, but their frequency and clinical significance is unknown.
  
  
  
  We prospectively analyzed 8551 consecutive lung adenocarcinomas using hybrid capture-based comprehensive genomic profiling (CGP) at the request of the individual treating physicians for the purpose of making therapy decisions.
  
  
  
  We identified 15 cases (0.18%) of HER2 TMD mutations (HER2V659E/D, HER2G660D) through CGP of 8551 lung adenocarcinomas. HER2 TMD mutations were mutually exclusive from HER2 kinase domain mutations and other oncogenic drivers in lung adenocarcinoma. Only two cases with HER2 TMD mutations (13%) had concurrent Erb-b2 receptor tyrosine kinase 2 gene (HER2) amplification. Structural analysis of HER2 TMD association revealed that mutations at positions V659 and G660 to the highly polar residues glutamic acid, aspartic acid, or arginine should stabilize homodimerization and heterodimerization of HER2 in the active conformation. Treatment with afatinib, a pan-HER inhibitor, resulted in durable clinical response in three of four patients with lung adenocarcinoma, with two harboring HER2V659Eand one with double HER2V659E/G660Rmutations. HER2 TMD mutations (V659 and G660) are found in other non-NSCLC malignancies, and analogous TMD mutations are also found in EGFR, HER3, and HER4.
  
  
  
  HER2 TMD mutations represent rare but distinct targetable driver mutations in lung adenocarcinoma. CGP capable of detecting diverse HER2 alterations, including HER2 TMD mutations, should be broadly adopted to identify all patients who may benefit from HER2-targeted therapies.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California. Electronic address: Ignatius.ou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SI
authors.lastname: Ou
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
authors.forename: Eduard V
authors.initials: EV
authors.lastname: Bocharov
authors.affiliation: The Angeles Clinic and Research Institute, Los Angeles, California.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: Hospital Sao Jose, Sao Paulo, Brazil.
authors.forename: Carolina Kawamura
authors.initials: CK
authors.lastname: Haddad
authors.affiliation: Affiliated Oncologists, LLC, Oak Lawn, Illinois.
authors.forename: Gary
authors.initials: G
authors.lastname: Steinecker
authors.affiliation: Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee.
authors.forename: Melissa
authors.initials: M
authors.lastname: Johnson
authors.affiliation: University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Gitlitz
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Jon
authors.initials: J
authors.lastname: Chung
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts; Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
authors.forename: Paulo V
authors.initials: PV
authors.lastname: Campregher
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts; Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: James H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Cleveland Clinic, Cleveland Clinic Main Campus, Cleveland, Ohio.
authors.forename: Vamsidhar
authors.initials: V
authors.lastname: Velcheti
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000595:Amino Acid Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011487:Protein Conformation; D000072417:Protein Domains; D055503:Protein Multimerization; D011799:Quinazolines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics*; D012189:Retrospective Studies; D016415:Sequence Alignment
chemical_list: D000077716:Afatinib; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Actionable driver mutation; Afatinib; HER2 G660; HER2 V659; NSCLC; Transmembrane mutation