1267P - HER2 V659 and G660 transmembrane mutations that stabilize homo- and hetero-dimerization are rare oncogenic drivers in lung adenocarcinoma that are...

Date 08 October 2016
Event ESMO 2016 Congress
Session Poster Display
Topics Non-Small Cell Lung Cancer
Presenter Sai-Hong Ignatius Ou
Citation Annals of Oncology (2016) 27 (6): 416-454. 10.1093/annonc/mdw383
Authors S.I. Ou1, A.B. Schrock2, E.V. Bocharov3, S.J. Klempner4, C.K. Haddad5, G. Steinecker6, M. Johnson7, B. Gitlitz8, J. Chung9, P. Campregher10, J.S. Ross11, P.J. Stephens12, V.A. Miller2, J. Suh13, S.M. Ali2, V. Velcheti14
  • 1Hematology/oncology, Chao Family Comprehensive Cancer Center, 92868 - Irvine/US
  • 2Clinical Development, Foundation Medicine, Inc., Cambridge/US
  • 3Department Of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow/RU
  • 4Medical Oncology, The Angeles Clinic and Research Institute, 90025 - Los Angeles/US
  • 5Medical Oncology, Hospital São José, Sao Paulo/BR
  • 6Medical Oncology, Affiliated Oncologists, Oak Lawn/US
  • 7Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville/US
  • 8Oncology, University of Southern California Norris Comprehensive Cancer Center, 90089 - Los Angeles/US
  • 9Biomedical Informatics, Foundation Medicine, Inc., Cambridge/US
  • 10Biologia Molecular, Hospital Israelita Albert Einstein, Sao Paulo/BR
  • 11Pathology, Foundation Medicine, Inc., Cambridge/US
  • 12Clinical Genomics, Foundation Medicine, Inc., Cambridge/US
  • 13Pathology, Foundation Medicine, Inc., 02141 - Cambridge/US
  • 14Medical Oncology, Cleveland Clinic Foundation, Cleveland/US



HER2 (ERBB2) transmembrane domain (TMD) mutations (V659E and G660D) have previously been identified in lung adenocarcinomas, but their frequency and clinical significance is unknown.


We prospectively analyzed 8,551 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 lung adenocarcinoma with HER2 TMD mutations at amino acid residues 659 or 660. These included 11 cases with V659D/E mutations, 2 with HER2 G660D, one with HER2 V659E/G660R, and one with a HER2 V659_660VE insertion. In comparison, HER2 kinase domain (KD) mutations, the majority of which were exon 20 insertions, were identified in 3.2% (273/8,551) of cases. 79% of patients with HER2 TMD mutations were female and of the 9 patients with known smoking history, 5 were never-smokers and 3 were light former-smokers. HER2 TMD mutations were mutually exclusive from HER2 KD mutations and other oncogenic drivers in lung adenocarcinoma. Only two cases with HER2 TMD mutations (13%) had concurrent HER2 amplification. Nuclear magnetic resonance analysis of HER2 TMD association revealed that mutations at position V659 and G660 to highly polar residues glutamic acid (E), aspartic acid (D) or arginine (R) stabilize homo- and hetero-dimerization of HER2 in the active conformation. Treatment of three patients with afatinib, a pan-HER inhibitor, resulted in ongoing clinical responses in all three cases, two harboring HER2 V659E and one with double HER2 V659E/G660R mutations (response > 14 months). 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.


This study expands the knowledge of targetable HER2 mutations in lung adenocarcinoma to the TMD and potentially other solid malignancies. 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.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine.


Foundation Medicine. Russian Science Foundation, project #14-50-00131 (to E.V. Bocharov). S-H I. Ou was partly supported by the University of California Irvine NIH P30 grant CA062203-19.


S-H.I. Ou: Honoraria as an advisory board and speaker bureau member for Boehringer Ingelheim. A.B. Schrock, J. Chung, P. Campregher, J.S. Ross, P.J. Stephens, V.A. Miller, J. Suh, S.M. Ali: Employee with stock ownership in Foundation Medicine. S.J. Klempner: Honoraria from Foundation Medicine. All other authors have declared no conflicts of interest.