Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E.

We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors' institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors', revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. KEY POINTS Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling.Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations.In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

[1]  Jana Marie Schwarz,et al.  MutationTaster evaluates disease-causing potential of sequence alterations , 2010, Nature Methods.

[2]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[3]  David Haussler,et al.  New Methods for Detecting Lineage-Specific Selection , 2006, RECOMB.

[4]  J. Soh,et al.  Antitumor effect of afatinib, as a human epidermal growth factor receptor 2‐targeted therapy, in lung cancers harboring HER2 oncogene alterations , 2015, Cancer Science.

[5]  X. Puente,et al.  Clinical response to a lapatinib-based therapy for a Li-Fraumeni syndrome patient with a novel HER2V659E mutation. , 2013, Cancer discovery.

[6]  Wendy Winckler,et al.  Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2 , 2012, Proceedings of the National Academy of Sciences.

[7]  Bin Li,et al.  Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients , 2015, Oncotarget.

[8]  Y. Okuno,et al.  The possibility of clinical sequencing in the management of cancer. , 2016, Japanese journal of clinical oncology.

[9]  Carlos L Arteaga,et al.  HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. , 2006, Cancer cell.

[10]  Justin C. Fay,et al.  Identification of deleterious mutations within three human genomes. , 2009, Genome research.

[11]  J. Soh,et al.  Novel Germline Mutation in the Transmembrane Domain of HER2 in Familial Lung Adenocarcinomas , 2013, Journal of the National Cancer Institute.

[12]  Vamsidhar Velcheti,et al.  HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo‐ and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[13]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[14]  O. Bocharova,et al.  Spatial structure of the transmembrane domain heterodimer of ErbB1 and ErbB2 receptor tyrosine kinases. , 2010, Journal of molecular biology.

[15]  Donavan T. Cheng,et al.  Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. , 2015, The Journal of molecular diagnostics : JMD.

[16]  Hiromasa Yamamoto,et al.  Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway , 2016, Scientific Reports.

[17]  K. Kiura,et al.  Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience , 2016, Cancer Chemotherapy and Pharmacology.

[18]  Roman G. Efremov,et al.  Spatial Structure of the Dimeric Transmembrane Domain of the Growth Factor Receptor ErbB2 Presumably Corresponding to the Receptor Active State* , 2008, Journal of Biological Chemistry.