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Ref Type Journal Article
PMID (29146616)
Authors Yamamoto H, Toyooka S, Ninomiya T, Matsumoto S, Kanai M, Tomida S, Kiura K, Muto M, Suzawa K, Desmeules P, Kris MG, Li BT, Ladanyi M
Title Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E.
Journal The oncologist
Vol 23
Issue 2
Date 2018 Feb
URL
Abstract Text 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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 S310F ERBB2 G660D ampulla of Vater carcinoma predicted - sensitive Afatinib Case Reports/Case Series Actionable In a clinical case study, Gilotrif (afatinib) treatment resulted in stable disease with slight lymph node metastasis reduction in a patient with ampulla of Vater carcinoma harboring ERBB2 S310F and G660D, but the disease eventually progressed after 4 months (PMID: 29146616). 29146616
ERBB2 G660D lung cancer sensitive Afatinib Case Reports/Case Series Actionable In a clinical case study, Gilotrif (afatinib) treatment resulted in partial response in the lung lesion and stable bone metastasis for over 16 months in a patient with familial lung cancer harboring germline ERBB2 G660D mutation (PMID: 29146616). 29146616