title: Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation.
abstract: Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S768I) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S768I) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations.
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors: Junko
authors: J
authors: Tanizaki
authors: Department of Genome Biology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors: Eri
authors: E
authors: Banno
authors: Department of Genome Biology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan; Division of Cancer Immunology, National Cancer Center, Kashiwa, 277-8577, Japan.
authors: Yosuke
authors: Y
authors: Togashi
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. Electronic address: hayashi_h@dotd.med.kindai.ac.jp.
authors: Hidetoshi
authors: H
authors: Hayashi
authors: Department of Genome Biology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors: Kazuko
authors: K
authors: Sakai
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors: Masayuki
authors: M
authors: Takeda
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan; Department of Medical Oncology, Kishiwada City Hospital, Kishiwada, 596-8501, Japan.
authors: Hiroyasu
authors: H
authors: Kaneda
authors: Department of Genome Biology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors: Kazuto
authors: K
authors: Nishio
authors: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors: Kazuhiko
authors: K
authors: Nakagawa
mesh_terms: D000077716:Afatinib; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D009154:Mutation; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Afatinib; EGFR mutation; KRAS mutation; Non–small cell lung cancer; Tyrosine kinase inhibitor