PMID- 30642448 OWN - NLM STAT- MEDLINE DCOM- 20191220 LR - 20191220 IS - 1872-8332 (Electronic) IS - 0169-5002 (Linking) VI - 128 DP - 2019 Feb TI - Exploration of germline variants responsible for adverse events of crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer by target-gene panel sequencing. PG - 20-25 LID - S0169-5002(18)30683-4 [pii] LID - 10.1016/j.lungcan.2018.12.002 [doi] AB - OBJECTIVES: Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. MATERIALS AND METHODS: DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher's exact test. RESULTS: We defined clinically significant AEs as grade 4 hematological toxicity, grade >/=3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. CONCLUSION: Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Mizugaki, Hidenori AU - Mizugaki H AD - Departments of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan. FAU - Hamada, Akinobu AU - Hamada A AD - Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. Electronic address: akhamad@ncc.go.jp. FAU - Shibata, Tatsuhiro AU - Shibata T AD - Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. Electronic address: tshibata2010@gmail.com. FAU - Hosoda, Fumie AU - Hosoda F AD - Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. FAU - Nakamura, Hiromi AU - Nakamura H AD - Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. FAU - Okuma, Yusuke AU - Okuma Y AD - Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. FAU - Shukuya, Takehito AU - Shukuya T AD - Department of Respiratory Medicine, Juntendo University, Tokyo, Japan. FAU - Umemura, Shigeki AU - Umemura S AD - Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Horiike, Atsushi AU - Horiike A AD - Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. FAU - Fukui, Tomoya AU - Fukui T AD - Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan. FAU - Kogure, Yoshihito AU - Kogure Y AD - Department of Medical Oncology, Nagoya Medical Center, Aichi, Japan. FAU - Daga, Haruko AU - Daga H AD - Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan. FAU - Urata, Yoshiko AU - Urata Y AD - Department of Thoracic Oncology, Hyogo Cancer Center, Hyogo, Japan. FAU - Yamada, Kazuhiko AU - Yamada K AD - Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. FAU - Saeki, Sho AU - Saeki S AD - Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan. FAU - Fujisaka, Yasuhito AU - Fujisaka Y AD - Clinical Research Center, Osaka Medical College Hospital, Osaka, Japan. FAU - Nakamura, Yukiko AU - Nakamura Y AD - Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan. FAU - Sato, Mitsuo AU - Sato M AD - Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. FAU - Yoshida, Tatsuya AU - Yoshida T AD - Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. FAU - Hotta, Takamasa AU - Hotta T AD - Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University, School of Medicine, Shimane, Japan. FAU - Oizumi, Satoshi AU - Oizumi S AD - First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan. FAU - Fujiwara, Yasuhiro AU - Fujiwara Y AD - Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Ohe, Yuichiro AU - Ohe Y AD - Departments of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan. FAU - Fujiwara, Yutaka AU - Fujiwara Y AD - Departments of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181204 PL - Ireland TA - Lung Cancer JT - Lung cancer (Amsterdam, Netherlands) JID - 8800805 RN - 0 (Protein Kinase Inhibitors) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Amino Acid Substitution MH - Anaplastic Lymphoma Kinase/*genetics MH - Carcinoma, Non-Small-Cell Lung/complications/drug therapy/*genetics MH - Crizotinib/*adverse effects/therapeutic use MH - Drug-Related Side Effects and Adverse Reactions/diagnosis/*genetics MH - Female MH - Germ-Line Mutation MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Lung Neoplasms/complications/drug therapy/*genetics MH - Male MH - Middle Aged MH - Neoplasm Staging MH - Pharmacogenomic Variants/*genetics MH - Polymorphism, Single Nucleotide MH - Protein Kinase Inhibitors/*adverse effects/therapeutic use OTO - NOTNLM OT - ALK OT - Crizotinib OT - Next-generation sequencing OT - Non-small cell lung cancer EDAT- 2019/01/16 06:00 MHDA- 2019/12/21 06:00 CRDT- 2019/01/16 06:00 PHST- 2018/08/14 00:00 [received] PHST- 2018/12/03 00:00 [revised] PHST- 2018/12/03 00:00 [accepted] PHST- 2019/01/16 06:00 [entrez] PHST- 2019/01/16 06:00 [pubmed] PHST- 2019/12/21 06:00 [medline] AID - S0169-5002(18)30683-4 [pii] AID - 10.1016/j.lungcan.2018.12.002 [doi] PST - ppublish SO - Lung Cancer. 2019 Feb;128:20-25. doi: 10.1016/j.lungcan.2018.12.002. Epub 2018 Dec 4.