title: Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials.
abstract: It is still controversial whether comprehensive genome screening of target molecules by next generation sequencing (NGS) is needed to increase clinical efficacy of investigational drugs or accelerate drug development, although several studies are being carried out. Therefore, we performed a prospective study to evaluate the feasibility of comprehensive gene screening in this setting. Our findings indicate that actionable alterations were identified in 45% of the analyzed patients, most frequently in those with breast cancer. Common actionable alterations were found in PIK3CA mutation, BRCA2 mutation, ERBB2 amplification, and CCND1 amplification. In total, 22% of the analyzed patients could be entered into phase I clinical trials, and 8% of them were treated with "matched" drugs. Among patients who received matched therapies, response and disease control rates were 33 and 78%, respectively. On the other hand, in the patients who received "non-matched" therapy, the objective response rate was 6%. We believe this data indicates that NGS-based molecular pre-screening is a potent platform for use before patient entry into phase I trials.
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjyo, Chuo-ku, Kumamoto, 104-0045, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Clinical Genomics, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Bioinformatics, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwasa
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. ketamura@ncc.go.jp.|Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. ketamura@ncc.go.jp.|Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjyo, Chuo-ku, Kumamoto, 104-0045, Japan. ketamura@ncc.go.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
mesh_terms: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017321:Clinical Trials, Phase I as Topic; D005820:Genetic Testing; D014644:Genetic Variation; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D018579:Patient Selection
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Driver mutation; Molecular pre-screening; Molecular targeted therapy; Next-generation sequencing; Phase I trial