Hibiki Udagawa1, Shigeki Umemura2, Isao Murakami3, Sachiyo Mimaki4, Hideki Makinoshima4, Genichiro Ishii5, Tomohiro Miyoshi6, Keisuke Kirita6, Shingo Matsumoto2, Kiyotaka Yoh6, Seiji Niho6, Katsuya Tsuchihara4, Koichi Goto6. 1. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. Electronic address: hudagawa@east.ncc.go.jp. 2. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. 3. Department of Respiratory Medicine, Higashi-Hiroshima Medical Center, Higashi-Hiroshima, Japan. 4. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. 5. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. 6. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Abstract
OBJECTIVES: Comprehensive genomic analysis of small-cell lung cancer (SCLC) revealed various genetic alterations. However, obtaining suitable samples for genetic analysis is difficult in advanced SCLC. Thus, the prognostic effect of genetic alterations on the outcome of SCLC patients has not been well investigated. Therefore, this study evaluated the effect of genetic alterations on the survival of SCLC patients. MATERIALS AND METHODS: We collected samples obtained from 220 patients with advanced SCLC before cancer treatment. Genomic DNA extracted from the samples was subjected to a 1.499 Mb-sized custom panel that captured all exons of 244 cancer-related genes, and the captured DNA was analyzed through next-generation sequencing. The associations between genetic alterations and overall survival were evaluated. RESULTS: Genetic analysis was successful in 204 samples (93%). Genetic alterations in the PI3K/AKT/mTOR pathway and inactivating mutations inTP53 and RB1 were detected in 14 (7%), 150 (74%), and 85 (42%) of the tumors. In extensive disease (ED, N = 126) patients, multivariate analysis revealed that the presence of genetic alterations in the PI3K/AKT/mTOR pathway was significantly associated with unfavorable survival [hazard ratio (HR), 2.14; 95% CI 1.02-4.06; P = 0.04]. In limited disease (LD, N = 78) patients, the presence of TP53 mutation and the absence of RB1 mutation were significantly associated with unfavorable survival (HR, 2.41; 95% CI 1.21-5.34; P = 0.01, and HR, 0.45; 95% CI 0.25-0.79; P < 0.01, respectively). CONCLUSIONS: Sequencing-based genetic profiling is feasible and useful to predict the prognosis in advanced SCLC. Genetic alterations in the PI3K/AKT/mTOR pathway, TP53 mutations and RB1 mutations were associated with prognosis in SCLC patients. The genetic alterations associated with the prognosis were different between ED-SCLC and LD-SCLC.
OBJECTIVES: Comprehensive genomic analysis of small-cell lung cancer (SCLC) revealed various genetic alterations. However, obtaining suitable samples for genetic analysis is difficult in advanced SCLC. Thus, the prognostic effect of genetic alterations on the outcome of SCLCpatients has not been well investigated. Therefore, this study evaluated the effect of genetic alterations on the survival of SCLCpatients. MATERIALS AND METHODS: We collected samples obtained from 220 patients with advanced SCLC before cancer treatment. Genomic DNA extracted from the samples was subjected to a 1.499 Mb-sized custom panel that captured all exons of 244 cancer-related genes, and the captured DNA was analyzed through next-generation sequencing. The associations between genetic alterations and overall survival were evaluated. RESULTS: Genetic analysis was successful in 204 samples (93%). Genetic alterations in the PI3K/AKT/mTOR pathway and inactivating mutations inTP53 and RB1 were detected in 14 (7%), 150 (74%), and 85 (42%) of the tumors. In extensive disease (ED, N = 126) patients, multivariate analysis revealed that the presence of genetic alterations in the PI3K/AKT/mTOR pathway was significantly associated with unfavorable survival [hazard ratio (HR), 2.14; 95% CI 1.02-4.06; P = 0.04]. In limited disease (LD, N = 78) patients, the presence of TP53 mutation and the absence of RB1 mutation were significantly associated with unfavorable survival (HR, 2.41; 95% CI 1.21-5.34; P = 0.01, and HR, 0.45; 95% CI 0.25-0.79; P < 0.01, respectively). CONCLUSIONS: Sequencing-based genetic profiling is feasible and useful to predict the prognosis in advanced SCLC. Genetic alterations in the PI3K/AKT/mTOR pathway, TP53 mutations and RB1 mutations were associated with prognosis in SCLCpatients. The genetic alterations associated with the prognosis were different between ED-SCLC and LD-SCLC.