{"title":"小细胞肺癌前瞻性大型基因组筛查的临床意义：基因分类和生物标记物驱动的吉达替尼 II 期试验。","authors":"Shigeki Umemura, Hibiki Udagawa, Takaya Ikeda, Haruyasu Murakami, Haruko Daga, Ryo Toyozawa, Toshiyuki Kozuki, Jun Sakakibara-Konishi, Yuichiro Ohe, Masahiro Morise, Terufumi Kato, Masato Shingyoji, Satoshi Hara, Naoki Furuya, Shuhei Teranishi, Saori Takata, Shingo Miyamoto, Ichiro Nakachi, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Genichiro Ishii, Katsuya Tsuchihara, Eri Sugiyama, Keisuke Kirita, Tetsuya Sakai, Yuji Shibata, Hiroki Izumi, Kaname Nosaki, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Koichi Goto","doi":"10.1016/j.jtho.2024.10.004","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>SCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial.</p><p><strong>Methods: </strong>A total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening.</p><p><strong>Results: </strong>On the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22-2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26-1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial.</p><p><strong>Conclusions: </strong>Molecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Clinical Significance of a Prospective Large Genomic Screening for SCLC: The Genetic Classification and a Biomarker-Driven Phase 2 Trial of Gedatolisib.\",\"authors\":\"Shigeki Umemura, Hibiki Udagawa, Takaya Ikeda, Haruyasu Murakami, Haruko Daga, Ryo Toyozawa, Toshiyuki Kozuki, Jun Sakakibara-Konishi, Yuichiro Ohe, Masahiro Morise, Terufumi Kato, Masato Shingyoji, Satoshi Hara, Naoki Furuya, Shuhei Teranishi, Saori Takata, Shingo Miyamoto, Ichiro Nakachi, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Genichiro Ishii, Katsuya Tsuchihara, Eri Sugiyama, Keisuke Kirita, Tetsuya Sakai, Yuji Shibata, Hiroki Izumi, Kaname Nosaki, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Koichi Goto\",\"doi\":\"10.1016/j.jtho.2024.10.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>SCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial.</p><p><strong>Methods: </strong>A total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening.</p><p><strong>Results: </strong>On the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22-2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26-1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial.</p><p><strong>Conclusions: </strong>Molecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices.</p>\",\"PeriodicalId\":17515,\"journal\":{\"name\":\"Journal of Thoracic Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":21.0000,\"publicationDate\":\"2024-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Thoracic Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jtho.2024.10.004\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thoracic Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtho.2024.10.004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Clinical Significance of a Prospective Large Genomic Screening for SCLC: The Genetic Classification and a Biomarker-Driven Phase 2 Trial of Gedatolisib.
Introduction: SCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial.
Methods: A total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening.
Results: On the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22-2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26-1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial.
Conclusions: Molecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices.
期刊介绍：
Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.
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