Naoki Shimizu1, Yusaku Akashi2, Tomomi Fujii3, Hiroyuki Shiono4, Katsunari Yane5, Tadashi Kitahara6, Yoshio Ohta7, Kennichi Kakudo7, Tomoko Wakasa7. 1. Department of Otolaryngology, Kindai University Nara Hospital School of Medicine, Nara, Japan naokish@med.kindai.ac.jp y-akashi@med.kindai.ac.jp. 2. Department of Medical Oncology, Kindai University Nara Hospital School of Medicine, Nara, Japan naokish@med.kindai.ac.jp y-akashi@med.kindai.ac.jp. 3. Department of Diagnostic Pathology, Head and Neck Surgery Nara Medical University School of Medicine, Nara, Japan. 4. Department of Thoracic Surgery, Kindai University Nara Hospital School of Medicine, Nara, Japan. 5. Department of Otolaryngology, Kindai University Nara Hospital School of Medicine, Nara, Japan. 6. Department of Otolaryngology, Head and Neck Surgery Nara Medical University School of Medicine, Nara, Japan. 7. Department of Diagnostic Pathology and Laboratory Medicine, Kindai University Nara Hospital School of Medicine, Nara, Japan.
Abstract
BACKGROUND: Patients with adenocarcinoma of the lung are routinely screened for anaplastic lymphoma kinase (ALK) rearrangement because they can be treated by ALK-specific targeted therapy. The clinical and molecular characteristics of large-cell neuroendocrine carcinoma (LCNEC) associated with ALK rearrangement are still unclear. Herein, we assessed the ALK status in a series of patients with LCNEC by testing methods commonly used for adenocarcinoma. MATERIALS AND METHODS: ALK expression was first examined by immunohistochemistry. For a positively stained tumor, molecular analyses were then conducted. The ALK fusion partner found in a patient with ALK rearrangement was further identified by direct DNA sequencing. Patient clinicopathological features were also analyzed, focusing on the ALK rearrangement-positive case. RESULTS: Immunohistochemistry of seven patients identified strong ALK expression in one case of stage IV LCNEC. Molecular analysis identified a novel rearranged gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 17 to ALK exon 20. The patient was treated with ALK-specific inhibitors, crizotinib and later, alectinib, and has remained alive for more than 24 months without disease progression. Three of the remaining six patients without ALK rearrangement had stage IV cancer and received cytotoxic chemotherapies. Their average overall survival was 5.4 months. CONCLUSION: To our knowledge, this is the first report of a KIF5B-ALK fusion gene in LCNEC. The patient was successfully treated with ALK inhibitors, suggesting that sensitivity to ALK inhibitor may define a specific LCNEC subtype. We propose that screening for ALK rearrangement in patients with LCNEC may assist in selecting potential candidates for targeted therapy. Copyright
BACKGROUND:Patients with adenocarcinoma of the lung are routinely screened for anaplastic lymphoma kinase (ALK) rearrangement because they can be treated by ALK-specific targeted therapy. The clinical and molecular characteristics of large-cell neuroendocrine carcinoma (LCNEC) associated with ALK rearrangement are still unclear. Herein, we assessed the ALK status in a series of patients with LCNEC by testing methods commonly used for adenocarcinoma. MATERIALS AND METHODS:ALK expression was first examined by immunohistochemistry. For a positively stained tumor, molecular analyses were then conducted. The ALK fusion partner found in a patient with ALK rearrangement was further identified by direct DNA sequencing. Patient clinicopathological features were also analyzed, focusing on the ALK rearrangement-positive case. RESULTS: Immunohistochemistry of seven patients identified strong ALK expression in one case of stage IV LCNEC. Molecular analysis identified a novel rearranged gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 17 to ALK exon 20. The patient was treated with ALK-specific inhibitors, crizotinib and later, alectinib, and has remained alive for more than 24 months without disease progression. Three of the remaining six patients without ALK rearrangement had stage IV cancer and received cytotoxic chemotherapies. Their average overall survival was 5.4 months. CONCLUSION: To our knowledge, this is the first report of a KIF5B-ALK fusion gene in LCNEC. The patient was successfully treated with ALK inhibitors, suggesting that sensitivity to ALK inhibitor may define a specific LCNEC subtype. We propose that screening for ALK rearrangement in patients with LCNEC may assist in selecting potential candidates for targeted therapy. Copyright
Authors: Reed I Ayabe; Michael Wach; Samantha Ruff; Sean Martin; Laurence Diggs; Timothy Wiemken; Leslie Hinyard; Jeremy L Davis; Carrie Luu; Jonathan M Hernandez Journal: Ann Surg Oncol Date: 2019-05-17 Impact factor: 5.344