Yuta Maruki1, Chigusa Morizane2, Yasuhito Arai3, Masafumi Ikeda4, Makoto Ueno5, Tatsuya Ioka6, Atsushi Naganuma7, Masayuki Furukawa8, Nobumasa Mizuno9, Tadashi Uwagawa10, Naminatsu Takahara11, Masashi Kanai12, Akinori Asagi13, Satoshi Shimizu14, Atsushi Miyamoto15, Seigo Yukisawa16, Makoto Kadokura17, Yasushi Kojima18, Junji Furuse19, Takako Eguchi Nakajima20,21, Kentaro Sudo22, Noritoshi Kobayashi23, Natsuko Hama3, Takeharu Yamanaka24, Tatsuhiro Shibata3, Takuji Okusaka1. 1. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 2. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. cmorizan@ncc.go.jp. 3. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. 4. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 5. Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Kanagawa, Japan. 6. Department of Oncology Center, Yamaguchi University Hospital, Yamaguchi, Japan. 7. Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Gunma, Japan. 8. Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 9. Department of Gastroenterology, Aichi Cancer Center Hospital, Aichi, Japan. 10. Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. 11. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 12. Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 13. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Ehime, Japan. 14. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan. 15. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan. 16. Department of Medical Oncology, Tochigi Cancer Center, Tochigi, Japan. 17. Department of Gastroenterology, Kofu Municipal Hospital, Yamanashi, Japan. 18. Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan. 19. Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan. 20. Department of Clinical Oncology, St.Marianna University School of Medicine, Kanagawa, Japan. 21. Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy, Kyoto University Hospital, Kyoto, Japan. 22. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan. 23. Department of Oncology Division, Yokohama City University School of Medicine, Kanagawa, Japan. 24. Department of Biostatistics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
Abstract
BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. METHODS: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. RESULTS: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). CONCLUSIONS: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.
BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. METHODS: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. RESULTS: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). CONCLUSIONS: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.
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