5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1)

Shuichi Mitsunaga^{1

2}, Masafumi Ikeda¹, Shogo Nomura³, Chigusa Morizane⁴, Akiko Todaka⁵, Naoto Yamamoto⁶, Ken Kamata⁷, Hiroo Yanagibashi⁸, Nobumasa Mizuno⁹, Yasuyuki Kawamoto¹⁰, Kunihito Gotoh¹¹, Hirofumi Shirakawa¹², Naohiro Okano¹³, Tatsuya Nomura¹⁴, Kazunari Tanaka¹⁵, Amane Takahashi¹⁶, Shintaro Yagi¹⁷, Koji Ohta¹⁸, Yukiko Takayama¹⁹, Haruo Miwa²⁰, Hiroaki Nagano²¹, Yasushi Kojima²², Terumasa Hisano²³, Munenori Tahara²⁴, Yasunaru Sakuma²⁵, Hiroyuki Arai²⁶, Ikuo Nakamura²⁷, Hiroshi Katayama³, Masaru Konishi²⁸, Makoto Ueno²⁹; Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG‐HBPOG)

Affiliations

¹ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
² Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
³ JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan.
⁴ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁵ Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto, Japan.
⁶ Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
⁷ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
⁸ Department of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chiba, Japan.
⁹ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁰ Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
¹¹ Department of Surgery, NHO Osaka National Hospital, Osaka, Japan.
¹² Department of Hepato-Biliary-Pancreatic Surgery, Tochigi Cancer Center, Utsunomiya, Japan.
¹³ Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.
¹⁴ Division of Digestive Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
¹⁵ Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan.
¹⁶ Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan.
¹⁷ Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Japan.
¹⁸ Department of Digestive Surgery, NHO Shikoku Cancer Center, Matsuyama, Ehime, Japan.
¹⁹ Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
²⁰ Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
²¹ Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
²² Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan.
²³ Department of Hepato-Biliary-Pancreatology, NHO Kyushu Cancer Center, Fukuoka, Japan.
²⁴ Department of Surgery, Sapporo Kosei General Hospital, Sapporo, Japan.
²⁵ Department of Surgery, Jichi Medical University, Shimotsuke, Japan.
²⁶ Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
²⁷ Department of Gastroenterological Surgery, Hyogo Medical University, Hyogo, Japan.
²⁸ Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
²⁹ Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan.

PMID: 39318258
DOI: 10.1002/jhbp.12071

Clinical Trial

5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1)

Shuichi Mitsunaga et al. J Hepatobiliary Pancreat Sci. 2024 Dec.

. 2024 Dec;31(12):886-896.

doi: 10.1002/jhbp.12071. Epub 2024 Sep 25.

Authors

Affiliations

¹ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
² Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
³ JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan.
⁴ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁵ Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto, Japan.
⁶ Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan.
⁷ Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
⁸ Department of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chiba, Japan.
⁹ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁰ Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
¹¹ Department of Surgery, NHO Osaka National Hospital, Osaka, Japan.
¹² Department of Hepato-Biliary-Pancreatic Surgery, Tochigi Cancer Center, Utsunomiya, Japan.
¹³ Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.
¹⁴ Division of Digestive Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
¹⁵ Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan.
¹⁶ Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan.
¹⁷ Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Japan.
¹⁸ Department of Digestive Surgery, NHO Shikoku Cancer Center, Matsuyama, Ehime, Japan.
¹⁹ Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
²⁰ Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan.
²¹ Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.
²² Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan.
²³ Department of Hepato-Biliary-Pancreatology, NHO Kyushu Cancer Center, Fukuoka, Japan.
²⁴ Department of Surgery, Sapporo Kosei General Hospital, Sapporo, Japan.
²⁵ Department of Surgery, Jichi Medical University, Shimotsuke, Japan.
²⁶ Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
²⁷ Department of Gastroenterological Surgery, Hyogo Medical University, Hyogo, Japan.
²⁸ Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
²⁹ Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan.

PMID: 39318258
DOI: 10.1002/jhbp.12071

Abstract

Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD).

Methods: The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm.

Results: RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332).

Conclusion: The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions.

Keywords: 5‐FU metabolic pathway; DPD; S‐1; adjuvant; biliary tract cancer.

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References

REFERENCES

1. Nakachi K, Ikeda M, Konishi M, Nomura S, Katayama H, Kataoka T, et al. Adjuvant S‐1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open‐label, randomised, controlled, phase 3 trial. Lancet. 2023;401(10372):195–203.
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5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1)

Affiliations

5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1)

Authors

Affiliations

Abstract

References

REFERENCES

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LinkOut - more resources

Full Text Sources