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Translational Therapeutics

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer

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Abstract

Background

Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC.

Methods

This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment.

Results

In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively).

Conclusion

The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

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Fig. 1: Genomic alterations identified with ctDNA analysis in patients with PDAC.
Fig. 2: The maximum VAF (%) and frequencies of the detection of KRAS mutation in ctDNA in patients with metastasis to a single site (n = 296).

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Data availability

The authors declare that all variant data used in the conduct of the analyses are available within the article and its Supplementary information. To protect the privacy and confidentiality of patients in this study, clinical data are not made publicly available in a repository or the supplementary material of the article but will be made available following reasonable request to the corresponding author.

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Acknowledgements

The authors thank all of the patients and their families who participated in this study; all investigators and site personnel; Translational Research Support Section; Y Sakamoto and M Hata (National Cancer Center Hospital East) for data management; and all the National Cancer Center Hospital East Translational Research Support Section members.

Funding

This work was supported by SCRUM-Japan Funds (http://www.scrum-japan.ncc.go.jp/index.html).

Author information

Authors and Affiliations

  1. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan

    Kumiko Umemoto & Yu Sunakawa

  2. Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan

    Makoto Ueno

  3. Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Masayuki Furukawa

  4. Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan

    Nobumasa Mizuno

  5. Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan

    Kentaro Sudo

  6. Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan

    Yasuyuki Kawamoto

  7. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan

    Takeshi Kajiwara

  8. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    Koushiro Ohtsubo

  9. Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan

    Naohiro Okano

  10. Department of Gastroenterological Surgery, Gifu University, Gifu, Japan

    Nobuhisa Matsuhashi

  11. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shinji Itoh

  12. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan

    Toshihiko Matsumoto

  13. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan

    Satoshi Shimizu

  14. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan

    Toru Otsuru

  15. Department of Gastroenterology and Hepatology, National Hospital Organization, Osaka National Hospital, Osaka, Japan

    Hiroko Hasegawa

  16. Department of Clinical Oncology, Kagawa University, Kagawa, Japan

    Hiroyuki Okuyama

  17. Department of Gastroenterology, Osaka Medical College, Osaka, Japan

    Hideko Ohama

  18. Department of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Japan

    Toshikazu Moriwaki

  19. Department of Clinical Oncology, Kansai Rosai Hospital, Hyogo, Japan

    Takashi Ohta

  20. Guardant Health, Redwood City, CA, USA

    Justin I. Odegaard

  21. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura, Hideaki Bando & Takayuki Yoshino

  22. Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura

  23. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Masafumi Ikeda

  24. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Chigusa Morizane

Authors
  1. Kumiko Umemoto
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  2. Yu Sunakawa
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  3. Makoto Ueno
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  4. Masayuki Furukawa
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  5. Nobumasa Mizuno
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  6. Kentaro Sudo
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  7. Yasuyuki Kawamoto
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  8. Takeshi Kajiwara
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  9. Koushiro Ohtsubo
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  10. Naohiro Okano
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  11. Nobuhisa Matsuhashi
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  12. Shinji Itoh
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  13. Toshihiko Matsumoto
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  14. Satoshi Shimizu
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  15. Toru Otsuru
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  16. Hiroko Hasegawa
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  17. Hiroyuki Okuyama
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  18. Hideko Ohama
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  19. Toshikazu Moriwaki
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  20. Takashi Ohta
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  21. Justin I. Odegaard
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  22. Yoshiaki Nakamura
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  23. Hideaki Bando
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  24. Takayuki Yoshino
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  25. Masafumi Ikeda
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  26. Chigusa Morizane
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Contributions

KU and YS contributed to the planning and conducting of studies, recruiting patients, acquisition of data, analysis and interpretation of the data and writing of the manuscript. MF, N Mizuno, KS, YK, TK, KO, NO, N Matsuhashi, SI, T Matsumoto, SS, T Otsuru, HH, H Okuyama, H Ohama, T Moriwaki and T Ohta contributed to the recruitment of patients and acquisition of data. JIO, YN, HB and TY contributed to the planning, conducting of studies and interpretation of data. MU, MI and CM contributed to the recruitment of patients, acquisition of data, planning and interpretation of data. All authors agree to be accountable for all aspects of the work and will ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Yu Sunakawa.

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Competing interests

MF, KO, N Matsuhashi, SI, T Matsumoto, T Otsuru, HH, H Okuyama and H Ohama have nothing to disclose. KU reports honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical and Yakult Honsha. YS reports honoraria from Takeda Pharmaceutical, Eli Lilly Japan, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Bayer, Daiichi Sankyo and Merck Biopharma; and grants from IQVIA and Parexel; and contributions or endowed chair from Takeda Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Sanofi and EN Otsuka Pharma. MU reports grants and personal fees from Taiho Pharmaceutical, AstraZeneca, Merck Biopharma, MSD, Ono Pharmaceutical, Incyte Corporation and Chugai Pharmaceutical; and personal fees from Nihon Servier; and grants from Astellas Pharma, Eisai and DFP. N Mizuno reports grants and personal fees from AstraZeneca, Novartis, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical; and grants from MSD, Dainippon Sumitomo Pharma, ASLAN Pharmaceuticals, Incyte Corporation. and Seagen; and personal fees from Teijin Pharma, FUJIFILM Toyama Chemical, outside the submitted work. KS reports honoraria from Ono Pharmaceutical and Yakult Honsha; and grants (for the institution) from Bristol-Myers Squibb/Ono Pharmaceutical, Eisai and Incyte corporation. YK reports honoraria from Taiho Pharmaceutical, Incyte, Merck Biopharma, Yakult Honsha, and Eli Lilly; and grants from Takeda Pharmaceutical. TK reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical and Eli Lilly. NO reports honoraria from Taiho Pharmaceutical, Eli Lilly, Eisai, Bayer Yakuhin, Chugai Pharmaceutical, Ono Pharmaceutical and Takeda Pharmaceutical; and advisory board from GlaxoSmithKline. SS reports grants from AstraZeneca, Incyte Corporation and Delta-Fly Pharma. T Moriwaki reports honoraria from Taiho Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Sanofi, Bayer Yakuhin, Merck Biopharma, Ono Pharmaceutical and Yakult Honsha; and grants from Taiho Pharmaceutical, MSD, Takeda Pharmaceutical, and Yakult Honsha. T Ohta reports honoraria from Chugai Pharmaceutical, Teijin Pharma, Takeda Pharmaceutical, Eisai, Yakult-Honsha, Daiichi Sankyo, Merck Biopharma, Ono Pharmaceutical, Taiho Pharmaceutical and Bristol-Myers Squibb; and grants from Takeda Pharmaceutical. JIO reports from, and stock interests in, Guardant Health. YN reports grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Guardant Health, Genomedia, Daiichi Sankyo, Seagen, Roche Diagnostics. HB reports honoraria from Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical; and grants from Ono Pharmaceutical outside the submitted work. TY reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical and MSD; and grants from Ono Pharmaceutical, Sanofi, Daiichi Sankyo, Parexel International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex, Chugai Pharmaceutical and Nippon Boehringer Ingelheim. MI reports honoraria from Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Sumitomo Dainippon Pharma, EA Pharma, Teijin Pharma, Yakult Honsha, Taiho Pharmaceutical, Otsuka, MSD, Mylan, Nihon Servier, Chugai Pharmaceutical, AstraZeneca, AbbVie, Abbott, Takeda, Novartis and Astellas Pharma; and advisory roles with Bayer, Eli Lilly, Eisai, Chugai Pharmaceutical, AstraZeneca, Takeda Pharmaceutical, Ono Pharmaceutical, GlaxoSmithKline and Nihon Servier; and grants from Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Takeda Pharmaceutical, AstraZeneca, Chugai Pharmaceutical, Merck Biopharma, ASLAN Pharmaceuticals, Novartis, Yakult Honsha, Taiho Pharmaceutical, Ono Pharmaceutical, MSD, Merus N.V., Nihon Servier, Pfizer, Chiome Bioscience, Delta-Fly Pharma, and J-Pharma. CM reports honoraria from Nihon Servier, Novartis, Yakult Honsha, Teijin Pharma, Taiho Pharmaceutical, Eisai and MSD; advisory roles with Yakult Honsha, Novartis, Servier, Taiho Pharmaceutical and Abbvie; and grants from Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, J-Pharma, Daiichi Sankyo, HITACHI, AstraZeneca and Merck Biopharma.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. The protocol of the GOZILA study was approved by the institutional review board of each participating institution and registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol no. UMIN000029315 for GOZILA.

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Umemoto, K., Sunakawa, Y., Ueno, M. et al. Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer. Br J Cancer 128, 1603–1608 (2023). https://doi.org/10.1038/s41416-023-02189-y

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