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Translational Therapeutics

Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer

British Journal of Cancer (2024)Cite this article

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Abstract

Background

Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC.

Methods

We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360.

Results

Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32–0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis.

Conclusion

Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

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Fig. 1: Comparison of progression-free survival (PFS) and overall survival (OS) between patients with or without putative germline BRCA (gBRCA) mutation in ctDNA.
Fig. 2
Fig. 3: A case with putative BRCA2 reversion mutation.

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Data availability

To protect the privacy and confidentiality of patients, 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

We would like to thank all of the patients and their families participated in this study; the Translational Research Support Section of the National Cancer Center Hospital East; and all GOZILA investigators.

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 Gastroenterology, Chiba Cancer Center, Chiba, Japan

    Kentaro Sudo

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

    Yoshiaki Nakamura, Hideaki Bando & Takayuki Yoshino

  3. Translational Research Support Office, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura & Hideaki Bando

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

    Makoto Ueno

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

    Masayuki Furukawa

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

    Nobumasa Mizuno

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

    Yasuyuki Kawamoto

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

    Naohiro Okano

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

    Kumiko Umemoto

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

    Akinori Asagi

  11. Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    Masato Ozaka

  12. Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan

    Koushiro Ohtsubo

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

    Satoshi Shimizu

  14. Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan

    Nobuhisa Matsuhashi

  15. Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan

    Nobuhisa Matsuhashi

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

    Shinji Itoh

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

    Toshihiko Matsumoto

  18. Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan

    Taroh Satoh

  19. Department of Medical Oncology, Kagawa University Hospital, Kagawa, Japan

    Hiroyuki Okuyama

  20. Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan

    Masahiro Goto

  21. Department of Gastroenterology and Hepatology, NHO, Osaka National Hospital, Osaka, Japan

    Hiroko Hasegawa

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

    Yoshiyuki Yamamoto

  23. Guardant Health, Redwood City, CA, USA

    Justin I. Odegaard

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

    Masafumi Ikeda

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

    Chigusa Morizane

Authors
  1. Kentaro Sudo
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  2. Yoshiaki Nakamura
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  3. Makoto Ueno
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  4. Masayuki Furukawa
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  6. Yasuyuki Kawamoto
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Contributions

KS contributed to the planning and conducting of the study, recruiting patients, acquisition of data, analysis and interpretation of the data and writing of the manuscript. YN contributed to the planning and conducting of the study, analysis and interpretation of the data and writing of the manuscript. MU, MI, and CM contributed to the planning and conducting of the study, recruiting patients, acquisition of data, interpretation of the data and the revision of the manuscript. MF, N. Mizuno, YK, NO, KU, AA, MO, KO, SS, N. Matsuhashi, SI, TM, TS, HO, MG, HH, and YY, contributed to the recruitment of patients, acquisition of data and the revision of the manuscript. HB and TY contributed to the planning, conducting of the study and the revision of the manuscript. JIO contributed to analysis and interpretation of the data and the revision of the manuscript. 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 Yoshiaki Nakamura.

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Competing interests

KS reports honoraria from Yakult Honsha, Novartis Pharmaceuticals and Ono. Pharmaceutical; and grants for their institution from Bristol-Myers Squibb/Ono Pharmaceutical, Merck, Eisai and Incyte. YN reports advisory role from Guardant Health Pte Ltd, Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation, Gilead Sciences, Inc.; speakers’ bureau from Guardant Health Pte Ltd., MSD K.K, Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company, Guardant Health Japan Corp; research funding from Seagen, Inc., Genomedia Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc./Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd. MU reports honoraria (personal fee) from Taiho Pharmaceutical, AstraZeneca, Yakult Honsha, MSD, Nihon Servier, Ono Pharmaceutical, Incyte, Chugai Pharmaceutical, Boehringer Ingelheim, J-pharma, Daiichi Sankyo, Eisai, Takeda Pharmaceutical and Novartis; and research funding (grant) from Taiho Pharmaceutical, AstraZeneca, MSD, Astellas Pharma, Eisai, Ono Pharmaceutical, Incyte, Chugai Pharmaceutical, DFP (Delta Fly Pharma), Daiichi Sankyo, Novartis, Boehringer Ingelheim, J-pharma and Chiome Bioscience. N. Mizuno has received grants or contracts from any entity from to his institution from Novartis, MSD, Incyte, Ono Pharmaceutical, Seagen, Dainippon Sumitomo Pharma and Boehringer Ingelheim; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Yakult Honsha, AstraZeneca, Novartis, FUJIFILM Toyama Chemical, Taiho Pharmaceutical and MSD; participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. YK reports honoraria from Taiho Pharmaceutical, Merck, Yakult Honsha, Ono Pharmaceutical, Incyte, AstraZeneca and Lilly Japan; consulting or advisory role from Taiho Pharmaceutical; and research funding from Japan Agency for Medical Research and Development and Takeda. NO reports honoraria from Taiho Pharmaceutical, Eli Lilly Japan, Eisai, Bayer Yakuhin, Chugai Pharma, Ono Pharmaceutical, Takeda, Daiichi Sankyo, AstraZeneca, MSD and Incyte; advisory board from GlaxoSmithKline; and non-financial support from J-pharma. KU reports honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical and Yakult Honsha. MO reports honoraria from Taiho, Ono, Yakult, Servier, MSD, Pfizer, Bayer and Novartis. SS reports grants from AstraZeneca, Incyte Corporation and Delta-Fly Pharma. TS reports grants and personal fees from Ono pharmaceutical, Chugai-Pharmaceutical, Elli-Lilly, Daiichi-Sankyo and Taiho-Pharmaceutical; and grants from Yakult-Honsha, MSD, Hutch-Med, Shionogi and Jansen, outside the submitted work. MG reports personal fees and non-financial support from Chugai Pharmaceutical, Taiho Pharmaceutical and Ono Pharmaceutical; and personal fees from Eli Lilly Japan K.K. and MSD K.K., outside the submitted work. YY reports honoraria for lectures from Ono Pharmaceutical, Taiho, Bristol Myers Squibb, Servier, Yakult, Takeda, Chugai, Daiichi Sankyo, Lilly, Incyte and Bayer. JIO is an employee and stockholder of Guardant Health. HB reports honoraria from Taiho Pharmaceutical, Eli Lilly Japan and Ono Pharmaceutical; and grants from Ono Pharmaceutical outside the submitted work. TY reports honoraria from Chugai Pharma, Takeda Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical and MSD K.K; consulting fee: Sumitomo Corp.; and research grant/funding: Amgen, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex and Taiho. MI reports honoraria from Abbott, AbbVie, AstraZeneca, Bayer, Guardant Health Japan, Bristol Myers Squibb, Chugai Pharmaceutical, EA Pharma, Eisai, Fujifilm, Incyte, Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Nihon Servier, Taiho Pharmaceutical, Taisho Pharmaceutical Holdings, Takeda, Teijin Pharma and Yakult Honsha; advisory roles with AbbVie, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Chugai Pharmaceutical, Eisai, Guardant Health Japan, Lilly Japan, MSD, Novartis, Ono Pharmaceutical and Nihon Servier; and research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharmaceutical, Delta-Fly Pharma, Eisai, InVitae, J-Pharma, Lilly Japan, Merck, Merus NV, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Pfizer and Syneos Health. CM reports honoraria from Novartis, Yakult Honsha, Teijin Pharma, Taiho Pharmaceutical, Eisai, MSD K.K., and AstraZeneca; consulting fees with Yakult Honsha, MSD K.K., Servier, Boehringer Ingelheim and Taiho; and grants (for the institution) from Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, J-Pharma, AstraZeneca, Merck Biopharma, Daiichi Sankyo, HITACHI and Boehringer Ingelheim. MF, AA, KO, N. Matsuhashi, SI, TM, HO and HH have nothing to disclose.

Ethical 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 Research Ethics Review Committee of National Cancer Center (National Cancer Center Hospital East; National Cancer Center Hospital) and by the ethics committee/institutional review board of other participating institutions (Aichi Cancer Center; National Hospital Organisation Kyushu Cancer Center; Hokkaido University Hospital; Saitama Cancer Center; Kanagawa Cancer Center; Kansai Rosai Hospital; National Hospital Organisation Shikoku Cancer Center; NHO Osaka National Hospital; University of Tsukuba Hospital; Chiba Cancer Center; Kyorin University Hospital; Kindai University Hospital; Kyushu University Hospital; St. Marianna University School of Medicine; Osaka University Hospital; Cancer Institute Hospital of Japanese Foundation for Cancer Research; Kobe City Medical Center General Hospital; Osaka Medical and Pharmaceutical University Hospital; Gifu University Hospital; Kanazawa University Hospital; Shizuoka Cancer Center; Kagawa University Hospital; Keio University Hospital; Saitama Medical University International Medical Center; Shimane Prefectural Central Hospital; Kansai Medical University Hospital; Kyoto Katsura Hospital; Osaka International Cancer Institute; Osaka General Medical Center). Eligible patients provided written informed consent.

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Sudo, K., Nakamura, Y., Ueno, M. et al. Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02834-0

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