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

Kentaro Sudo¹, Yoshiaki Nakamura^{2

3}, Makoto Ueno⁴, Masayuki Furukawa⁵, Nobumasa Mizuno⁶, Yasuyuki Kawamoto⁷, Naohiro Okano⁸, Kumiko Umemoto⁹, Akinori Asagi¹⁰, Masato Ozaka¹¹, Koushiro Ohtsubo¹², Satoshi Shimizu¹³, Nobuhisa Matsuhashi^{14

15}, Shinji Itoh¹⁶, Toshihiko Matsumoto¹⁷, Taroh Satoh¹⁸, Hiroyuki Okuyama¹⁹, Masahiro Goto²⁰, Hiroko Hasegawa²¹, Yoshiyuki Yamamoto²², Justin I Odegaard²³, Hideaki Bando^{24

25}, Takayuki Yoshino²⁴, Masafumi Ikeda²⁶, Chigusa Morizane²⁷

Affiliations

¹ Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
² Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. yoshinak@east.ncc.go.jp.
³ Translational Research Support Office, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan. yoshinak@east.ncc.go.jp.
⁴ Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan.
⁵ Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
⁶ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁷ Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
⁸ Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan.
⁹ Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁰ Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹¹ Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
¹² Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
¹³ Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
¹⁴ Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan.
¹⁵ Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan.
¹⁶ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁷ Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.
¹⁸ Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan.
¹⁹ Department of Medical Oncology, Kagawa University Hospital, Kagawa, Japan.
²⁰ Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan.
²¹ Department of Gastroenterology and Hepatology, NHO, Osaka National Hospital, Osaka, Japan.
²² Department of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Japan.
²³ Guardant Health, Redwood City, CA, USA.
²⁴ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²⁵ Translational Research Support Office, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan.
²⁶ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²⁷ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

PMID: 39198618
PMCID: PMC11443054
DOI: 10.1038/s41416-024-02834-0

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

Kentaro Sudo et al. Br J Cancer. 2024 Oct.

. 2024 Oct;131(7):1237-1245.

doi: 10.1038/s41416-024-02834-0. Epub 2024 Aug 28.

Authors

Affiliations

¹ Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
² Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. yoshinak@east.ncc.go.jp.
³ Translational Research Support Office, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan. yoshinak@east.ncc.go.jp.
⁴ Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan.
⁵ Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
⁶ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁷ Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
⁸ Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan.
⁹ Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
¹⁰ Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹¹ Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
¹² Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
¹³ Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
¹⁴ Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan.
¹⁵ Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan.
¹⁶ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹⁷ Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.
¹⁸ Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan.
¹⁹ Department of Medical Oncology, Kagawa University Hospital, Kagawa, Japan.
²⁰ Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan.
²¹ Department of Gastroenterology and Hepatology, NHO, Osaka National Hospital, Osaka, Japan.
²² Department of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Japan.
²³ Guardant Health, Redwood City, CA, USA.
²⁴ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²⁵ Translational Research Support Office, Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan.
²⁶ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²⁷ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

PMID: 39198618
PMCID: PMC11443054
DOI: 10.1038/s41416-024-02834-0

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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Conflict of interest statement

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.

Figures

**Fig. 1. Comparison of progression-free survival (PFS) and overall survival (OS) between patients with or without putative germline *BRCA* (gBRCA) mutation in ctDNA.**
a PFS after starting platinum-containing therapy. b OS after starting platinum-containing therapy. c PFS after starting gemcitabine plus nab-paclitaxel (GnP). d OS after starting GnP.

**Fig. 2**
We focused on the efficacy of platinum-containing chemotherapy among patients without putative germline *BRCA* mutation and the panel shows the comparison of progression-free survival (PFS) after platinum-containing chemotherapy between patients with putative germline and/or somatic *ATM* mutation versus those without *BRCA*/*ATM* mutation in ctDNA.

**Fig. 3. A case with putative *BRCA2* reversion mutation.**
Major mutations detected in ctDNA analysis are listed in the upper frame of the figure. Nucleotide sequences and corresponding amino acid are shown. *BRCA2* c.1278del (D427fs) mutation resulted in a truncated protein. When *BRCA2* c.1287_1315del (L429fs) mutation occurred *in cis* and secondary to c.1278del (D427fs) mutation, original reading frame can be restored.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous