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Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies


Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.

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Fig. 1: Utility of ctDNA genotyping versus tissue genotyping in screening for targeted therapy trials.
Fig. 2: Landscape of ctDNA alterations in advanced GI cancers.
Fig. 3: Clonal architecture of ctDNA genomic alterations.

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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The authors thank all of the patients and their families who participated in this study; all SCRUM-Japan GI-SCREEN and GOZILA investigators and site personnel; M. Yuasa, Y. Ogata, S. Horasawa, M. Fujita, T. Nakamura, K. Kitajima, N. Kuramoto, H. Sokuoka and H. Uchigata (Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan) for study management and data center support; and Genomedia Inc. for data analysis. This work was supported by grants from the Japan Agency for Medical Research and Development (no. 19ck0106445h0002 to Y.N.), National Cancer Center Research and Development Fund (no. 31-A-5 to A.O.) and SCRUM-Japan Funds (

Author information




Y.N. and H.T. contributed equally to planning and conducting of studies, recruiting patients, acquisition of data, analysis and interpretation of data, statistical analysis and writing of the manuscript. M.I., H.B., K.K., C.M., T.E., Y. Komatsu, Y. Kawamoto, N.T., M.U., Y. Kagawa, T. Nishina, T.K., Y.Y., J.F., T.D., H.K., E.O., T. Nakajima, N.N., K. Yamaguchi, H.Y., M.G., N.M., K.O., K. Yamazaki and A.T. contributed to recruitment of patients and acquisition of data. W.O., K.T., I.M., Y.S., H.I. and M.H. contributed acquisition and analysis of data. T. Yamanaka contributed to statistical analyses. R.Y. contributed to bioinformatics analyses. A.O., J.I.O. and T. Yoshino contributed to planning and conducting of studies, interpretation of data and writing 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 Takayuki Yoshino.

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Competing interests

N.T., N.M., K.O., W.O., I.M., Y.S., H.I. and M.H. declare no competing interests. Y.N. reports research funding from Taiho Pharmaceutical. H.T. reports honoraria from Bayer, Sanofi, Takeda, Chugai, Taiho Pharmaceutical, Lilly Japan, Merck Serono, Yakult Honsha, MBL, Bristol-Myers Squibb, MSD, Novartis, Daiichi Sankyo, Mitsubishi Tanabe Pharma and Nippon Kayaku; and research funding from Sumitomo Dainippon Pharma, Array BioPharma, MSD Oncology, Ono Pharmaceutical, Daiichi Sankyo, Sysmex, Novartis and Takeda. M.I. reports honoraria from Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Sumitomo Dainippon Pharma, EA Pharma, Gilead, Teijin Pharma, Yakult, Taiho, Nobelpharma, Otsukam MSD, Mylan, NIHON SERVIER and Astellas; advisory roles with Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Chugai, Teijin Pharma, Kyowa Hakko Kirin, NanoCarrier and Shire; and research funding from Bayer, Bristol-Myers Squibb, Eli Lilly, Eisai, Takeda Pharmaceutical, AstraZeneca, Chugai, Merck Serono, ASLAN, Daiichi Sankyo, Novartis, Kyowa Hakko Kirin, NanoCarrier, Yakult, Taiho, Baxalta, Ono Pharmaceutical and J-Pharma. H.B. reports honoraria from Taiho Pharmaceutical, Lilly Japan, Takeda Pharmaceutical, Chugai, Sanofi and Yakult Honsha; and research funding from AstraZeneca and Sysmex. K.K. reports research funding from Ono Pharmaceutical, MSD, Shionogi, Merck Bio, Oncolys Biopharma and Beigene. C.M. reports honoraria from Novartis, Yakult Honsha, Teijin Pharma, Taiho Pharmaceutical, Eisai and MSD; advisory roles with Yakult Honsha, Novartis, Taiho Pharmaceutical and Abbvie; and research funding from Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, J-Pharma, AstraZeneca and Merck biopharma. T.E. reports honoraria from Eli Lilly and Chugai; and research funding from Novartis, Merck Serono, Sumitomo Dainippon Pharma, Ono Pharmaceutical, Daiichi Sankyo, MSD, Astellas, Parexel International, Amgen Astellas BioPharma and IQVIA. Y. Komatsu reports honoraria from Asahi Kasei Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, Medical Review, Merck Biopharma, Mitsubishi Tanabe Pharma, Moroo, Nipro, Ono Pharmaceutical, Pfizer Japan, Sanofi, Shire Japan and Taiho Pharmaceutical; and research funding from A2 Healthcare, Asahi Kasei Pharma, Astellas Pharma, Bayer Yakuhin, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eisai, Mediscience Planning, NanoCarrier, Ono Pharmaceutical, Parexel International, Sanofi-aventis, Shionogi & Co., Ltd, Taiho Pharmaceutical, Yakult Honsha, Incyte, IQVIA, MSD, Nippon Zoki Pharmaceutical, Syneos Health Clinical and Sysmex. Y. Kawamoto reports honoraria from Taiho Pharmaceutical, Takeda, Chugai, Daiichi Sankyo, Merck Serono and Lilly. M.U. reports honoraria from Taiho Pharmaceutical, Yakult Honsha, AstraZeneca, Teijin Pharma, Merck Serono, Nipro Corporation, MSD and Daiichi Sankyo; and research funding from Astellas Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Eisai, AstraZeneca, Ono Pharmaceutical, MSD, Merck Serono, Sumitomo Dainippon Pharma, Incyte, ASLAN Pharmaceutical and Yakult Honsha. Y. Kagawa reports honoraria from Chugai, Taiho Pharmaceutical, Bayer Yakuhin Japan, Eli Lilly, Yakult Honsha, Takeda Pharmaceutical, Ono Pharmaceutical and Merck Biopharma. T. Nishina reports honoraria from Taiho Pharmaceutical, Chugai, Ono Pharmaceutical, Bristol-Meyers Squibb and Lilly; and research funding from Taiho Pharmaceutical, Chugai, Daiichi Sankyo, MSD, Ono Pharmaceutical, Bristol-Meyers Squibb, Lilly and Sumitomo Dainippon Pharma. T.K. reports honoraria from Chugai, Yakult Honsha, Ono Pharmaceutical, Bayer, Takeda, Lilly Japan, Taiho Pharmaceutical, Mochida Pharmaceutical, Merck Serono and Asahi Kasei; and research funding from Chugai. Y.Y. reports honoraria from Taiho Pharmaceutical, Ono Pharmaceutical, Asahi Kasei, Sanofi, Nihonkayaku, Merck Serono and Yakult, Eisai. J.F. reports honoraria from Eisai, Bayer Yakuhin, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Yakult Honsha, Teijin Pharma, Shionogi, EA Pharma, Eli Lilly Japan, Takeda, Chugai, Mochida Pharmaceutical, Nihon Servier, Sanofi, Fujifilm Toyama Chemical, Nobelpharma, Pfizer, Sawai Pharmaceutical, Daiichi Sankyo, Sumitomo Dainippon Pharma, Merck Serono, Nippon Kayaku, MSD, Shire and Kyowa Hakko Kirin; advisory roles with Eisai, Fujifilm, Ono Pharmaceutical, Yakult Honsha, MSD, Merck Bio and J-Pharma; and research funding from Ono Pharmaceutical, MSD, Sumitomo Dainippon Pharma, J-Pharma, Yakult Honsha, AstraZeneca, Daiichi Sankyo, Eisai, Bayer, Pfizer, NanoCarrier, Kyowa Hakko Kirin, Taiho Pharmaceutical, Chugai, Sanofi, Takeda, Mochida Pharmaceutical, Astellas Pharma and Eli Lilly Japan. T.D. reports honoraria from Sawai Pharmaceutical; a speakers’ bureau with Sysmex; and research funding from MSD and Ono Pharmaceutical. H.K reports honoraria from Bristol-Myers Squibb, AstraZeneca, Bayer, Eli Lilly Japan, MSD, Ono Pharmaceutical, Chugai, Daiichi Sankyo, Takeda Pharmaceutical and Taiho Pharmaceutical; lecture fees from Bristol-Myers Squibb, Eli Lilly Japan, MSD, Ono Pharmaceutical, Chugai, Takeda Pharmaceutical and Taiho Pharmaceutical; consulting fees from Bristol-Myers Squibb, Eli Lilly Japan, MSD, Ono Pharmaceutical, Daiichi Sankyo and Taiho Pharmaceutical Co. Ltd; and research funding from Chugai, Taiho Pharmaceutical and Eisai. E.O. reports honoraria from Chugai, Taiho Pharmaceutical, Bayer Yakuhin Japan, Eli Lilly, Yakult Honsha, Takeda Pharmaceutical, Ono Pharmaceutical and Merck Biopharma. T. Nakajima reports honoraria from Celltrion Healthcare Japan, Taiho Pharmaceutical, Merck Serono, Chugai, Takeda Pharmaceutical, Sanofi, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku, Ono Pharmaceutical, MSD, Sawai Pharmaceutical, Bayer Yakuhin, Bristol-Myers Squibb, Teijin Pharma, Pfizer Japan, Novartis Japan, Yakult Honsha and Nipro; advisory roles with Bristol-Myers Squibb and Taiho Pharmaceutical; and research funding from Ono Pharmaceutical, MSD, Astellas Pharma, Sumitomo Dainippon Pharma, Eisai, Nippon Kayaku, Solasia Pharma, Chugai, Taiho Pharmaceutical, Daiichi Sankyo, Sanofi, Merck Serono, Daiichi Sankyo, Takeda Pharmaceutical and Eli Lilly Japan. N.N. reports research funding from Chugai, Yakult Honsha and Ono Pharmaceutical. K. Yamaguchi reports advisory roles with Bristol-Myers Squibb and Daiichi Sankyo; speakers’ bureaux with Chugai, Merck Serono, Bristol-Myers Squibb, Taiho Pharmaceutical, Lilly, Ono Pharmaceutical and Daiichi Sankyo; and research funding from Ono Pharmaceutical, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Lilly, Gilead Sciences, Yakult Honsha, Chugai, Boehringer Ingelheim, Eisai and MSD. H.Y. reports honoraria from Taiho Pharmaceutical, Chugai, Bristol-Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha and Bayer Yakuhin; and research funding from MSD, Daiichi Sankyo and Ono Pharmaceutical. M.G. reports honoraria from Yakult Honsha, Taiho Pharmaceutical, Daiichi Sankyo, Eisai and Ono Pharmaceutical; and research funding from Chugai, Taiho Pharmaceutical, Nippon Kayaku, Ono Pharmaceutical and Eli Lilly. K. Yamazaki reports honoraria from Chugai, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Lilly, Sanofi, Ono Pharmaceutical, MSD and Bristol-Myers Squibb. A.T. reports speakers’ bureaux with Taiho Pharmaceutical, Chugai, Eli Lilly Japan, Merck Serono, Sanofi and Bristol-Myers Squibb; and research funding from Taiho Pharmaceutical, Sanofi and Ono Pharmaceutical. K.T. reports honoraria from SRL Diagnostics, DNA Chip Research, Chugai, Novartis, Takeda, MSD, Sysmex, Nippon Kayaku, Illumina, Fujitsu, Varian Medical Systems, Miyarisan Pharmaceutical, Bristol-Myers Squibb, AstraZeneca and Novartis. T. Yamanaka reports honoraria from Chugai, Bayer, Boehringer Ingelheim and Takeda; and research funding from Chugai, Bayer and Mochida. R.Y. reports honoraria from Takeda Pharmaceutical. A.O. reports personal fees from Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical and Chugai; and a grant from Bristol-Myers Squibb. J.I.O. reports employment from, and stock interests in, Guardant Health. T. Yoshino reports research funding from Novartis Pharma, MSD, Sumitomo Dainippon Pharma, Chugai, Sanofi, Daiichi Sankyo, Parexel International, Ono Pharmaceutical and GlaxoSmithKline.

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Peer review information Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Patient disposition diagram.

This study included 5,621 of 5,742 patients enrolled in GI-SCREEN between February 2015 and April 2019, and 1,687 of 1,787 patients enrolled in GOZILA between January 2018 and August 2019.

Extended Data Fig. 2 Screening period duration.

a, Median interval between screening initiation and matched clinical trial enrollment. Two-sided P value is based on the Mann-Whitney test. b, Median interval between sample collection and matched clinical trial enrollment. Two-sided P value is based on the Mann-Whitney test.

Extended Data Fig. 3 Distribution of ctDNA fractions by cancer type.

The distribution of ctDNA fractions for all detected mutations by cancer type. CRC, colorectal cancer; GEA, gastroesophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; PDAC, pancreatic ductal adenocarcinoma; CCA, cholangiocarcinoma.

Extended Data Fig. 4 TMB score by MSI status identified by ctDNA genotyping.

The distribution of TMB score according to MSI status identified by ctDNA genotyping (MSS/MSI-L, N = 1408; MSI-H, N = 30). The boxes represent 25th–75th percentiles, centerlines indicate the median, whiskers extend to the maximum and minimum values within 1.5× of the interquartile range, and dots indicate outliers. Two-sided P value is based on the Mann-Whitney test. MSS, microsatellite stable; MSI-L, microsatellite low; MSI-H, microsatellite high.

Extended Data Fig. 5 Clonality of ctDNA mutations.

The distribution of clonality of ctDNA mutations in all GI cancers.

Supplementary information

Supplementary Information

Supplementary Fig. 1, Tables 1–5 and Protocol.

Reporting Summary

Supplementary Table

Supplementary Table 6.

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Nakamura, Y., Taniguchi, H., Ikeda, M. et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med 26, 1859–1864 (2020).

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