Combined Analysis of Concordance Between Liquid and Tumor Tissue Biopsies for RAS Mutations 3 in Colorectal Cancer with a Single Metastasis Site: the METABEAM Study
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Author Manuscript Published OnlineFirst on February 18, 2021; DOI: 10.1158/1078-0432.CCR-20-3677 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Article type: Research article 2 Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for RAS Mutations 3 in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study 4 Yoshinori Kagawa1, Elena Elez Fernandez2, Jesus Garcia-Foncillas3, Hideaki Bando4, Hiroya Taniguchi5, 5 Ana Vivancos6, Kiwamu Akagi7, Ariadna Garcia2, Tadamichi Denda8, Javier Ros2, Tomohiro Nishina9, 6 Iosune Baraibar2, Yoshito Komatsu10, Davide Ciardiello2,11, Eiji Oki12, Toshihiro Kudo13, Takeshi Kato14, 7 Takeharu Yamanaka15, Josep Tabernero2, Takayuki Yoshino5 8 9 1Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan 10 2Department of Medical Oncology, Vall d’Hebron University Hospital (HUVH), Vall d’Hebron Institute 11 of Oncology (VHIO); IOB-Quiron, UVic-UCC, Barcelona, Spain 12 3Oncology Department, Fundacion Jimenez Diaz University Hospital, Autonomous University; Madrid, 13 Spain 14 4Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan 15 5Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, 16 Japan 17 6Cancer Genomics Group, Vall d’Hebron Institute of Oncology, Barcelona, Barcelona, Spain 18 7Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Ina, Saitama, Japan 19 8Division of Gastroenterology, Chiba Cancer Center, Chiba, Chiba, Japan 20 9Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer 21 Center, Matsuyama, Ehime, Japan 22 10Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, 23 Hokkaido, Japan 24 11Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy 25 12Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, 26 Fukuoka, Fukuoka, Japan 27 13Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, 28 Osaka University, Suita, Osaka, Japan 29 14Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Osaka, 30 Japan. 31 15Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Kanagawa, 32 Japan 33 34 Running title: RAS Mutations in CRC Tested by Liquid and Tumor Biopsies 35 36 Keywords 1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 18, 2021; DOI: 10.1158/1078-0432.CCR-20-3677 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 37 Colorectal cancer, circulating tumor DNA, liquid biopsy, organ specificity, RAS mutations 38 39 Funding 40 This work was funded and sponsored by Sysmex Corporation. 41 42 Correspondence to: Dr. Takayuki Yoshino 43 Department of Gastrointestinal Oncology, National Cancer Center Hospital East 44 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277-8577, Japan 45 Tel: +81-4-7133-1111 46 Fax: +81-4-7131-9960 47 E-mail: [email protected] 48 49 Disclosure of Conflict of Interest 50 Y Kagawa reports personal fees received from Bayer, Chugai, Eli Lilly, Merck, Ono, and Taiho, grants 51 and personal fees from Takeda, and personal fees from Yakult Honsha outside the submitted work. E 52 Elez reports personal financial interests in the form of a scientific consultancy role for AbbVie, 53 Amgen, Array BioPharma, Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Roche, MedImmune, 54 Merck Serono, MSD, Novartis, Pierre-Fabre, Sanofi-Aventis, and Servier. J Garcia-Foncillas reports 55 consultancies/advisories undertaken for Abbott, Amgen, Astellas, AstraZeneca, Bayer, Biocartis, 56 Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisai, Foundation Medicine, GSK, Hospira, 57 Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, 58 and Tesaro. H Bando reports honoraria received from Chugai, Eli Lilly, Merck Serono, Taiho, Takeda, 59 Sanofi, and Yakult Honsha. H Taniguchi reports honoraria received from Bayer, Bristol-Myers Squibb, 60 Chugai, Daiichi Sankyo, Eli Lilly, MBL, Merck Serono, Mitsubishi Tanabe Pharma, MSD, Nippon 61 Kayaku, Novartis, Sanofi, Taiho, Takeda, and Yakult Honsha; research funding received from Array 62 BioPharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, MSD, Novartis, Ono, Sysmex, and Takeda. 63 K Akagi reports honoraria received from MSD and Taiho. T Denda reports lecture fees received from 64 Sysmex; honoraria received from Sawai; research funding received from MSD and Ono. T Nishina 65 reports honoraria received from Bristol-Myers Squibb, Chugai, Eli Lilly, Merck Serono, Nippon Kayaku, 66 Taiho, and Takeda; research funding received from Chugai, Daiichi Sankyo, Dainippon Sumitomo 67 Pharma, Eisai, Eli Lilly, Merck Serono, MSD, Ono, and Taiho. Y Komatsu reports research funding 68 received from Astellas, A2 Healthcare, Bayer, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli 69 Lilly, EP-CRSU, EPS, Incyte, IQVIA, Kyowa Kirin, Linical, Mediscience Planning, MSD, NanoCarrier, Ono, 70 Parexel, QuintilesIMS, Sanofi-Aventis, Syneos Health, Sysmex, Taiho, and Yakult Honsha; lecture fees 71 from Asahi Kasei Pharma, Bayer, Bristol-Myers Squibb, Chugai, CROee, Daiichi Sankyo, EA Pharma, Eli 72 Lilly, Kyowa Kirin, Mitsubishi Tanabe Pharma, Moroo, Nippon Kayaku, Nipro, Ono, Otsuka, Pfizer, 73 Sanofi-Aventis, Sanofi, Taiho, Takeda, and Yakult Honsha; honoraria received from Asahi Kasei, Bayer, 74 Chugai, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, Medical Review, Merck, MSD, Nippon Kayaku, Nipro, 75 Novartis, Ono, Pfizer, Sanofi-Aventis, Sanofi, Sawai, Shiseido, Taiho, Takeda, and Yakult Honsha. E 76 Oki reports lecture fees received from Bayer, Chugai, Eli Lilly, Merck, Ono, Taiho, Takeda, and Yakult 77 Honsha. T Kato reports honoraria received from Bayer, Boehringer Ingelheim, Chugai, Ono, Taiho, 78 and Takeda; research funding from Chugai and Takeda. J Tabernero reports personal financial 79 interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, 2 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 18, 2021; DOI: 10.1158/1078-0432.CCR-20-3677 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 80 Biocartis, Boehringer Ingelheim, Chugai, Foundation Medicine, Roche, Genentech, Genmab, HalioDX 81 SAS, Halozyme, Imugene, Inflection Biosciences, Ipsen, Kura, Eli Lilly, Menarini, Merck Serono, 82 Merrimack, Merus, Molecular Partners, MSD, Novartis, Peptomyc, Pfizer, Pharmacyclics, 83 ProteoDesign SL, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, SeaGen, Seattle Genetics, 84 Servier, Symphogen, Taiho, and VCN Biosciences. T Yoshino reports research funding received from 85 Chugai, Daiichi Sankyo, Dainippon Sumitomo Pharma, GSK, MSD, Novartis, Ono, Parexel, and Sanofi. 86 All remaining authors have declared no conflicts of interest. 87 88 Word count (main text): 2747 89 Number of Figures: 4 90 Number of Tables: 1 3 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 18, 2021; DOI: 10.1158/1078-0432.CCR-20-3677 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 91 Translational Relevance 92 The BEAMing technology with the OncoBEAMTM RAS CRC Kit can detect the plasma RAS status in 93 patients with metastatic colorectal cancer (mCRC). However, the concordance rate in circulating 94 tumor DNA (ctDNA) and tumor tissue RAS status varies by metastatic site. We conducted the first 95 international collaboration study on the concordance rate of liquid and tumor biopsy RAS status by 96 metastatic site. The utility of OncoBEAMTM may depend on tumor burden and/or the metastatic site. 97 There is no need to consider the cut-off for patients with only liver metastases. The baseline longest 98 diameter and number of lesions are associated with the concordance rate. Peritoneal metastases 99 alone with a lesion diameter <20 mm, lung metastases alone with a lesion diameter <20 mm, and 100 <10 lesions are discordant for ctDNA testing. Careful consideration should be given to patients with 101 mCRC with lung or peritoneal metastases only when using liquid biopsy. 4 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 18, 2021; DOI: 10.1158/1078-0432.CCR-20-3677 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 102 Abstract 103 Background: OncoBEAMTM is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital 104 polymerase chain reaction technology. We clarified the association between the baseline tumor 105 burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site. 106 Patients and methods: Data from previous Spanish and Japanese studies investigating the 107 concordance of the RAS status between OncoBEAMTM and tissue biopsy in 221 patients with 108 metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, 109 peritoneal,