Clinical Validation of Plasma-Based Genotyping for RAS and BRAF V600E Mutation in Metastatic Colorectal Cancer: SCRUM-Japan GOZILA Substudy
Open accessAbstract
PURPOSE: Circulating tumor DNA (ctDNA) genotyping on the basis of next-generation sequencing (NGS) may guide targeted therapy for metastatic colorectal cancer (mCRC). However, the validity of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment and the efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA results remains unclear. PATIENTS AND METHODS: The performance of NGS-based ctDNA genotyping for RAS/BRAF V600E mutation assessment was compared with that of a validated polymerase chain reaction–based tissue testing in patients with mCRC enrolled in the GOZILA study, a nationwide plasma genotyping study. The primary end points were concordance rate, sensitivity, and specificity. The efficacy of anti-EGFR and BRAF-targeted therapies on the basis of ctDNA were also evaluated. RESULTS: In 212 eligible patients, the concordance rate, sensitivity, and specificity were 92.9% (95% CI, 88.6 to 96.0), 88.7% (95% CI, 81.1 to 94.0), and 97.2% (95% CI, 92.0 to 99.4) for RAS and 96.2% (95% CI, 92.7 to 98.4), 88.0% (95% CI, 68.8 to 97.5), and 97.3% (95% CI, 93.9 to 99.1) for BRAF V600E, respectively. In patients with a ctDNA fraction of ≥1.0%, sensitivity rose to 97.5% (95% CI, 91.2 to 99.7) and 100% (95% CI, 80.5 to 100.0) for RAS and BRAF V600E mutations, respectively. In addition to a low ctDNA fraction, previous chemotherapy, lung and peritoneal metastases, and interval between dates of tissue and blood collection were associated with discordance. The progression-free survival of anti-EGFR therapy and BRAF-targeted treatment was 12.9 months (95% CI, 8.1 to 18.5) and 3.7 (95% CI, 1.3 to not evaluated) months, respectively, for matched patients with RAS/BRAF V600E results by ctDNA. CONCLUSION: ctDNA genotyping effectively detected RAS/BRAF mutations, especially with sufficient ctDNA shedding. Clinical outcomes support ctDNA genotyping for determining the use of anti-EGFR and BRAF-targeted therapies in patients with mCRC.
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In SCRUM-Japan GOZILA, 19% of patients transitioned to NeoRAS WT status, where EGFR inhibitors showed potential efficacy, achieving partial responses or stable disease for six months or more.
“The SCRUM-Japan GOZILA study found 19% of patients transitioned to NeoRAS WT status, where EGFR inhibitors showed potential efficacy, achieving partial responses or stable disease for six months or more [53].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [53]
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Cites
Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer
André, T., Shiu, K.-K., Kim, T. W., Jensen, B. V., Jensen, L. H., Punt, C., Smith, D., Garcia-Carbonero, R., Benavides, M., Gibbs, P., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2017699 · Cited by 3,099 · see citing works
Self-citationPanitumumab–FOLFOX4 Treatment and <i>RAS</i> Mutations in Colorectal Cancer
Douillard, J.-Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305275 · Cited by 2,263 · see citing works
Overman, M. J., Lonardi, S., Wong, K. Y. M., Lenz, H.-J., Gelsomino, F., Aglietta, M., Morse, M. A., Van Cutsem, E., McDermott, R., Hill, A., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.9901 · Cited by 2,079 · see citing works
Douillard, J., Siena, S., Cassidy, J., Tabernero, J. M., Burkes, R. L., Barugel, M. E., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.4860 · Cited by 1,802 · see citing works
Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600E–Mutated Colorectal Cancer
Kopetz, S., Grothey, A., Yaeger, R., Van Cutsem, E., Desai, J., Yoshino, T., Wasan, H., Ciardiello, F., Loupakis, F., Hong, Y. S., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908075 · Cited by 1,491 · see citing works
Self-citationSartore-Bianchi, A., Trusolino, L., Martino, C., Bencardino, K., Lonardi, S., Bergamo, F., Zagonel, V., Leone, F., Depetris, I., Martinelli, E., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)00150-9 · Cited by 1,016 · see citing works
Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA
Thierry, A. R., Mouliere, F. C., Messaoudi, S. E., Mollévi, C., Lopez‐Crapez, E., Rolet, F., Gillet, B., Gongora, C., Dechelotte, P., Robert, B., et al. (2014) · Nature Medicine · doi:10.1038/nm.3511 · Cited by 681 · see citing works
Odegaard, J. I., Vincent, J. J., Mortimer, S., Vowles, J. V., Ulrich, B. C., Banks, K. C., Fairclough, S. R., Zill, O. A., Sikora, M., Mokhtari, R. B., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3831 · Cited by 437 · see citing works
Nakamura, Y., Taniguchi, H., Ikeda, M., Bando, H., Kato, K., Morizane, C., Esaki, T., Komatsu, Y., Kawamoto, Y., Takahashi, N., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-1063-5 · Cited by 373 · see citing works
Self-citationNakamura, Y., Okamoto, W., Kato, T., Esaki, T., Kato, K., Komatsu, Y., Yuki, S., Masuishi, T., Nishina, T., Ebi, H., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01553-w · Cited by 231 · see citing works
Self-citationGrasselli, J., Élez, E., Caratù, G., Matito, J., Santos, C., Macarulla, T. M., Vidal, J., García, M. D. S., Viéitez, J. M., Páez, D., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx112 · Cited by 187 · see citing works
Bachet, J., Bouché, O., Taı̈eb, J., Dubreuil, O., Garcia‐Larnicol, M., Meurisse, A., Normand, C., Gornet, J., Artru, P., Louafi, S., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy061 · Cited by 178 · see citing works
Schmiegel, W., Scott, R. J., Dooley, S., Lewis, W., Meldrum, C. J., Pockney, P. G., Draganic, B. D., Smith, S., Hewitt, C., Phillimore, H., et al. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12023 · Cited by 152 · see citing works
Effects of Metastatic Sites on Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer
Bando, H., Nakamura, Y., Taniguchi, H., Shiozawa, M., Yasui, H., Esaki, T., Kagawa, Y., Denda, T., Satoh, T., Yamazaki, K., et al. (2022) · JCO Precision Oncology · doi:10.1200/po.21.00535 · Cited by 111 · see citing works
Self-citationGarcía‐Foncillas, J., Alba, E., Aranda, E., Díaz‐Rubio, E., López‐López, R., Tabernero, J. M., & Vivancos, A. P. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx501 · Cited by 101 · see citing works
Bando, H., Kagawa, Y., Kato, T., Akagi, K., Denda, T., Nishina, T., Komatsu, Y., Oki, E., Kudo, T., Kumamoto, H., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0457-y · Cited by 92 · see citing works
Self-citationYamada, T., Iwai, T., Takahashi, G., Kan, H., Koizumi, M., Matsuda, A., Shinji, S., Yamagishi, A., Yokoyama, Y., Tatsuguchi, A., et al. (2016) · Cancer Science · doi:10.1111/cas.12959 · Cited by 84 · see citing works
Kagawa, Y., Élez, E., García‐Foncillas, J., Bando, H., Taniguchi, H., Vivancos, A. P., Akagi, K., García, A., Denda, T., Ros, J., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3677 · Cited by 78 · see citing works
Self-citationWang, F., Huang, Y., Wu, H., Wang, Z., Jin, Y., Yao, Y.-C., Chen, Y., Zhao, Q., Chen, S., He, M.-M., et al. (2021) · Gut · doi:10.1136/gutjnl-2021-324852 · Cited by 48 · see citing works
Mas, L., Bachet, J., Taly, V., Bouché, O., Taı̈eb, J., Cohen, R., Meurisse, A., Normand, C., Gornet, J., Artru, P., et al. (2019) · Cancers · doi:10.3390/cancers11070998 · Cited by 35 · see citing works
Taniguchi, H., Okamoto, W., Muro, K., Akagi, K., Hara, H., Nishina, T., Kajiwara, T., Denda, T., Hironaka, S., Kudo, T., et al. (2018) · Neoplasia · doi:10.1016/j.neo.2018.10.004 · Cited by 33 · see citing works
Self-citationNakamura, Y., Okamoto, W., Denda, T., Nishina, T., Komatsu, Y., Yuki, S., Yasui, H., Esaki, T., Sunakawa, Y., Ueno, M., et al. (2022) · JCO Precision Oncology · doi:10.1200/po.21.00383 · Cited by 30 · see citing works
Self-citationBenavides, M., Alcaide, J., Torres, E., et al. (2022) · ESMO Open · doi:10.1016/j.esmoop.2022.100481 · Cited by 24 · see citing works
BRAF V600E mutations in right-side colon cancer: Heterogeneity detected by liquid biopsy
Ueda, K., Yamada, T., Ohta, R., Matsuda, A., Sonoda, H., Kuriyama, S., Takahashi, G., Iwai, T., Takeda, K., Miyasaka, T., et al. (2022) · European Journal of Surgical Oncology · doi:10.1016/j.ejso.2022.01.016 · Cited by 14 · see citing works
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Osumi, H., Shinozaki, E., Nakamura, Y., Esaki, T., Yasui, H., Taniguchi, H., Satake, H., Sunakawa, Y., Komatsu, Y., Kagawa, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50026-4 · Cited by 17 · see citing works
Self-citationSütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Aoki, Y., Nakamura, Y., Denda, T., Ohta, T., Esaki, T., Shiozawa, M., Yamaguchi, K., Yamazaki, K., Sunakawa, Y., Kato, T., Okano, N., Taniguchi, H., Sato, T., Oki, E., Nishina, T., Komatsu, Y., Matsuhashi, N., Goto, M., Yasui, H., Ohtsubo, K., Moriwaki, T., Takahashi, N., Horita, Y., Boku, S., Wakabayashi, M., Ikeno, T., Mitani, R., Yuasa, M., & Yoshino, T.
- Affiliations
- Keio University (JP)
- National Cancer Center Hospital East (JP)
- Chiba Cancer Center (JP)
- Kansai Rosai Hospital (JP)
- National Hospital Organization Kyushu Cancer Center (JP)
- Kanagawa Cancer Center (JP)
- The Cancer Institute Hospital (JP)
- Shizuoka Cancer Center (JP)
- St. Marianna University School of Medicine (JP)
- Osaka National Hospital (JP)
- Kyorin University (JP)
- Aichi Cancer Center (JP)
- Osaka University Hospital (JP)
- Kyushu University (JP)
- Shikoku Cancer Center (JP)
- Hokkaido University Hospital (JP)
- Gifu University (JP)
- Osaka Medical and Pharmaceutical University (JP)
- Kobe Medical Center (JP)
- Kanazawa University (JP)
- University of Tsukuba Hospital (JP)
- Saitama Cancer Center (JP)
- Saitama International Medical Center (JP)
- Kansai Medical University Hospital (JP)
- Corresponding author
- Yoshino, Takayuki
- ORCID
- Aoki, Yu
- Nakamura, Yoshiaki
- Denda, Tadamichi
- Ohta, Takashi
- Esaki, Taito
- Shiozawa, Manabu
- Yamaguchi, Kensei
- Yamazaki, Kentaro
- Sunakawa, Yu
- Kato, Takeshi
- Okano, Naohiro
- Taniguchi, Hiroya
- Sato, Taro
- Oki, Eiji
- Nishina, Tomohiro
- Komatsu, Yoshito
- Matsuhashi, Nobuhisa
- Goto, Masahiro
- Yasui, Hisateru
- Ohtsubo, Koushiro
- Moriwaki, Toshikazu
- Takahashi, Naoki
- Horita, Yosuke
- Boku, Shogen
- Wakabayashi, Masashi
- Ikeno, Takashi
- Mitani, Ryuta
- Yoshino, Takayuki
- Venue
- JCO Precision Oncology
- Published
- 2023-06
- Volume
- 7
- Issue
- 7
- Pages
- e2200688-e2200688
- ISSN
- 2473-4284 (ISSN-L)
- PMC
- PMC10309506
- OpenAlex
- W4381487631
- Cited by
- 11
- References
- 24
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 2
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- JCO Precision Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Gilead Sciences
- Array BioPharma
- Merck KGaA
- Taiho Pharmaceutical
- Nihon Medi-Physics
- Parexel
- BeiGene
- Boehringer Ingelheim Japan
- Incyte
- Nipro
- Kaken Pharmaceutical
- Azərbaycan Milli Elmlər Akademiyası
- Daiichi-Sankyo
- Dainippon Sumitomo Pharma
- Eisai
- Astellas Pharma
- Shionogi
- Yakult Honsha
- Mitsubishi Tanabe Pharma Corporation
- Ono Pharmaceutical
- Chugai Pharmaceutical
- Eli Lilly Japan
- Bayer Yakuhin
- Daiichi Sankyo Company
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- metastatic colorectal cancer, circulating tumor DNA, liquid biopsy, BRAF V600E mutation, plasma genotyping, ctDNA fraction, anti-EGFR therapy, BRAF-targeted therapy, targeted therapy selection, progression-free survival, KRAS mutation, KRAS wild-type
- MeSH terms
- Colonic Neoplasms, Genotype, Humans, Japan, Mutation, Rectal Neoplasms, Colorectal Neoplasms, Proto-Oncogene Proteins B-raf
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