BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer: Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS)

Hiroya Taniguchi¹, Kay Uehara^{2

3}, Toshiaki Ishikawa^{4

5}, Osamu Okochi⁶, Naoya Akazawa⁷, Hiroyuki Okuda⁸, Hiroko Hasegawa⁹, Manabu Shiozawa¹⁰, Masato Kataoka¹¹, Hironaga Satake^{12

13}, Takaya Shimura¹⁴, Chihiro Kondoh^{15

16}, Hidekazu Kuramochi^{17

18}, Toshihiko Matsumoto^{19

20}, Naoki Takegawa²¹, Toshifumi Yamaguchi²², Michitaka Nagase²³, Masato Nakamura²⁴, Nao Takano^{25

26}, Hideto Fujita²⁷, Takanori Watanabe^{28

29}, Tomohiro Nishina³⁰, Yasuhiro Sakamoto³¹, Toshikazu Moriwaki^{32

33}, Hisatsugu Ohori³⁴, Masayoshi Nakanishi^{35

36}, Yosuke Kito³⁷, Setsuo Utsunomiya³⁸, Takeshi Ishikawa³⁹, Dai Manaka⁴⁰, Hiroshi Matsuoka⁴¹, Takeshi Suto⁴², Toshiyuki Arai⁴³, Shinichiro Shinzaki⁴⁴, Tohru Funakoshi⁴⁵, Goro Nakayama⁴⁶, Yuji Negoro⁴⁷, Yasushi Tsuji⁴⁸, Akitaka Makiyama^{49

50}, Kunio Takuma⁵¹, Atsuki Arimoto⁵², Katsunori Shinozaki⁵³, Ayako Mishima¹, Toshiki Masuishi¹

Affiliations

¹ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
² Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya 466-8560, Japan.
³ Department of Gastroenterological Surgery, Nippon Medical School, Tokyo 113-8603, Japan.
⁴ Department of Specialized Surgeries, Institute of Science Tokyo, Tokyo 113-8519, Japan.
⁵ Department of Medical Oncology, Juntendo University, Tokyo 113-8431, Japan.
⁶ Department of Surgery, Tosei General Hospital, Seto 489-8642, Japan.
⁷ Department of Gastroenterological Surgery, Sendai City Medical Center Sendai Open Hospital, Sendai 983-0824, Japan.
⁸ Department of Clinical Oncology, Keiyukai Sapporo Hospital, Sapporo 003-0026, Japan.
⁹ Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka 540-0006, Japan.
¹⁰ Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama 241-0815, Japan.
¹¹ Department of Surgery, NHO Nagoya Medical Center, Nagoya 460-0001, Japan.
¹² Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan.
¹³ Department of Medical Oncology, Kochi Medical School, Nankoku 783-8505, Japan.
¹⁴ Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8602, Japan.
¹⁵ Department of Medical Oncology, Toranomon Hospital, Tokyo 105-8470, Japan.
¹⁶ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
¹⁷ Department of Chemotherapy, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo 276-8524, Japan.
¹⁸ Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan.
¹⁹ Department of Internal medicine, Himeji Red Cross Hospital, Himeji 670-8540, Japan.
²⁰ Department of Medical Oncology, Ichinomiyanishi Hospital, Ichinomiya 494-0001, Japan.
²¹ Department of Gastroenterology, Hyogo Cancer Center, Akashi 673-8558, Japan.
²² Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki 569-0801, Japan.
²³ Department of Medical Oncology, Saku Central Hospital Advanced Care Center, Saku 385-0051, Japan.
²⁴ Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto 390-8510, Japan.
²⁵ Department of Surgery, Tokai Central Hospital, Kagamihara 504-8601, Japan.
²⁶ Department of Advanced Medicine, Nagoya University Hospital, Nagoya 466-8560, Japan.
²⁷ Department of General and Digestive surgery, Kanazawa Medical University, Uchinadamachi 920-0293, Japan.
²⁸ Department of Surgery, Japanese Red Cross Society Himeji Hospital, Himeji 670-8540, Japan.
²⁹ Department of Surgery, Tokushima Municipal Hospital, Tokushima 770-0812, Japan.
³⁰ Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama 791-0245, Japan.
³¹ Department of Medical Oncology, Osaki Citizen Hospital, Osaki 989-6183, Japan.
³² Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8576, Japan.
³³ Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki 710-8602, Japan.
³⁴ Department of Medical Oncology, Ishinomaki Red Cross Hospital, Ishinomaki 986-8522, Japan.
³⁵ Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
³⁶ Department of Surgery, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan.
³⁷ Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan.
³⁸ Department of Clinical Oncology, Kainan Hospital, Yatomi 498-8502, Japan.
³⁹ Outpatient Oncology Unit, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
⁴⁰ Department of Surgery, Kyoto Katsura Hospital, Kyoto 615-8256, Japan.
⁴¹ Department of Surgery, Fujita Health University, Toyoake 470-1192, Japan.
⁴² Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata 990-2292, Japan.
⁴³ Department of Surgery, Anjo Kosei Hospital, Anjo 446-8602, Japan.
⁴⁴ Department of Gastroenterology, School of Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan.
⁴⁵ Department of Surgery, Asahikawa Kosei General Hospital, Asahikawa 078-8211, Japan.
⁴⁶ Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
⁴⁷ Department of Oncological Medicine, Kochi Health Sciences Center, Kochi 781-8555, Japan.
⁴⁸ Department of Medical Oncology, Tonan Hospital, Sapporo 060-0004, Japan.
⁴⁹ Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushyu 806-0034, Japan.
⁵⁰ Cancer Center, Gifu University Hospital, Gifu 501-1194, Japan.
⁵¹ Department of Surgery, Tokyo Metropolitan Tama Medical Center, Fuchu 183-8524, Japan.
⁵² Department of General Surgery, Toyohashi Municipal Hospital, Toyohashi 441-8570, Japan.
⁵³ Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima 734-8530, Japan.

PMID: 39941768
PMCID: PMC11815755
DOI: 10.3390/cancers17030399

BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer: Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS)

Hiroya Taniguchi et al. Cancers (Basel). 2025.

. 2025 Jan 25;17(3):399.

doi: 10.3390/cancers17030399.

Authors

Affiliations

¹ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
² Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya 466-8560, Japan.
³ Department of Gastroenterological Surgery, Nippon Medical School, Tokyo 113-8603, Japan.
⁴ Department of Specialized Surgeries, Institute of Science Tokyo, Tokyo 113-8519, Japan.
⁵ Department of Medical Oncology, Juntendo University, Tokyo 113-8431, Japan.
⁶ Department of Surgery, Tosei General Hospital, Seto 489-8642, Japan.
⁷ Department of Gastroenterological Surgery, Sendai City Medical Center Sendai Open Hospital, Sendai 983-0824, Japan.
⁸ Department of Clinical Oncology, Keiyukai Sapporo Hospital, Sapporo 003-0026, Japan.
⁹ Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka 540-0006, Japan.
¹⁰ Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama 241-0815, Japan.
¹¹ Department of Surgery, NHO Nagoya Medical Center, Nagoya 460-0001, Japan.
¹² Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan.
¹³ Department of Medical Oncology, Kochi Medical School, Nankoku 783-8505, Japan.
¹⁴ Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8602, Japan.
¹⁵ Department of Medical Oncology, Toranomon Hospital, Tokyo 105-8470, Japan.
¹⁶ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
¹⁷ Department of Chemotherapy, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo 276-8524, Japan.
¹⁸ Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan.
¹⁹ Department of Internal medicine, Himeji Red Cross Hospital, Himeji 670-8540, Japan.
²⁰ Department of Medical Oncology, Ichinomiyanishi Hospital, Ichinomiya 494-0001, Japan.
²¹ Department of Gastroenterology, Hyogo Cancer Center, Akashi 673-8558, Japan.
²² Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki 569-0801, Japan.
²³ Department of Medical Oncology, Saku Central Hospital Advanced Care Center, Saku 385-0051, Japan.
²⁴ Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto 390-8510, Japan.
²⁵ Department of Surgery, Tokai Central Hospital, Kagamihara 504-8601, Japan.
²⁶ Department of Advanced Medicine, Nagoya University Hospital, Nagoya 466-8560, Japan.
²⁷ Department of General and Digestive surgery, Kanazawa Medical University, Uchinadamachi 920-0293, Japan.
²⁸ Department of Surgery, Japanese Red Cross Society Himeji Hospital, Himeji 670-8540, Japan.
²⁹ Department of Surgery, Tokushima Municipal Hospital, Tokushima 770-0812, Japan.
³⁰ Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama 791-0245, Japan.
³¹ Department of Medical Oncology, Osaki Citizen Hospital, Osaki 989-6183, Japan.
³² Department of Gastroenterology, University of Tsukuba, Tsukuba 305-8576, Japan.
³³ Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki 710-8602, Japan.
³⁴ Department of Medical Oncology, Ishinomaki Red Cross Hospital, Ishinomaki 986-8522, Japan.
³⁵ Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
³⁶ Department of Surgery, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan.
³⁷ Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan.
³⁸ Department of Clinical Oncology, Kainan Hospital, Yatomi 498-8502, Japan.
³⁹ Outpatient Oncology Unit, Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
⁴⁰ Department of Surgery, Kyoto Katsura Hospital, Kyoto 615-8256, Japan.
⁴¹ Department of Surgery, Fujita Health University, Toyoake 470-1192, Japan.
⁴² Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata 990-2292, Japan.
⁴³ Department of Surgery, Anjo Kosei Hospital, Anjo 446-8602, Japan.
⁴⁴ Department of Gastroenterology, School of Medicine, Hyogo Medical University, Nishinomiya 663-8501, Japan.
⁴⁵ Department of Surgery, Asahikawa Kosei General Hospital, Asahikawa 078-8211, Japan.
⁴⁶ Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
⁴⁷ Department of Oncological Medicine, Kochi Health Sciences Center, Kochi 781-8555, Japan.
⁴⁸ Department of Medical Oncology, Tonan Hospital, Sapporo 060-0004, Japan.
⁴⁹ Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kitakyushyu 806-0034, Japan.
⁵⁰ Cancer Center, Gifu University Hospital, Gifu 501-1194, Japan.
⁵¹ Department of Surgery, Tokyo Metropolitan Tama Medical Center, Fuchu 183-8524, Japan.
⁵² Department of General Surgery, Toyohashi Municipal Hospital, Toyohashi 441-8570, Japan.
⁵³ Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima 734-8530, Japan.

PMID: 39941768
PMCID: PMC11815755
DOI: 10.3390/cancers17030399

Abstract

Background/objectives: BRAF mutations occur in 5-10% of metastatic colorectal cancer (mCRC) cases, but their implications for prognosis and optimal treatment remain unclear.

Methods: This multicenter, prospective observational study analyzed 377 RAS wild-type cases from 511 patients across 32 centers, using PCR-based methods.

Results: BRAF mutations were identified in 21% (79/377) of cases, predominantly V600E (89.9%) with a minority of non-V600E (10.1%). Microsatellite instability (MSI) testing revealed MSI-high in 11.3%, exclusively among V600E cases. V600E mutations were linked to right-sided tumors, poor differentiation, and elevated CA19-9 levels. Median survival was significantly lower in V600E cases compared to BRAF wild-type (12.4 vs. 37.5 months, HR 3.25, p < 0.001) and marginally lower non-V600E cases (12.4 vs. 34.7 months, HR 0.61, p = 0.057). Chemotherapy regimens (doublet vs. triplet) and targeted treatments (bevacizumab vs. anti-EGFR) showed no significant survival differences in V600E patients. Similarly, RAS/BRAF wild-type patients had comparable survival with bevacizumab versus anti-EGFR, even for left-sided tumors.

Conclusions: These findings highlight distinct clinical and prognostic profiles for BRAF V600E and non-V600E mutations, while treatment choice appears to have limited impact on survival in these subgroups or RAS/BRAF wild-type cases.

Keywords: BRAF mutations; RAS wild-type; V600 mutation; anti-EGFR therapy; bevacizumab; chemotherapy regimens; metastatic colorectal cancer; microsatellite instability-high; non-V600 mutation; prognosis.

PubMed Disclaimer

Conflict of interest statement

Hiroya Taniguchi has received speaking honoraria from Takeda, Eli Lilly, and Ono, as well as research funding from Daiichi-Sankyo and Takeda. Kay Uehara has received speaking honoraria from Eli Lilly. Toshihiko Matsumoto has received speaking honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Merck BioPharma, MSD, Ono, Sanofi, Taiho, Takeda, and Yakult Honsha and research funding from Astellas and Sanofi. Yasuhiro Sakamoto has received honoraria from Eli Lilly, MSD, Ono, Daiichi-Sankyo, Taiho, Chugai, Takeda, Yakult Honsha, Bristol-Myers Squibb, Nippon Kayaku, and Kyowa Kirin. Toshifumi Yamaguchi has received honoraria for speaking from Ono MSD and Taiho. Toshikazu Moriwaki has received speaking honoraria and research funding from Takeda. Tomohiro Nishina has received speaking honoraria from Bristol Myers Squibb, Ono, Taiho, Eli Lilly, Daiichi-Sankyo, Astellas, and MSD. Takeshi Ishikawa has received speaking honoraria from MSD. Chihiro Kondoh has received research funding from Astellas, Daiichi-Sankyo, MSD, and Linical. Yosuke Kito has received speaking honoraria from Ono, Taiho, and Daiichi-Sankyo. Masato Nakamura has received speaking honoraria from Ono, MSD, Astra Zeneca, Chugai, Taiho Takeda, Merck BioPharma, Bayer, Eli Lilly Servier, and Daiichi-Sankyo. Akitaka Makiyama has received speaking honoraria from Eli Lilly, Ono, Bristol Myers Squibb, and Daiichi-Sankyo. Goro Nakayama has received speaking honoraria from Johnson-Johnson, AbbVie, Takeda, Miyarisan, Chugai, and Intuitive and research funding from Eli Lilly, AbbVie, and Towa. Hironaga Satake has received speaking honoraria from Sanofi, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Merck BioPharma, MSD, Ono, Taiho, Takeda, and Yakult Honsha, as well as research funding from Asahi KASEI, Ono, Daiichi-Sankyo, Taiho, and Takeda. Toshiki Masuishi has received speaking honoraria from Eli Lilly and research funding from Syneos Health and Amgen. All other authors declare no conflicts of interest.

Figures

**Figure 1**
Overall survival according to BRAF status. (a) BRAF V600E-mutant group versus BRAF wild-type group; (b) BRAF V600E-mutant group versus BRAF non-V600E mutant group.

**Figure 2**
Survival analysis according to treatment regimen in BRAF V600E-mutant group. (a) PFS and (b) OS analysis between doublet versus triplet regimen.; (c) PFS and (d) OS analysis between BEV versus anti-EGFR group.

**Figure 3**
Survival analysis according to treatment regimen in BRAF wild-type group. (a) PFS and (b) OS analysis between BEV versus anti-EGFR group in whole population.; (c) PFS and (d) OS analysis between BEV versus anti-EGFR group in patients with left-sided tumors.

See this image and copyright information in PMC

References

1. Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74:229–263. doi: 10.3322/caac.21834. - DOI - PubMed
1. Siegel R.L., Wagle N.S., Cercek A., Smith R.A., Jemal A. Colorectal cancer statistics, 2023. CA Cancer J. Clin. 2023;73:233–254. doi: 10.3322/caac.21772. - DOI - PubMed
1. Cancer Statistics Cancer Information Service, National Cancer Center, Japan (Vital Statistics of Japan, Ministry of Health, Labour and Welfare) [(accessed on 1 November 2024)]. Available online: https://ganjoho.jp/public/qa_links/report/statistics/pdf/cancer_statisti....
1. Kobayashi H., Asano M., Ishiguro M., Ishihara S., Inomata M., Kanemitsu Y., Komori K., Matsumoto H., Sugihara K., Ajioka Y. Multi-institutional Registry of Large Bowel Cancer in Japan Conducted by the Japanese Society for Cancer of the Colon and Rectum in 2023: Cases Treated in 2015. J. Anus Rectum Colon. 2024;8:265–270. doi: 10.23922/jarc.2024-065. - DOI - PMC - PubMed
1. Kawakami T., Masuishi T., Kawamoto Y., Go H., Kato K., Kumanishi R., Sawada K., Yuki S., Yamamoto K., Komatsu Y., et al. The survival benefit of increasing the number of active drugs for metastatic colorectal cancer: A multicenter retrospective study. Cancer Med. 2022;11:2184–2192. doi: 10.1002/cam4.4599. - DOI - PMC - PubMed

Grants and funding

Nothing/TAKEDA PHARMA

LinkOut - more resources

Full Text Sources
- MDPI
- PubMed Central
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer: Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS)

Affiliations

BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer: Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous