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; Kay Uehara; Toshiaki Ishikawa; Osamu Okochi; Naoya Akazawa; Hiroyuki Okuda; Hiroko Hasegawa; Manabu Shiozawa; Masato Kataoka; Hironaga Satake; Takaya Shimura; Chihiro Kondoh; Hidekazu Kuramochi; Toshihiko Matsumoto; Naoki Takegawa; Toshifumi Yamaguchi; Michitaka Nagase; Masato Nakamura; Nao Takano; Hideto Fujita; Takanori Watanabe; Tomohiro Nishina; Yasuhiro Sakamoto; Toshikazu Moriwaki; Hisatsugu Ohori; Masayoshi Nakanishi; Yosuke Kito; Setsuo Utsunomiya; Takeshi Ishikawa; Dai Manaka; Hiroshi Matsuoka; Takeshi Suto; Toshiyuki Arai; Shinichiro Shinzaki; Tohru Funakoshi; Goro Nakayama; Yuji Negoro; Yasushi Tsuji; Akitaka Makiyama; Kunio Takuma; Atsuki Arimoto; Katsunori Shinozaki; Ayako Mishima; Toshiki Masuishi

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
, Kay Uehara
, Toshiaki Ishikawa
, Osamu Okochi
, Naoya Akazawa
, Hiroyuki Okuda
, Hiroko Hasegawa
, Manabu Shiozawa
, Masato Kataoka
, Hironaga Satake
, Takaya Shimura
, Chihiro Kondoh
, Hidekazu Kuramochi
, Toshihiko Matsumoto
, Naoki Takegawa
, Toshifumi Yamaguchi
, Michitaka Nagase
, Masato Nakamura
, Nao Takano
, Hideto Fujita

Takanori Watanabe, Tomohiro Nishina, Yasuhiro Sakamoto, Toshikazu Moriwaki, Hisatsugu Ohori, Masayoshi Nakanishi, Yosuke Kito, Setsuo Utsunomiya, Takeshi Ishikawa, Dai Manaka, Hiroshi Matsuoka, Takeshi Suto, Toshiyuki Arai, Shinichiro Shinzaki, Tohru Funakoshi, Goro Nakayama, Yuji Negoro, Yasushi Tsuji, Akitaka Makiyama, Kunio Takuma, Atsuki Arimoto, Katsunori Shinozaki, Ayako Mishima, Toshiki Masuishi

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	399
Journal	Cancers
Volume	17
Issue number	3
DOIs	https://doi.org/10.3390/cancers17030399
Publication status	Published - 02-2025
Externally published	Yes

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/cancers17030399

Cite this

Taniguchi, H., Uehara, K., Ishikawa, T., Okochi, O., Akazawa, N., Okuda, H., Hasegawa, H., Shiozawa, M., Kataoka, M., Satake, H., Shimura, T., Kondoh, C., Kuramochi, H., Matsumoto, T., Takegawa, N., Yamaguchi, T., Nagase, M., Nakamura, M., Takano, N., ... Masuishi, T. (2025). 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). Cancers, 17(3), Article 399. https://doi.org/10.3390/cancers17030399

@article{a78280e361fb45738a98edfab947ad92,

title = "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)",

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",

author = "Hiroya Taniguchi and Kay Uehara and Toshiaki Ishikawa and Osamu Okochi and Naoya Akazawa and Hiroyuki Okuda and Hiroko Hasegawa and Manabu Shiozawa and Masato Kataoka and Hironaga Satake and Takaya Shimura and Chihiro Kondoh and Hidekazu Kuramochi and Toshihiko Matsumoto and Naoki Takegawa and Toshifumi Yamaguchi and Michitaka Nagase and Masato Nakamura and Nao Takano and Hideto Fujita and Takanori Watanabe and Tomohiro Nishina and Yasuhiro Sakamoto and Toshikazu Moriwaki and Hisatsugu Ohori and Masayoshi Nakanishi and Yosuke Kito and Setsuo Utsunomiya and Takeshi Ishikawa and Dai Manaka and Hiroshi Matsuoka and Takeshi Suto and Toshiyuki Arai and Shinichiro Shinzaki and Tohru Funakoshi and Goro Nakayama and Yuji Negoro and Yasushi Tsuji and Akitaka Makiyama and Kunio Takuma and Atsuki Arimoto and Katsunori Shinozaki and Ayako Mishima and Toshiki Masuishi",

note = "Publisher Copyright: {\textcopyright} 2025 by the authors.",

year = "2025",

month = feb,

doi = "10.3390/cancers17030399",

language = "English",

volume = "17",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "3",

}

Taniguchi, H, Uehara, K, Ishikawa, T, Okochi, O, Akazawa, N, Okuda, H, Hasegawa, H, Shiozawa, M, Kataoka, M, Satake, H, Shimura, T, Kondoh, C, Kuramochi, H, Matsumoto, T, Takegawa, N, Yamaguchi, T, Nagase, M, Nakamura, M, Takano, N, Fujita, H, Watanabe, T, Nishina, T, Sakamoto, Y, Moriwaki, T, Ohori, H, Nakanishi, M, Kito, Y, Utsunomiya, S, Ishikawa, T, Manaka, D, Matsuoka, H, Suto, T, Arai, T, Shinzaki, S, Funakoshi, T, Nakayama, G, Negoro, Y, Tsuji, Y, Makiyama, A, Takuma, K, Arimoto, A, Shinozaki, K, Mishima, A & Masuishi, T 2025, '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)', Cancers, vol. 17, no. 3, 399. https://doi.org/10.3390/cancers17030399

TY - JOUR

T1 - BRAF V600E and Non-V600E Mutations in RAS Wild-Type Metastatic Colorectal Cancer

T2 - Prognostic and Therapeutic Insights from a Nationwide, Multicenter, Observational Study (J-BROS)

AU - Taniguchi, Hiroya

AU - Uehara, Kay

AU - Ishikawa, Toshiaki

AU - Okochi, Osamu

AU - Akazawa, Naoya

AU - Okuda, Hiroyuki

AU - Hasegawa, Hiroko

AU - Shiozawa, Manabu

AU - Kataoka, Masato

AU - Satake, Hironaga

AU - Shimura, Takaya

AU - Kondoh, Chihiro

AU - Kuramochi, Hidekazu

AU - Matsumoto, Toshihiko

AU - Takegawa, Naoki

AU - Yamaguchi, Toshifumi

AU - Nagase, Michitaka

AU - Nakamura, Masato

AU - Takano, Nao

AU - Fujita, Hideto

AU - Watanabe, Takanori

AU - Nishina, Tomohiro

AU - Sakamoto, Yasuhiro

AU - Moriwaki, Toshikazu

AU - Ohori, Hisatsugu

AU - Nakanishi, Masayoshi

AU - Kito, Yosuke

AU - Utsunomiya, Setsuo

AU - Ishikawa, Takeshi

AU - Manaka, Dai

AU - Matsuoka, Hiroshi

AU - Suto, Takeshi

AU - Arai, Toshiyuki

AU - Shinzaki, Shinichiro

AU - Funakoshi, Tohru

AU - Nakayama, Goro

AU - Negoro, Yuji

AU - Tsuji, Yasushi

AU - Makiyama, Akitaka

AU - Takuma, Kunio

AU - Arimoto, Atsuki

AU - Shinozaki, Katsunori

AU - Mishima, Ayako

AU - Masuishi, Toshiki

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

KW - BRAF mutations

KW - RAS wild-type

KW - V600 mutation

KW - anti-EGFR therapy

KW - bevacizumab

KW - chemotherapy regimens

KW - metastatic colorectal cancer

KW - microsatellite instability-high

KW - non-V600 mutation

KW - prognosis

UR - https://www.scopus.com/pages/publications/85217542735

UR - https://www.scopus.com/pages/publications/85217542735#tab=citedBy

U2 - 10.3390/cancers17030399

DO - 10.3390/cancers17030399

M3 - Article

AN - SCOPUS:85217542735

SN - 2072-6694

VL - 17

JO - Cancers

JF - Cancers

IS - 3

M1 - 399

ER -

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)

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this