Abstract“NeoRAS WT” refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible.

摘要“NeoRAS WT”是指转移性结直肠癌（mCRC）一线治疗后RAS突变（MTs）的丧失。我们使用血浆循环肿瘤DNA的下一代测序来评估NeoRAS WT mCRC的发生率和临床病理特征。参加GOZILA研究的mCRC患者最初被诊断为组织RAS-MT mCRC并接受了随后的全身治疗，符合条件。

NeoRAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. NeoRAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B.

NeoRAS WT定义为血浆中不存在可检测的RAS-MT，并在所有符合条件的患者（A组）和血浆中检测到至少一种体细胞改变的亚组（B组）中进行评估。总体而言，包括478名患者。A组NeoRAS WT患病率为19.0%（91/478），B组为9.8%（42/429）。

Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with NeoRAS WT emergence. Overall, 1/6 and 2/6 patients with NeoRAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively.

除KRAS外显子2 MT外，没有肝脏或淋巴结转移以及组织RAS MT与NeoRAS WT的出现显着相关。总体而言，用抗EGFR单克隆抗体（mAb）治疗的NeoRAS WT患者中有1/6和2/6分别显示部分缓解和疾病稳定≥6个月。

NeoRAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective..

NeoRAS WT mCRC的患病率很高，基于抗EGFR mAb的治疗可能是有效的。。

IntroductionRAS genes (KRAS, NRAS, and HRAS) are oncogenes that produce RAS proteins responsible for transmitting signals that promote cell growth1. RAS mutations (MTs) are associated with carcinogenesis in many cancers; however, effective therapies for these cancers are limited2. Overall, 17% of solid tumors involve KRAS MTs, including ~50% of metastatic colorectal cancer (mCRC) cases3,4.

引言RAS基因（KRAS，NRAS和HRAS）是产生RAS蛋白的致癌基因，负责传递促进细胞生长的信号1。RAS突变（MTs）与许多癌症的致癌作用有关；然而，对这些癌症的有效治疗是有限的2。总体而言，17%的实体瘤涉及KRAS MTs，包括约50%的转移性结直肠癌（mCRC）病例3,4。

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs), namely, cetuximab and panitumumab, are a mainstay of mCRC therapy, but they are ineffective against RAS MT mCRC5,6. The current clinical practice guidelines recommend RAS gene testing before administering anti-EGFR mAb-based therapy to patients with mCRC7,8,9.

抗表皮生长因子受体（EGFR）单克隆抗体（mAb），即西妥昔单抗和帕尼单抗，是mCRC治疗的主要手段，但它们对RAS-MT mCRC5,6无效。目前的临床实践指南建议在对mCRC7,8,9患者进行基于抗EGFR mAb的治疗之前进行RAS基因检测。

Given the lack of treatment options for these patients and their poor prognosis10, further therapeutic developments are urgently needed.Understanding of the mechanisms by which the RAS mutational status evolves before and after treatment has recently advanced, primarily owing to advances in circulating tumor DNA (ctDNA)-based diagnostics that enable minimally invasive, simple, and repeatable testing11,12,13.

鉴于这些患者缺乏治疗选择，预后不佳10，迫切需要进一步的治疗发展。对RAS突变状态在治疗前后演变的机制的理解最近有所进展，主要是由于基于循环肿瘤DNA（ctDNA）的诊断技术的进步，这些诊断技术能够实现微创，简单和可重复的测试11,12,13。

RAS MTs in ctDNA have been identified in patients with anti-EGFR mAb-resistant RAS “WT” mCRC, many of whom acquire the condition after exposure to anti-EGFR mAbs14,15. Contrarily, initially diagnosed RAS MT patients have RAS WT after chemotherapy-based treatment. This phenomenon, called “NeoRAS WT” mCRC, has attracted research attention because anti-EGFR mAbs, conventionally ineffective against RAS MT mCRC, may be effective in NeoRAS WT mCRC16,17,18.

已经在抗EGFR mAb抗性RAS“WT”mCRC患者中鉴定出ctDNA中的RAS-MT，其中许多患者在暴露于抗EGFR mAb14,15后获得该病症。相反，最初诊断的RAS MT患者在基于化疗的治疗后患有RAS WT。这种被称为“NeoRAS-WT”mCRC的现象引起了研究关注，因为抗EGFR单克隆抗体通常对RAS-MT mCRC无效，可能对NeoRAS-WT mCRC16,17,18有效。

Several clinical trials on the safety and efficacy of anti-EGFR mAbs for the treatment of NeoRAS WT mCRC are ongoing19,20.The incidence of NeoRAS WT mCRC varied widely from 20% to 80% among previous studi.

关于抗EGFR单克隆抗体治疗NeoRAS WT mCRC的安全性和有效性的几项临床试验正在进行中19,20。在以前的研究中，NeoRAS WT mCRC的发生率从20%到80%不等。

Data availability

数据可用性

The authors declare that all variant data used in the conduct of the analyses are available within the article and its supplementary information. The datasets, including individual participant data supporting the results reported in this article, will be made available within 3 months from initial request to researchers depending on methodological considerations.

。这些数据集，包括支持本文报告结果的个人参与者数据，将在最初向研究人员提出要求后的3个月内提供，具体取决于方法学考虑。

The initial contact for the request will be made with the corresponding authors Eiji Shinozaki (eiji.shinozaki@jfcr.or.jp) and Takayuki Yoshino (tyoshino@east.ncc.go.jp). In this cohort, raw ctDNA sequence data was not provided by Guardant Health, other than the source data used for the analysis because of data privacy regulations and restrictions on their use in patient consent forms.

该请求的初始联系将与通讯作者Eiji Shinozaki进行(eiji.shinozaki@jfcr.or.jp)和吉野隆之(tyoshino@east.ncc.go.jp)。在这个队列中，原始ctDNA序列数据不是由Guardant Health提供的，而是用于分析的源数据，因为数据隐私规定以及在患者同意书中使用它们的限制。

Source data are provided as a source data file. Source data are provided with this paper..

。本文提供了源数据。。

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Download referencesAcknowledgementsThe authors would like to thank all the patients and their families, all the investigators, research nurses, and study coordinators who participated in this study. Collaborators with GI-SCREEN and GOZILA study Aichi Cancer Center Hospital: Yukiya Narita and Toshiki Masuishi; Gifu University Hospital: Kazuhiro Yoshida; Kagawa University Hospital: Akihito Tsuji; Kanazawa University: Yuta Adachi and Koushiro Ohtsubo; Kyorin University: Junji Furuse; Kyushu University: Eiji Oki; National Cancer Center Hospital: Ken Kato; Saitama Medical University: Yosuke Horita; Shimane Prefectural Central Hospital: Akiyoshi Kanazawa; Shizuoka Cancer Center: Kentaro Yamazaki; St.

下载参考文献致谢作者要感谢所有参与本研究的患者及其家属，所有研究人员，研究护士和研究协调员。GI-SCREEN和GOZILA研究爱知癌症中心医院的合作者：成田由纪和Masuishi Toshiki；岐阜大学医院：吉田和弘；Kagawa大学医院：明仁町；金泽大学：Yuta Adachi和Koushiro Ohtsubo；Kyorin大学：Junji Furuse；九州大学：Eiji Oki；国家癌症中心医院：加藤；埼玉医科大学：Yosuke Horita；岛根县中央医院：金泽明吉；静冈癌症中心：山崎健太郎；圣。

Marianna University: Takako Nakajima; University of Tsukuba Hospital: Toshikazu Moriwaki. This work was supported by the National Cancer Center Research and Development Fund (31-A-5 to A. Ohtsu) and SCRUM-Japan Funds (http://www.scrum-japan.ncc.go.jp/index.html).Author informationAuthors and AffiliationsDepartment of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanHiroki Osumi, Eiji Shinozaki & Kensei YamaguchiDepartment of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, JapanYoshiaki Nakamura, Hideaki Bando & Takayuki YoshinoDepartment of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, JapanTaito EsakiDepartment of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, JapanHisateru YasuiDepartment of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, JapanHiroya TaniguchiDepartment of Medical Oncology, Kochi Medical School, Kochi, JapanHironaga SatakeDepartment of Clinical Oncolo.

马里安娜大学：中岛隆子；筑波大学医院：Toshikazu Moriwaki。这项工作得到了国家癌症中心研究与发展基金（A.Ohtsu的31-A-5）和SCRUM日本基金的支持(http://www.scrum-japan.ncc.go.jp/index.html)。作者信息作者和附属机构日本东京癌症研究基金会癌症研究所医院胃肠化疗科，东京，日本小须弥，Eiji Shinozaki＆Kensei Yamaguchi国家癌症中心医院东消化道和胃肠道肿瘤学系，Kashiwa，JapanYoshiaki Nakamura，Hideaki Bando＆Takayuki YoshinoDepartment胃肠道和医学肿瘤学，国家医院组织九州癌症中心，福冈，日本安藤-以斯基医学肿瘤学系，神户市医学中心总医院，神户，日本安史太鲁临床肿瘤学系，爱知癌症中心日本名古屋医院日本高知市高知医学院医学肿瘤学系临床肿瘤学系。

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PubMed Google ScholarContributionsHiroki Osumi (conceptualization: lead; data curation: lead; formal analysis: lead; investigation: lead; methodology: lead; project administration: lead; and writing – original draft: lead). Eiji Shinozaki (conceptualization: equal; project administration: lead; supervision: lead; and writing – review & editing: lead).

PubMed Google ScholarContributionsHiroki Osumi（概念化：领导；数据管理：领导；形式分析：领导；调查：领导；方法：领导；项目管理：领导；写作-原稿：领导）。Eiji Shinozaki（概念化：平等；项目管理：领导；监督：领导；写作-评论和编辑：领导）。

Yoshiaki Nakamura (funding acquisition: lead; methodology: lead; resources: lead; and visualization: lead; writing – review & editing: lead) Taito Esaki (writing – review & editing: supporting). Hiroya Taniguchi (writing – review & editing: supporting). Hironaga Satake (writing – review & editing: supporting).

。Hiroya Taniguchi（写作-评论和编辑：支持）。Hironaga Satake（写作-评论和编辑：支持）。

Yu Sunakawa (writing – review & editing: supporting). Yoshito Komatsu (writing – review & editing: supporting). Yoshinori Kagawa (writing – review & editing: supporting). Tadamichi Denda (writing – review & editing: supporting). Manabu Shiozawa (writing – review & editing: supporting). Taroh Satoh (writing – review & editing: supporting).

Yu Sunakawa（写作-评论和编辑：支持）。小松吉人（写作-评论与编辑：支持）。Kagawa Yoshinori（写作-评论和编辑：支持）。Tadamichi Denda（写作-评论和编辑：支持）。Manabu Shiozawa（写作-评论和编辑：支持）。Taroh Satoh（写作-评论和编辑：支持）。

Tomohiro Nishina (writing – review & editing: supporting). Masahiro Goto (writing – review & editing: supporting). Naoki Takahashi (writing – review & editing: supporting). Takeshi Kato (writing – review & editing: supporting). Hideaki Bando (writing – review & editing: supporting). Kensei Yamaguchi (supervision: supporting; writing – review & editing: supporting).

西泽友弘（写作-评论和编辑：支持）。Masahiro Goto（写作-评论和编辑：支持）。Naoki Takahashi（写作-评论和编辑：支持）。。Hideaki Bando（写作-评论和编辑：支持）。Kensei Yamaguchi（监督：支持；写作-评论和编辑：支持）。

Takayuki Yoshino (funding acquisition: lead; methodology: lead; project administration: lead; resources: lead; supervision: equal; writing – review & editing: supporting).Corresponding authorsCorrespondence to.

Takayuki Yoshino（资金获取：领导；方法：领导；项目管理：领导；资源：领导；监督：平等；写作-评论和编辑：支持）。通讯作者通讯。

Eiji Shinozaki or Takayuki Yoshino.Ethics declarations

Eiji Shinozaki或Takayuki Yoshino。道德宣言

Competing interests

相互竞争的利益

Eiji Shinozaki: Takeda Pharma, Merck, Lily, and Chugai Pharma. Yoshiaki Nakamura: Chugai Pharma, Guardant Health AMEA, and Merck Research Funding: Taiho Pharmaceutical (Inst), Guardant Health (Inst), Genomedia (Inst), Chugai Pharma (Inst), Guardant Health (Inst), Seattle Genetics (Inst), and Roche (Inst) Taito Esaki: Lilly, Taiho Pharmaceutical, Daiichi Sankyo, and Chugai Pharma Research Funding: Daiichi Sankyo (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Astellas Pharma (Inst), Lilly (Inst), Bayer (Inst), Nihon Kayaku (Inst), Amgen Astellas BioPharma (Inst), Parexel (Inst), IQVIA (Inst), Quintiles (Inst), Eisai (Inst), Pfizer (Inst), Chugai Pharma (Inst), Syneos Health (Inst), Asahi Kasei Pharma (Inst), Amgen (Inst), Dainippon Sumitomo (Inst), and Dainippon Sumitomo (Inst) Hisateru Yasui: Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb Japan, Daiichi Sankyo, Lilly, Yakult Honsha, Bayer Yakuhin, Takeda, and Ono Pharmaceutical Research Funding: MSD (Inst), Ono Pharmaceutical (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), and Daiichi Sankyo (Inst) Hiroya Taniguchi: Bayer, Sanofi, Takeda, Chugai Pharma, Taiho Pharmaceutical, Lilly, Merck Serono, Yakult Honsha, Medical & Biological Laboratories Co., Ltd, Bristol-Myers Squibb Japan, MSD K.K, Novartis, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Kayaku, and Ono Yakuhin Research Funding: Dainippon Sumitomo Pharma (Inst), Array BioPharma (Inst), MSD Oncology (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Sysmex (Inst), Novartis (Inst), and Takeda (Inst) Satake Hironaga: Bristol-Myers Squibb Co., Ltd., Bayer Co., Ltd., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Eli Lilly Japan Co., Ltd., Merck Bio Pharma Co., Ltd., MSD Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanof.

Eiji Shinozaki：武田制药、默克、莉莉和中外制药。Yoshishiaki Nakamura：中外制药、Guardant Health AMEA和默克研究基金：泰和制药、Guardian Health、Genomedia、中外制药、Guardant Health、Seattle Genetics、Seattle遗传学和罗氏制药。制药公司（Inst）、礼来公司（InstInstr）、LilillillillillillilillilInstinst）、拜耳公司日本、第一三共、礼来、养乐多、拜耳养乐满、武田和小野制药研究资助：MSD（Inst）、小野制药（Inst，以及Daiichi Sankyo（Inst）Hiroya Taniguchi：Bayer、Sanofi、Takeda、Chugai Pharma、Taiho Pharmaceutical、Lilly、Merck Serono、Yakult Honsha、Medical&Biological Laboratories Co.，Ltd、Bristol-Myers Squibb Japan、MSD K K、Novartis、Daiichi San kyo、Mitsububbishi Tanabe Pharmas、Nippon Kayaku和Ono Yakuhin Research Funding：Dainippon Sumitomo Pharma（Inst Inst）、Sysmex（Inst），Novartis（Inst。

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Reprints and permissionsAbout this articleCite this articleOsumi, H., Shinozaki, E., Nakamura, Y. et al. Clinical features associated with NeoRAS wild-type metastatic colorectal cancer A SCRUM-Japan GOZILA substudy.

转载和许可本文引用本文Osumi，H.，Shinozaki，E.，Nakamura，Y。等人。与NeoRAS野生型转移性结直肠癌相关的临床特征SCRUM Japan-GOZILA亚研究。

Nat Commun 15, 5885 (2024). https://doi.org/10.1038/s41467-024-50026-4Download citationReceived: 31 October 2023Accepted: 11 June 2024Published: 13 July 2024DOI: https://doi.org/10.1038/s41467-024-50026-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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