AbstractSecondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients.

摘要继发性BRAF变异已被确定为驱动基因阳性NSCLC患者对酪氨酸激酶抑制剂（TKIs）耐药的机制。然而，对于这些患者的特征和随后的治疗策略仍然缺乏共识。

We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival.

我们回顾性分析了2016年5月至2023年12月在浙江省肿瘤医院接受TKIs治疗的驱动基因阳性NSCLC患者的病历。评估了这些患者的临床和遗传特征，以及各种治疗策略对生存的影响。

This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival.

这项研究招募了27例晚期非小细胞肺癌患者，其中BRAF变异发生在靶向治疗开始后的中位时间28个月。多变量加速失败时间（AFT）模型显示，与基于化疗的方案组相比，联合靶向治疗组（p<0.001）和联合局部治疗组的寡核苷酸进展（p<0.001）显着延长了患者的生存期。

In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months.

相反，继续原始信号通路的靶向单一疗法与较短的生存期相关（p=0.034）。每个治疗组的中位全球OS如下：基于化疗的方案组，45个月；联合靶向治疗组，59个月；联合局部治疗组用于寡核苷酸进展患者，46个月；和靶向单药治疗组，36个月。

Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves les.

研究结果表明，联合靶向治疗组（包括TKIs，BRAF抑制剂和/或MEK抑制剂）和局部治疗组在改善生存率方面比传统的基于化疗的方案更有效。此外，沿着原始信号通路继续进行靶向单一疗法证明了les。

IntroductionTKIs have improved survival for patients with advanced NSCLC harboring driver mutations. However, resistance to targeted therapies is inevitable. Currently, the mechanisms of acquired resistance to TKIs, primarily involve the activation of pathways dependent on or independent of driver genes, as well as histological transformation1,2.

引言TKIs提高了携带驱动突变的晚期NSCLC患者的生存率。然而，对靶向治疗的抵抗是不可避免的。目前，获得性TKIs抗性的机制主要涉及依赖于或独立于驱动基因的途径的激活，以及组织学转化1,2。

Advances in genomic testing have made it easier to detect variations in the BRAF gene. However, the clinical significance of acquired BRAF variations remains unclear due to their low incidence. Only 1%-7% of NSCLC patients with resistance to EGFR TKIs exhibit acquired BRAF variations3,4. The BRAF gene, part of the RAF serine/threonine kinase family, encodes a kinase that regulates cell growth and differentiation by activating the downstream RAS-MAPK pathway.

基因组测试的进步使检测BRAF基因变异变得更加容易。然而，由于获得性BRAF变异的发生率低，其临床意义仍不清楚。只有1%〜7%对EGFR-TKIs耐药的NSCLC患者表现出获得性BRAF变异3,4。BRAF基因是RAF丝氨酸/苏氨酸激酶家族的一部分，编码一种通过激活下游RAS-MAPK途径调节细胞生长和分化的激酶。

BRAF variations, including mutations and fusions, activate downstream pathways via bypass signaling, driving uncontrolled cell proliferation and resistance. BRAF mutations are categorized into BRAF V600 and BRAF Non-V600 mutations. BRAFV600 mutations continuously activate the MEK/ERK signaling pathway through their monomeric protein form, while BRAF Non-V600 mutations activate downstream pathways by dimerizing with CRAF or wild-type BRAF.

BRAF变异，包括突变和融合，通过旁路信号激活下游途径，驱动不受控制的细胞增殖和抗性。BRAF突变分为BRAF V600和BRAF非V600突变。BRAFV600突变通过其单体蛋白形式不断激活MEK/ERK信号通路，而BRAF非V600突变通过与CRAF或野生型BRAF二聚化激活下游通路。

BRAF fusions result in the loss of the auto-inhibitory domain, leading to the formation of constitutive dimers that continuously activate downstream pathways5,6. Research on subsequent treatments for these patients mainly consists of case reports and in vitro studies, and the best treatment strategy post-resistance remains controversial.

BRAF融合导致自动抑制结构域的丧失，导致形成持续激活下游途径的组成型二聚体5,6。。

Therefore, we conducted a retrospective study to explore the clinical and genetic characteristics of patients with driver gene-positive (EGFR/ALK/ROS1) advanced NSCLC who developed BRAF variations after re.

因此，我们进行了一项回顾性研究，以探讨驱动基因阳性（EGFR/ALK/ROS1）晚期NSCLC患者在re后发生BRAF变异的临床和遗传特征。

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

本研究中使用和/或分析的数据集可根据合理要求从通讯作者处获得。

AbbreviationsTKIs:

缩写TKI：

Tyrosine kinase inhibitors

酪氨酸激酶抑制剂

AFT:

Accelerated failure time

加速失效时间

TR:

交易记录：

Time ratio

时间比率

PFS:

PFS：

Progression-free survival

无进展生存期

OS:

操作系统：

Overall survival

总体生存率

CI:

CI公司：

Confidence interval

置信区间

PR:

公共关系：

Partial response

部分响应

SD:

标准差：

Stable disease

PD:

PD公司：

Progressive disease

进行性疾病

ORR:

ORR：

Objective response rate

客观回应率

DCR:

DCR:

Disease control rate

疾病控制率

NCCN:

NCCN：

National comprehensive cancer network

国家综合癌症网络

FDA:

FDA：

Food and drug administration

美国食品药品监督管理局

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Download referencesAcknowledgementsThe authors thank the patients and their families for participating in this study.FundingThis study was supported by the Natural Scientific Foundation of Zhejiang Province, China (Grant No.LTGY23H160007).Author informationAuthor notesThese authors contributed equally: DuJiang Liu and KaiBo Ding.Authors and AffiliationsDepartment of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, No.1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, ChinaDuJiang Liu, KaiBo Ding, ZhongSheng Peng, Xinyue Li & YanJun XuPostgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, ChinaDuJiang Liu, KaiBo Ding, KaiLai Yin, ZhongSheng Peng & Yang PanDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, ChinaKaiLai YinDepartment of Pulmonary Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, ChinaYang PanDepartment of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaXuanHong JinAuthorsDuJiang LiuView author publicationsYou can also search for this author in.

下载参考文献致谢作者感谢患者及其家属参与这项研究。资助本研究得到了中国浙江省自然科学基金（批准号：LTGY23H160007）的支持。作者信息作者注意到这些作者做出了同样的贡献：刘都江和丁凯波。，ChinaXuanhongJinAuthorsDujiang LiuView作者出版物您也可以在中搜索此作者。

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PubMed Google ScholarContributionsDuJiang Liu: Visualization, Writing—original draft, and Writing—review & editing. KaiBo Ding: Validation, Writing—original draft. KaiLai Ying: Methodology. ZhongSheng Peng: Software. Xinyue Li: Investigation. Yang Pan: Investigation. XuanHong Jin: Formal analysis.

PubMed谷歌学术贡献刘杜江：可视化，撰写原稿，撰写评论和编辑。丁开波：验证，撰写原稿。凯莱英：方法论。彭中胜：软件。李新月：调查。杨攀：调查。金玄虹：形式分析。

YanJun Xu: Conceptualization, Data curation, Funding acquisition, Project administration, Resources; Supervision.Corresponding authorCorrespondence to.

徐燕军：概念化，数据管理，资金获取，项目管理，资源；监督。对应作者对应。

YanJun Xu.Ethics declarations

徐燕军。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval and consent to participate

道德批准和同意参与

This study was approved by the Ethics Committee of Zhejiang Cancer Hospital (approval number IRB-2020–324). All participants signed informed consent forms, and the study adhered to the ethical principles of the Declaration of Helsinki.

这项研究得到了浙江省肿瘤医院伦理委员会的批准（批准号IRB-2020-324）。所有参与者都签署了知情同意书，该研究遵守了《赫尔辛基宣言》的道德原则。

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Reprints and permissionsAbout this articleCite this articleLiu, D., Ding, K., Yin, K. et al. A real world analysis of secondary BRAF variations after targeted therapy resistance in driver gene positive NSCLC.

转载和许可本文引用本文Liu，D.，Ding，K.，Yin，K。等人对驱动基因阳性NSCLC靶向治疗耐药后继发性BRAF变异的现实世界分析。

Sci Rep 14, 20302 (2024). https://doi.org/10.1038/s41598-024-71143-6Download citationReceived: 21 June 2024Accepted: 26 August 2024Published: 01 September 2024DOI: https://doi.org/10.1038/s41598-024-71143-6Share 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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KeywordsBRAFSecondary variationsNSCLCCharacteristicsTreatment strategies

关键词BRAFsecondary variationSNSCLCcharacteristics治疗策略

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