Association of BRAF Variants With Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma.
Association of BRAF Variants With Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma.
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DOI：
10.1001/jamanetworkopen.2023.1476
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发表时间：
2023-03-01
影响因子：
13.8
通讯作者：
Zhou, Shao-Lai
中科院分区：
文献类型：
--
作者：
Xin, Hao-Yang;Sun, Rong-Qi;Zou, Ji-Xue;Wang, Peng-Cheng;Wang, Jia-Yin;Ye, Yu-Hang;Liu, Kai-Xuan;Hu, Zhi-Qiang;Zhou, Zheng-Jun;Fan, Jia;Zhou, Jian;Zhou, Shao-Lai
BRAF变异亚型的患病率及其与肝内胆管癌患者的疾病特征、预后和靶向治疗反应的关系如何？在这项包括1175名患者的队列研究中，共发现了影响49名患者的20种不同亚型的BRAF体细胞变异，包括V600 E（27%）、K601 E（14%）、D594 G（12%）和N581 S（6%）。携带BRAF V600 E变异的患者更可能具有更大的肿瘤大小、多个肿瘤和更多的血管/胆管浸润。这项队列研究的结果表明，具有不同BRAF变体亚型的类器官对BRAF或MEK抑制剂的敏感性存在广泛差异。BRAF变异与肿瘤进展相关;然而，BRAF变异亚型的患病率及其与肝内胆管癌（ICC）患者的疾病特征、预后和靶向治疗反应的相关性在很大程度上尚不清楚。探讨BRAF变异亚型与ICC患者的疾病特征、预后和靶向治疗反应的关系。在这项队列研究中，对2009年1月1日至2017年12月31日期间在中国一家医院接受ICC根治性切除术的1175例患者进行了评价。进行全外显子组测序、靶向测序和桑格测序以鉴定BRAF变体。采用Kaplan-Meier法和log-rank检验比较总生存期（OS）和无病生存期（DFS）。采用考克斯比例风险回归进行单变量和多变量分析。在6个BRAF变体、患者来源的类器官系和这些系的3个患者供体中测试了BRAF变体和靶向治疗反应之间的关联。数据分析时间为2021年6月1日至2022年3月15日。ICC患者的肝切除术。BRAF变异亚型与OS和DFS的相关性。在1175例ICC患者中，平均（SD）年龄为59.4（10.4）岁，701例（59.7%）为男性。共确定了20种不同的BRAF体细胞变异亚型，影响49例患者（4.2%）; V600 E是该队列中最常见的等位基因，占确定的BRAF变异的27%，其次是K601 E（14%），D594 G（12%）和N581 S（6%）。与携带非V600 E BRAF变异的患者相比，携带BRAF V600 E变异的患者更可能具有大的肿瘤大小（10/13 [77%] vs 12/36 [33%]; P = 0.007），多发性肿瘤（7/13 [54%] vs 8/36 [22%]; P = 0.04）和更多的血管/胆管浸润（7/13 [54%] vs 8/36 [22%]; P = 0.04）。多变量分析显示，BRAF V600 E变体与OS（风险比[HR]，1.87; 95% CI，1.05-3.33; P = 0.03）和DFS（HR，1.66; 95% CI，1.03-2.97; P = 0.04）差相关，但与总体BRAF变体或非V600 E BRAF变体无关。具有不同BRAF变体亚型的类器官对BRAF或MEK抑制剂的敏感性也存在广泛差异。这项队列研究的结果表明，具有不同BRAF变体亚型的类器官对BRAF或MEK抑制剂的敏感性存在广泛差异。识别和分类BRAF变异可能有助于指导ICC患者的精确治疗。这项队列研究检查了BRAF变异亚型，对它们进行分类，并分析了肝内胆管癌患者对治疗的反应。
What is the prevalence of BRAF variant subtypes and their association with disease characteristics, prognosis, and targeted therapy response in patients with intrahepatic cholangiocarcinoma? In this cohort study including 1175 patients, a total of 20 different subtypes of BRAF somatic variants affecting 49 patients were identified, including V600E (27%), K601E (14%), D594G (12%), and N581S (6%). Patients with BRAF V600E variants were more likely to have larger tumor size, multiple tumors and more vascular/bile duct invasion. The findings of this cohort study suggest that there are broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. BRAF variants are associated with tumor progression; however, the prevalence of BRAF variant subtypes and their association with disease characteristics, prognosis, and targeted therapy response in patients with intrahepatic cholangiocarcinoma (ICC) are largely unknown. To explore the association of BRAF variant subtypes with disease characteristics, prognosis, and targeted therapy response in patients with ICC. In this cohort study, 1175 patients who underwent curative resection for ICC from January 1, 2009, through December 31, 2017, were evaluated at a single hospital in China. Whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify BRAF variants. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using Cox proportional hazards regression. Associations between BRAF variants and targeted therapy response were tested in 6 BRAF-variant, patient-derived organoid lines and in 3 of the patient donors of those lines. Data were analyzed from June 1, 2021, to March 15, 2022. Hepatectomy in patients with ICC. The association of BRAF variant subtypes with OS and DFS. Of 1175 patients with ICC, the mean (SD) age was 59.4 (10.4) years and 701 (59.7%) were men. A total of 20 different subtypes of BRAF somatic variance affecting 49 patients (4.2%) were identified; V600E was the most frequent allele in this cohort, accounting for 27% of the identified BRAF variants, followed by K601E (14%), D594G (12%), and N581S (6%). Compared with patients with non-V600E BRAF variants, patients with BRAF V600E variants were more likely to have large tumor size (10 of 13 [77%] vs 12 of 36 [33%]; P = .007), multiple tumors (7 of 13 [54%] vs 8 of 36 [22%]; P = .04), and more vascular/bile duct invasion (7 of 13 [54%] vs 8 of 36 [22%]; P = .04). Multivariate analysis revealed that BRAF V600E variants, but not overall BRAF variants or non-V600E BRAF variants, were associated with poor OS (hazard ratio [HR], 1.87; 95% CI, 1.05-3.33; P = .03) and DFS (HR, 1.66; 95% CI, 1.03-2.97; P = .04). There were also broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. The findings of this cohort study suggest that there are broad differences among organoids with different BRAF variant subtypes in sensitivity to BRAF or MEK inhibitors. Identifying and classifying BRAF variants may be able to help guide precise treatment for patients with ICC. This cohort study examines BRAF variant subtypes, classifying them and analyzing response to therapy in patients with intrahepatic cholangiocarcinoma.
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影响因子：
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作者：
Wittekind, C.
通讯作者：
Wittekind, C.
DOI：
10.1016/s1470-2045(20)30157-1
发表时间：
2020-06
期刊：
The Lancet. Oncology
影响因子：
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作者：
Abou-Alfa GK;Macarulla T;Javle MM;Kelley RK;Lubner SJ;Adeva J;Cleary JM;Catenacci DV;Borad MJ;Bridgewater J;Harris WP;Murphy AG;Oh DY;Whisenant J;Lowery MA;Goyal L;Shroff RT;El-Khoueiry AB;Fan B;Wu B;Chamberlain CX;Jiang L;Gliser C;Pandya SS;Valle JW;Zhu AX
通讯作者：
Zhu AX
DOI：
10.1158/1078-0432.ccr-13-0657
发表时间：
2013-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cardarella S;Ogino A;Nishino M;Butaney M;Shen J;Lydon C;Yeap BY;Sholl LM;Johnson BE;Jänne PA
通讯作者：
Jänne PA
DOI：
10.1016/s1470-2045(20)30109-1
发表时间：
2020-05
期刊：
The Lancet. Oncology
影响因子：
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作者：
Abou-Alfa GK;Sahai V;Hollebecque A;Vaccaro G;Melisi D;Al-Rajabi R;Paulson AS;Borad MJ;Gallinson D;Murphy AG;Oh DY;Dotan E;Catenacci DV;Van Cutsem E;Ji T;Lihou CF;Zhen H;Féliz L;Vogel A
通讯作者：
Vogel A
肿瘤相关中性粒细胞和巨噬细胞相互作用通过激活 STAT3 促进肝内胆管癌进展
影响因子：
10.9
作者：
Zhou Z;Wang P;Sun R;Li J;Hu Z;Xin H;Luo C;Zhou J;Fan J;Zhou S
通讯作者：
Zhou S