Javle Milind, Bekaii-Saab Tanios, Jain Apurva, Wang Ying, Kelley Robin Katie, Wang Kai, Kang Hyunseon C, Catenacci Daniel, Ali Siraj, Krishnan Sunil, Ahn Daniel, Bocobo Andrea Grace, Zuo Mingxin, Kaseb Ahmed, Miller Vincent, Stephens Philip J, Meric-Bernstam Funda, Shroff Rachna, Ross Jeffrey
Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Division of Medical Oncology, Ohio State University Medical Center, Columbus, Ohio.
Cancer. 2016 Dec 15;122(24):3838-3847. doi: 10.1002/cncr.30254. Epub 2016 Sep 13.
Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit.
Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 412 intrahepatic cholangiocarcinomas (IHCCAs), 57 extrahepatic cholangiocarcinomas (EHCCAs), and 85 gallbladder carcinomas (GBCAs). The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients. Clinical variables, detected mutations, and administered therapies were correlated with overall survival (OS) in a Cox regression model.
The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA. Fibroblast growth factor receptor (FGFR; 11%) and IDH mutations (20%) were mostly limited to IHCCA but appeared to be mutually exclusive. In the IHCCA group, TP53 and KRAS mutations were associated significantly with poor OS, whereas FGFR2 mutations were associated with improved OS (P = .001), a younger age at onset, and female sex. IDH1/2 mutations were not prognostic. In a multivariate model, the effects of TP53 and FGFR GAs remained significant (P < .05). Patients with FGFR GAs had superior OS with FGFR-targeted therapy versus standard regimens (P = .006). Targeted therapy in IHCCA was associated with a numerical OS improvement (P = .07).
This is the largest clinically annotated data set of BTC cases with CGP and indicates the potential of CGP for improving outcomes. CGP should be strongly considered in the management of BTC patients. Cancer 2016;122:3838-3847. © 2016 American Cancer Society.
胆管癌（BTC）通常在晚期出现，全身化疗往往获益有限。
对412例肝内胆管癌（IHCCA）、57例肝外胆管癌（EHCCA）和85例胆囊癌（GBCA）进行基于杂交捕获的综合基因组分析（CGP）。将突变谱与321例患者的标准和实验性治疗的临床结果相关联。在Cox回归模型中，将临床变量、检测到的突变和给予的治疗与总生存期（OS）相关联。
在IHCCA中观察到的最常见的基因畸变（GA）是肿瘤蛋白53（TP53；27%）、细胞周期蛋白依赖性激酶抑制剂2A/B（CDKN2A/B；27%）、KRAS（22%）、富含AT的相互作用结构域蛋白1A（ARID1A；18%）和异柠檬酸脱氢酶1（IDH1；16%）；在EHCCA中为KRAS（42%）、TP53（40%）、CDKN2A/B（17%）和SMAD4（21%）；在GBCA中为TP53（59%）、CDKN2A/B（19%）、ARID1A（13%）和ERBB2（16%）。成纤维细胞生长因子受体（FGFR；11%）和IDH突变（20%）大多局限于IHCCA，但似乎相互排斥。在IHCCA组中，TP53和KRAS突变与较差的OS显著相关，而FGFR2突变与较好的OS相关（P = 0.001）、发病年龄较轻和女性性别。IDH1/2突变无预后意义。在多变量模型中，TP53和FGFR GA的影响仍然显著（P < 0.05）。与标准方案相比，FGFR GA患者接受FGFR靶向治疗的OS更好（P = 0.006）。IHCCA中的靶向治疗与OS的数值改善相关（P = 0.07）。
这是最大的具有CGP注释的BTC病例临床数据集，表明CGP在改善预后方面的潜力。在BTC患者的管理中应强烈考虑CGP。《癌症》2016年；122：3838 - 3847。©2016美国癌症协会。
