Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France.
Ann Oncol. 2022 Dec;33(12):1269-1283. doi: 10.1016/j.annonc.2022.09.150. Epub 2022 Sep 9.
Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.
We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes.
Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%).
These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.
靶向治疗改变了晚期胆道癌（BTC）的临床治疗管理模式。无细胞 DNA（cfDNA）分析是一种用于癌症基因组分析的有吸引力的方法，它克服了传统组织分析的许多局限性。我们研究了 cfDNA 作为一种工具，以告知晚期 BTC 患者的临床管理，并为 BTC 肿瘤生物学提供新的见解。
我们分析了 1671 名晚期 BTC 患者的 2068 个 cfDNA 样本的下一代测序数据，这些样本是使用 Guardant360 生成的。我们对一个多机构的亚组（n=225）进行了临床注释，以评估患者内 cfDNA-肿瘤的一致性以及 cfDNA 变异等位基因分数（VAF）与临床结果的关联。
在 84%的患者中检测到 cfDNA 中的遗传改变，在 44%的患者中检测到可靶向的改变。成纤维细胞生长因子受体 2（FGFR2）融合、异柠檬酸脱氢酶 1（IDH1）突变和 BRAF V600E 在大多数情况下是克隆的，这证实了这些可靶向的改变是 BTC 的早期驱动事件。cfDNA 与组织中用于检测突变的一致性在 IDH1 突变（87%）和 BRAF V600E（100%）中较高，而在 FGFR2 融合（18%）中较低。cfDNA 分析揭示了新的潜在的针对靶向治疗的耐药机制，包括 FGFR 抑制剂结合的半胱氨酸残基（FGFR2 C492F）的突变。高预处理 cfDNA VAF 与预后不良和化疗及靶向治疗反应时间短有关。最后，我们报告了在其他晚期实体瘤中目前正在研究的晚期 BTC 中具有前景的靶点的频率，包括 KRAS G12C（1.0%）、KRAS G12D（5.1%）、PIK3CA 突变（6.8%）和 ERBB2 扩增（4.9%）。
这些来自迄今为止最大和最全面的晚期 BTC 患者 cfDNA 研究的结果强调了 cfDNA 分析在该疾病目前管理中的实用性。本研究中对致癌驱动因素和治疗耐药机制的特征描述将为药物开发工作提供信息，以降低 BTC 患者的死亡率。
