Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, California.
Tokyo Medical and Dental University, Tokyo, Japan.
Mol Cancer Ther. 2018 May;17(5):1114-1122. doi: 10.1158/1535-7163.MCT-17-0604. Epub 2018 Feb 26.
Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. However, biopsy is not routinely performed in HCC. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. We performed 32 ctDNA NGS analyses on 26 patients; 10 of these patients had tissue NGS (236 to 626 genes). ctDNA was evaluated using an assay that detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion alterations in 54 to 70 genes. The ctDNA demonstrated that 23 of 26 patients (88.5%) had ≥1 characterized alteration, and all these individuals had ≥1 potentially actionable alteration. The most frequently mutated gene was (16 of 26 patients, 61.5%). There were 47 unique characterized molecular alterations among 18 total gene alterations [variants of unknown significance (VUS) excluded)]. ctDNA and tissue NGS frequently showed different profiles, perhaps due to length of time between tissue and blood samples [median = 370 days (range, 29 to 876 days)]. Serial ctDNA evaluation in an illustrative patient treated with capecitabine demonstrated emergence of a new alteration after progression. In conclusion, ctDNA profiling is feasible in advanced HCC, and serial assessment using ctDNA NGS can reveal genomic changes with time. NGS of ctDNA provides a minimally invasive alternative for identifying potentially actionable gene alterations and potential molecular targeted therapies. Dynamic changes in molecular portfolio associated with therapeutic pressure in difficult-to-biopsy patients can be observed. .
肝细胞癌 (HCC) 的治疗选择有限。对其突变景观的分子分析可能有助于确定新的治疗方法。然而，活检在 HCC 中并不常规进行。通过下一代测序 (NGS) 分析游离循环肿瘤 DNA (ctDNA) 的效用尚未确定。我们对 26 名患者进行了 32 次 ctDNA NGS 分析；其中 10 名患者进行了组织 NGS（236 至 626 个基因）。ctDNA 采用一种检测 54 至 70 个基因中单核苷酸变异、扩增、融合和特定插入/缺失改变的检测方法进行评估。ctDNA 表明 26 名患者中的 23 名（88.5%）有≥1 种特征性改变，所有这些患者都有≥1 种潜在的可操作性改变。突变最频繁的基因是 （26 名患者中的 16 名，61.5%）。在 18 个总基因改变中有 47 个独特的特征分子改变[排除了变异意义不明 (VUS)]。ctDNA 和组织 NGS 经常显示不同的谱，可能是由于组织和血液样本之间的时间长短不同[中位数=370 天（范围，29 至 876 天）]。一名接受卡培他滨治疗的患者的代表性病例中，连续进行 ctDNA 评估显示在进展后出现了新的 改变。总之，ctDNA 谱分析在晚期 HCC 中是可行的，使用 ctDNA NGS 进行连续评估可以随着时间的推移揭示基因组变化。ctDNA 的 NGS 为识别潜在可操作的基因改变和潜在的分子靶向治疗提供了一种微创替代方法。在难以活检的患者中，与治疗压力相关的分子组合的动态变化可以观察到。
