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 TP53 (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 TP53 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. Mol Cancer Ther; 17(5); 1114–22. ©2018 AACR.

中文翻译：

---

通过肝细胞癌的下一代测序分析组织和循环肿瘤 DNA：对靶向治疗的影响

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识别新疗法。然而，活检在 HCC 中并不常规进行。尚未建立通过下一代测序 (NGS) 分析无细胞循环肿瘤 DNA (ctDNA) 的效用。我们对 26 名患者进行了 32 次 ctDNA NGS 分析；其中 10 名患者有组织 NGS（236 至 626 个基因）。使用检测 54 到 70 个基因中的单核苷酸变异、扩增、融合和特定插入/缺失改变的测定法对 ctDNA 进行了评估。ctDNA 表明 26 名患者中有 23 名 (88.5%) 有≥1 个特征性改变，并且所有这些个体都有≥1 个潜在可操作的改变。最常见的突变基因是 TP53（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 [排除意义不明的变异 (VUS)]。ctDNA 和组织 NGS 经常显示不同的特征，这可能是由于组织和血液样本之间的时间长度 [中位数 = 370 天（范围，29 至 876 天）]。使用卡培他滨治疗的一名说明性患者的连续 ctDNA 评估表明，在进展后出现了新的 TP53 改变。总之，ctDNA 分析在晚期 HCC 中是可行的，使用 ctDNA NGS 的连续评估可以揭示基因组随时间的变化。ctDNA 的 NGS 为识别潜在可行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案。可以观察到与难以活检患者的治疗压力相关的分子组合的动态变化。摩尔癌症治疗; 17(5); 1114-22。©2018 AACR。