Background: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC.
Materials and methods: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated.
Results: All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1-8]); median mutant allele fraction, 0.29% (range, 0.1%-37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A-inactivating and a CTNNB1-activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX-2/Wnt inhibitor); des-gamma-carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN-inactivating and a MET-activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0-15 ng/mL]).
Conclusion: ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC.
Implications for practice: This study reports that blood-derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy.
摘要
背景.因为影像学诊断肝细胞癌（HCC）的敏感度较高且组织活检有出血等风险, 所以通常不在HCC患者中进行组织活检。血液源性循环肿瘤DNA（ctDNA）分析可识别体细胞变异, 但其在HCC中的用途尚未描述。
材料和方法.我们评价了14例晚期HCC患者[数字ctDNA测序（68个基因）]。计算了相应的野生型等位基因部分的突变体。
结果.所有患者（100%）均有体细胞变异[中位数=3种变异/患者（范围为1‐8）]；中位突变等位基因分数为0.29%（范围为0.1%–37.77%）。在若干基因中发现突变：TP53（57%的患者）、CTNNB1（29%）、PTEN（7%）、CDKN2A（7%）、ARID1A（7%）和 MET（7%）；在若干基因中发现扩增：CDK6（14%）、EGFR（14%）、MYC（14%）、BRAF（7%）、RAF1（7%）、FGFR1（7%）、CCNE1（7%）、PIK3CA（7%）和 ERBB2/HER2（7%）。11例患者（79%）具有≥1个理论上可行的变异。未出现两例患者共有相同基因组组合的情况, 表明需要个性化治疗。携带CDKN2A失活和CTNNB1激活突变的患者接受了匹配治疗：帕博西尼（CDK4/6抑制剂）和塞来昔布（COX‐2/Wnt抑制剂）；2个月时脱‐γ‐羧基凝血酶原水平下降84% [1 410至242 ng/mL（正常：≤7.4ng/mL）；甲胎蛋白（AFP）于基线值时低]。携带PTEN失活和MET激活突变（计算机动态模拟提示的效应）的患者接受西罗莫司（雷帕霉素抑制剂的机制性靶标）和卡博替尼（MET抑制剂）治疗；AFP下降63% [8 320至3 045 ng/mL（正常值：0–15 ng/mL）]。
结论. 来自无创血检的ctDNA可为HCC患者提供可用的基因组谱。
对临床实践的提示：本研究报告, 血源性循环肿瘤DNA可提供治疗可用的肝细胞癌（已知难以进行活检的一种恶性肿瘤）基因组谱。
Keywords: Circulating tumor DNA; Hepatocellular carcinoma; Liquid biopsy; Next‐generation sequencing.
© AlphaMed Press 2018.