Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California, USA.
Tokyo Medical and Dental University, Tokyo, Japan.
Oncologist. 2018 May;23(5):586-593. doi: 10.1634/theoncologist.2017-0479. Epub 2018 Feb 27.
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.
We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated.
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: (57% of patients), (29%), (7%), (7%), (7%), and (7%); amplifications, in (14%), (14%), (14%), (7%), (7%), (7%), (7%), (7%), and (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 -inactivating and a -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 -inactivating and a -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]).
ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC.
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.
由于影像学具有很高的灵敏度来诊断肝细胞癌 (HCC)，而组织活检存在出血等风险，因此 HCC 通常不进行组织活检。血液衍生的循环肿瘤 DNA (ctDNA) 分析可以识别体细胞改变，但尚未在 HCC 中对其进行特征描述。
我们评估了 14 例晚期 HCC 患者（数字 ctDNA 测序[68 个基因]）。计算突变相对于野生型等位基因的比例。
所有患者（100%）均存在体细胞改变（中位数= 3 个/患者[范围 1-8]）；中位突变等位基因比例为 0.29%（范围 0.1%-37.77%）。在多个基因中发现了突变：（57%的患者），（29%），（7%），（7%），（7%）和（7%）；扩增，在（14%），（14%），（14%），（7%），（7%），（7%），（7%），（7%）和（7%）。11 例（79%）患者存在≥1 种理论上可治疗的改变。没有两个患者具有相同的基因组组合，表明需要定制治疗。一名同时存在 -失活和 -激活突变的患者接受了匹配的治疗：哌柏西利（CDK4/6 抑制剂）和塞来昔布（COX-2/Wnt 抑制剂）；2 个月时去甲羧基凝血酶原水平下降 84%（从 1410 降至 242ng/mL[正常值：≤7.4ng/mL]；甲胎蛋白[AFP]基线低）。一名同时存在 -失活和 -激活突变的患者（通过计算机分子动力学模拟提示存在这种效果）接受了依维莫司（雷帕霉素靶蛋白抑制剂）和卡博替尼（MET 抑制剂）治疗；AFP 下降 63%（从 8320 降至 3045ng/mL[正常值：0-15ng/mL]）。
非侵入性血液检测衍生的 ctDNA 可为 HCC 患者提供可利用的基因组谱。
本研究报告称，血液衍生的循环肿瘤 DNA 可提供治疗性的基因组谱，用于肝癌，众所周知，肝癌活检难度大。
