Imperial Robin, Nazer Marjan, Ahmed Zaheer, Kam Audrey E, Pluard Timothy J, Bahaj Waled, Levy Mia, Kuzel Timothy M, Hayden Dana M, Pappas Sam G, Subramanian Janakiraman, Masood Ashiq
Department of Medicine, Kansas City School of Medicine, University of Missouri, Kansas City, MO 64110, USA.
Division of Hematology/Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA.
Cancers (Basel). 2019 Sep 19;11(9):1399. doi: 10.3390/cancers11091399.
Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast ( = 12), gastrointestinal ( = 20), lung ( = 19), and other tumor types ( = 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28) = 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets.
肿瘤异质性，尤其是肿瘤内异质性，是治疗失败的主要原因。单次活检可能无法反映做出治疗决策所需的肿瘤完整基因组结构。循环肿瘤DNA（ctDNA）被认为可以克服这些局限性。我们分析了来自乳腺癌患者（n = 12）、胃肠道癌患者（n = 20）、肺癌患者（n = 19）和其他肿瘤类型患者（n = 13）的肿瘤样本的ctDNA与全外显子测序/全基因组测序（WES/WGS）之间的一致性。研究了驱动基因、热点基因和可操作改变的相关性。展示了3例需要更深入基因组分析的病例。总共58%（37/64）的患者至少有一个一致的突变。在组织进行下一代测序（NGS）和ctDNA分析之前接受过全身治疗的患者显示出高度一致性（分别为78%（21/27）对43%（12/28），P = 0.01）。在我们的患者中，同时进行NGS和ctDNA检测使可操作改变从28%（18/64）增加到52%（33/64）。21例患者在组织NGS或ctDNA样本中仅出现相互排斥的可操作改变。体细胞热点突变分析显示组织NGS和ctDNA分析之间存在显著不一致，表明这些恶性肿瘤中存在显著的肿瘤异质性。在接受过全身治疗的患者中，组织肿瘤突变负荷（TMB）增加与ctDNA突变数量呈正相关，但在未接受过治疗的患者中并非如此。先前的全身治疗和TMB可能会影响一致性，在未来的研究中应予以考虑。纳入驱动基因、可操作基因和热点基因分析可能有助于进一步完善这两个平台之间的相关性。组织NGS和ctDNA是互补的，如果联合进行，可能会提高可操作改变和潜在治疗靶点的检测率。
