Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
Oncologist. 2018 Nov;23(11):1310-1318. doi: 10.1634/theoncologist.2017-0621. Epub 2018 Apr 26.
Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in , , , and , as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue-based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC.
过去十年，治疗压力诱导的克隆进化引起的多种基因组改变和相应的肿瘤内异质性对转移性结直肠癌（mCRC）的个体化治疗提出了巨大挑战。液体活检作为一种优秀的分子诊断工具，以微创的方式评估主要的空间和时间肿瘤内异质性。先前的研究表明，通过循环肿瘤 DNA（ctDNA）分析，可以以较高的诊断准确性分析、、、和其他与抗表皮生长因子受体（EGFR）治疗耐药相关的癌症相关基因的基因组改变。此外，通过在抗 EGFR 治疗期间纵向监测 ctDNA，可以检测到特定基因中获得性耐药机制的出现，主要与丝裂原活化蛋白激酶信号通路相关的基因。ctDNA 分析还可以识别免疫检查点抑制剂的预测生物标志物，如错配修复基因、微卫星不稳定高表型和肿瘤突变负荷的突变。一些评估 ctDNA 中基因组改变的靶向药物的前瞻性临床试验或通过监测 ctDNA 探索耐药生物标志物的临床试验正在进行中。为了通过更准确的基于分子标志物的患者选择和确定针对靶向治疗的耐药机制或针对免疫检查点抑制剂的敏感生物标志物来确定 ctDNA 分析的价值，临床试验必须进行细化，以评估 ctDNA 分析确认的具有靶向基因组改变的患者的研究治疗的疗效，并且应该通过大规模临床试验监测 ctDNA 来探索耐药生物标志物。在不久的将来，ctDNA 分析将在 mCRC 的精准医学中发挥重要作用。
转移性结直肠癌（mCRC）的治疗策略根据分子谱确定，该谱通过分析肿瘤组织得到证实。循环肿瘤 DNA（ctDNA）分析可能通过捕获 mCRC 的空间和时间肿瘤内异质性来克服基于组织分析的局限性。临床试验必须进行细化，以测试 ctDNA 分析在患者选择和生物标志物识别中的价值。本综述描述了 ctDNA 分析，它将在 mCRC 的精准医学中发挥重要作用。
