Gracie Lara, Pan Yi, Atenafu Eshetu G, Ward Douglas G, Teng Mabel, Pallan Lallit, Stevens Neil M, Khoja Leila
College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Centre for Computational Biology and Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Eur J Cancer. 2021 Oct 30;158:191-207. doi: 10.1016/j.ejca.2021.09.019.
Circulating tumour DNA (ctDNA) is an emerging biomarker in melanoma. We performed a systematic review and meta-analysis to explore its clinical utility as a prognostic, pharmacodynamic (PD) and predictive biomarker.
A systematic search was conducted from Jan 2015 to April 2021, of the electronic databases PubMed, Cochrane Library and Ovid MEDLINE to identify studies. Studies were restricted to those published in English within the last 5 years, evaluating ctDNA in humans in ≥10 patients. Survival data were extracted for meta-analysis using pooled treatment effect (TE), i.e. log hazard ratios (HRs) and corresponding standard error of TE for progression-free survival or overall survival differences in patients who were ctDNA positive or negative. PRISMA statement guidelines were followed.
A meta-analysis of 19 studies grouped according to methodology of ctDNA detection, revealed a combined estimate for HR of progression-free survival (13 studies using droplet digital Polymerase Chain Reaction (ddPCR) methodology (N = 1002) of 2.10 (95% CI: 1.71-2.59) revealing a poorer prognosis when ctDNA was detected. This result was confirmed in the smaller analysis of (non-ddPCR, N = 347) five studies: HR = 2.45 (95% CI: 1.29-4.63). Similar findings were found in the overall survival analysis of nine studies (ddPCR methodology, N = 841) where the combined HR was 2.78 (95% CI: 2.21-3.49) and of the five studies (non-ddPCR methodology, N = 326) where the combined HR was 2.58 (95% CI: 1.74-3.84). Serial ctDNA levels on treatment showed a pharmacodynamic role reflecting response or resistance earlier than radiological assessment.
Circulating tumour DNA is a predictive, prognostic and PD biomarker in melanoma. Technical standardisation of assays is required before clinical adoption.
循环肿瘤DNA（ctDNA）是黑色素瘤中一种新兴的生物标志物。我们进行了一项系统综述和荟萃分析，以探讨其作为预后、药效学（PD）和预测生物标志物的临床效用。
于2015年1月至2021年4月对电子数据库PubMed、Cochrane图书馆和Ovid MEDLINE进行系统检索，以识别相关研究。研究仅限于过去5年内以英文发表的、评估≥10例人类患者ctDNA的研究。使用合并治疗效应（TE）提取生存数据进行荟萃分析，即ctDNA阳性或阴性患者无进展生存期或总生存期差异的对数风险比（HR）及相应的TE标准误差。遵循PRISMA声明指南。
根据ctDNA检测方法对19项研究进行的荟萃分析显示，无进展生存期HR的合并估计值（13项研究采用液滴数字聚合酶链反应（ddPCR）方法（N = 1002）为2.10（95%CI：1.71 - 2.59），表明检测到ctDNA时预后较差。在对5项研究（非ddPCR，N = 347）的较小分析中也证实了这一结果：HR = 2.45（95%CI：1.29 - 4.63）。在9项研究（ddPCR方法，N = 841）的总生存期分析中也发现了类似结果，合并HR为2.78（95%CI：2.21 - 3.49），在5项研究（非ddPCR方法，N = 326）中合并HR为2.58（95%CI：1.74 - 3.84）。治疗期间的连续ctDNA水平显示出药效学作用，比影像学评估更早地反映反应或耐药性。
循环肿瘤DNA是黑色素瘤中的一种预测、预后和PD生物标志物。在临床应用之前，需要对检测方法进行技术标准化。
