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杰享第01期:早期乳腺癌MRD超灵敏检测方法
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·杰享

杰享是迈杰转化医学微信公众号新推出的专栏,作为精准诊断整体解决方案的领导者,我们在这里会以文献解读的方式,分享精准医学领域关于生物标志物、伴随诊断等主题的最新进展。


图1. Heather A. Parsons等发表了文章:Sensitive Detection of Minimal Residual Diseasein Patients Treated for Early-Stage Breast Cancer



导读


微小残留疾病(Minimal Residual Disease,MRD)最早是指白血病治疗后仍残留少量肿瘤细胞的状态,是白血病复发的首要原因。2018年FDA发布MRD指南草案,首次批准NGS技术用于检测血液肿瘤中的MRD。最新研究进展表明,MRD的概念逐渐延伸至实体瘤领域,肿瘤根治术后,体内仍然残留少量的肿瘤细胞,但是常规影像学、血液检测无法检测到,通过ctDNA检测,可在分子层面上分析MRD,在早期就可预测肿瘤复发风险,并已在多种实体瘤中得到验证1



背景介绍


全世界每年有60多万人死于乳腺癌,主要是由于转移性复发。虽然这些复发可以发生在初诊治疗后早期,但大多数激素受体阳性乳腺癌患者在初诊治疗5年以后才会复发,并且数十年内均存在复发风险。MRD引起的复发可能在初诊时就发生,但无法通过影像学或常规血液检测方法检测到。一旦发生转移性乳腺癌,通常是无法治愈的。适当的辅助全身治疗可大大降低复发的风险,然而,在确定哪些患者需要辅助全身治疗和实时评估哪些治疗方法正在达到预期的治疗效果方面,目前的临床检测方法还不能满足需求。当前的美国临床肿瘤学会指南建议,II期或III期的雌激素受体阳性乳腺癌(ER +)女性患者接受10年的内分泌治疗,与5年的内分泌治疗相比,无疾病生存期患者比例可由1.4%提高到1.9%。更灵敏的MRD检测方法可使高风险患者尽早接受治疗,同时使其他患者避免不必要治疗的副作用。因此临床需要更灵敏的MRD检测方法来满足需求2


2020年7月,Heather A. Parsons等发表了文章:Sensitive Detection of Minimal Residual Diseasein Patients Treated for Early-Stage Breast Cancer,文章中描述了一种超灵敏的MRD检测方法,该方法首先通过全外显子组测序方法检测患者的肿瘤组织样本,筛选出数百个患者特异性的突变位点,然后合成检测这些位点的Panel来检测患者血液中的cfDNA,来达到动态监测MRD的目的。



文献快读


  • 当血液样本中肿瘤成分低于GE Limit(Genomic Equivalent Limit )时,传统的检测方法如只检测一个或少数几个突变的方法,无法有效检测出MRD:


图2. A, Overview of MRD testing including why tracking many mutations is important, particularly when there is a low fraction of cancerous cfDNA in the bloodstream, B, Theoretical detection power for varied numbers of mutations tracked per patient, C, Cumulative fraction of patients harboring varied numbers of mutations (and in turn, the predicted detection limits based on B)using breast cancer gene sequencing panels versus individualized MRD tests.


  • 作者研究了当血液样本中肿瘤成分低于GE Limit时,其开发的方法是否能有效检测出MRD:


图3. Serial dilution benchmarking of our MRD test for 100 and 500 mutations, versus digital droplet PCR for a single mutation, using 20 ng admixtures of sheared genomic DNA from two well-characterized cell lines. A, Detection power for arange of tumor fractions using our MRD assay and an equivalent ddPCR single mutation assay. B, Fraction of replicate dilutions detected by our MRD assay and an equivalent ddPCR assayand the median detection power for those samples. C, Tumor fraction estimation benchmarking for several replicates across a range of tumor fractions.


  • 作者使用来自新确诊的16例HR+的转移性乳腺癌患者的35例样本,验证了该方法的有效性:


图4. MRD testing in patients with newly diagnosed, HR+ MBC. A, Patient timelines with samples collected less than six months after metastatic recurrence. B, Number of MRD+ and MRD− samples including corresponding tumor fractions. Many patients had multiple blood draws, both pretreatment and on-treatment. C, Comparison of detection limit for MRD− vs. MRD+ samples from patients on treatment and experiencing clinical benefit.


  • 通过分析手术治疗后MRD状态与远处转移复发的关系,发现术后不久发现MRD可高度预测远处转移复发(HR=5.1;95%可信区间(CI)):


图5. MRD testing in early stage breast cancer. A and B, Kaplan–Meier curves showing distant recurrence-free survival for patients treated for early-stage breast cancer and in whom MRD was detected or not at the postoperative and year1 (Y1) time points. Postoperative and Y1 blood samples were drawn at a median of 3.6 months (0.23–8.43) and 14.3 months (6.77–21.70) after surgery,respectively. C, Comparison of patients with distant recurrence in which MRD was detected or not at the postoperative or Y1 time points. D, Timelines for patients with distant recurrence that were detected at postoperative or Y1 time points. Endpoints represent distant recurrence.


文献链接:

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer | Clinical Cancer Research (aacrjournals.org)https://clincancerres.aacrjournals.org/content/26/11/2556


杰论


除了乳腺癌等实体瘤外,MRD检测在急性淋巴细胞白血病(Acute Lymphoblastic Leukemia,ALL)、慢性粒细胞白血病(Chronic Myelogenous Leukemia,CML)等血液肿瘤的预后评估中也具有重要意义。过去20多年里,基于多参数流式细胞(Multi-parametric Flow Cytometry,MFC)、定量聚合酶链式反应(Quantitative Polymerase Chain Reaction,qPCR)、二代测序(Next Generation Sequencing,NGS)等技术,已经开发出多种MRD检测方法,然而由于MRD独特的生物学特性,现有的方法尚不能完全满足临床需求,MRD检测方法的开发还有很长的路要走。

迈杰转化医学作为国内精准诊断整体解决方案的领导者,致力于解决精准医疗药物研发及患者用药痛点,围绕生物标志物研究、伴随诊断开发,建立了完善的核酸组学、蛋白组学、细胞组学技术平台,可为MRD的转化医学研究及检测方法开发提供强有力的支撑。



参考文献


1. 2020年第五届基因检测和体外诊断大会,ctDNA在实体瘤MRD监测中的进展及实践分享,复旦大学附属中山医院临床检验科.

2. Heather A. Parsons,et al. Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer,Clinical Cancer Research,June 2020 Volume 26, Issue 11.