[ELCC2014]miRNA对肺癌预测诊断、评估预后的价值

导语：

最近的研究表明，低剂量的胸部CT筛查能够降低高危人群肺癌的死亡率。然而，其过高的假阳性率、过高的费用和潜在伤害都突出了对于互补生物标志物的需要。

由UgoPastorino医生领导的一组研究人员在多中心的意大利肺癌筛查(MILD)随机试验中回顾性评估了非侵入性血浆miRNA识别分类器的作用。他们的发现表明，miRNA识别分类器有预测、诊断和评估预后价值。结果公布于第4届ELCC会议上。

研究背景：

miRNAs是组织和疾病特异性分子，由循环系统的细胞释放。循环miRNAs相当稳定，很容易在体液中检测到，很可能成为一种新的、有前途的生物标志物。

该研究的作者以前在美国国家科学院院刊杂志上报道，参与两个独立的螺旋CT筛查试验的无病吸烟者血浆样本中的miRNAs的表达谱显示，miRNAs识别分类器有较强的预测、诊断、评估预后的价值。

研究详情：血浆miRNA的表达谱

在目前的研究中，研究者已经在MILD试验中从吸烟者中收集的样本中评估了非侵入性血浆miRNA识别分类器的诊断性能。总共有939位受试者参与了试验，其中69位肺癌患者，870位无病的受试者。652人在低剂量CT组，287人在观察组。

应用聚合酶链反应试验对血浆样本进行分析。通过使用预先确定的风险分配组的双盲效度研究评估miRNA识别分类器的诊断性能。

两组中，miRNA识别分类器的对肺癌的诊断性能的敏感性为87%，特异性为81%，而低剂量CT组诊断性能的敏感性为88%，特异性为80%。所有受试者中，miRNA识别分类器检测的阴性预测值为99%，疾病所致死亡的阴性预测值为99.86%。低剂量CT检查在肺癌筛查的敏感性为79%，特异性为81%，假阳性率为19.4%。

时间依赖性关系分析确认了miRNA识别分类器的诊断性能。miRNA检测与CT检查的同时使用与只用CT检查相比，降低了五倍假阳性率，为3.7%。miRNA识别分类器风险分配组与生存期有关(p<0.0001)。

作者们推断，较高的研究效度表明miRNA识别分类器有预测、诊断和评估预后的价值。能够降低低剂量CT检查的假阳性率，提高肺癌筛查的效率。

编译自：ELCC 2014 News: Clinical Utility of miRNA Signature in Plasma of Smokers Included in LD-CT Lung Cancer Screening,28 Mar 2014

MicroRNA Test Reduces False-Positive CT Screening Rate for Lung Cancer
http://www.ascopost.com/ViewNews.aspx?nid=12882
Key Points:
The microRNA test reduced the false-positive rate of low-dose CT screening from 19.4% to 3.7%.
The microRNA test had 87% sensitivity and 81% specificity for detection of lung cancer across CT and observation groups and negative predictive values of 99% for detection and 99.86% for prediction of lung cancer death.
Although recent data indicate that low-dose computed tomography (CT) reduces lung cancer mortality in high-risk patients, high false-positive rates, costs, and the potential for harm point out the need for biomarkers that can improve risk assessment. In a study reported in the Journal of Clinical Oncology, Sozzi et al evaluated a plasma microRNA signature classifier in detection of lung cancer in smokers. They found that use of low-dose CT and the classifier together resulted in a fivefold reduction in CT false-positives.
In the study, plasma samples from 939 participants in the randomized Multicenter Italian Lung Detection (MILD) trial, including 69 patients with lung cancer and 870 disease-free subjects, were analyzed using a quantitative reverse transcriptase polymerase chain reaction–based assay for a microRNA signature classifier. Of the 939 subjects, 652 were in the CT group and 287 in the observation group of the MILD trial. Diagnostic performance of the microRNA signature classifier was evaluated in blinded fashion using three prespecified risk groups based on expression ratio signatures of 24 microRNAs.
Subjects with lung cancer were older (mean, 61 vs 56 years; 19% vs 43% < 55 years, 26% vs 10% ≥ 65 years, P < .001 for trend), more likely to be male (81% vs 63%, P = .003), and had longer smoking history (40–49 years in 59% vs 38%, ≥ 50 years in 13% vs 5%, P < .001 for trend). There were no significant differences between groups in smoking status (80% and 79% current smokers) or number of cigarettes per day (eg, 20–29 in 45% and 51%, ≥ 40 in 19% vs 11%).
Cancer Detection
The microRNA intermediate- and high-risk classification had 87% sensitivity, 81% specificity, 27% positive predictive value, and 99% negative predictive value for lung cancer across both the CT and observation groups, including values of 88%, 80%, 31%, and 99% in the CT group and 82%, 83%, 16%, and 99% in the observation group. Low-dose CT had 79% sensitivity, 81% specificity, and a false-positive rate of 19.4% in lung cancer detection. The combination of the microRNA test and CT resulted in a fivefold reduction of the CT false-positive rate to 3.7% with a decrease in sensitivity to 69%. With positive outcome on at least one test, sensitivity was 98% and specificity was 65%, and the microRNA test detected 82% of lung cancers in the observation group. The microRNA test risk groups were not significantly associated with tumor stage (P = .40), histologic subtypes (P = .4485), or adenocarcinoma vs squamous cell carcinoma (P = .759).
Association With Survival
MicroRNA signature classifier risk groups were significantly associated with survival (χ21 = 49.53, P < .001); 2- and 3-year survival rates were 100%, 98%, and 87%, and 100%, 97%, and 77% for high, intermediate, and low microRNA test risk. The test had 95% sensitivity, 81% specificity, 10% positive predictive value, and 100% negative predictive value for lung cancer death.
The investigators concluded, “This large validation study indicates that [microRNA signature classifier] has predictive, diagnostic, and prognostic value and could reduce the false-positive rate of [low-dose] CT, thus improving the efficacy of lung cancer screening.”

2014年，Sozzi 等对意大利多中心肺癌检测 (Multicenter Italian Lung Detection，MILD) 项目获取到的血清进行了 miRNA 检测。研究者共选择了24种 miRNA，根据其表达情况，分为高危、中危和低危三组。结果显示，这种 miRNA 检测方案与低剂量螺旋 CT 筛查相结合，可以将前者的假阳性率大幅降低5倍。

A microRNA blood test used in combination with low-dose CT screening reduced unnecessary repeat imaging and demonstrated value as a tool to assess individual lung cancer risk, according to results of the bioMILD trial presented during the presidential symposium of International Association for the Study of Lung Cancer World Conference on Lung Cancer.

“We know that CT screening can reduce mortality; the question is how to use it best in high-risk individuals,” Ugo Pastorino, MD, of the Istituto Nazionale dei Tumori Foundation, said during a press conference. “The bioMILD trial evaluated the utility of combined blood microRNA testing and low-dose CT screening to predict individual lung cancer risk. For a group of individuals of the same age and the same [smoking] exposure, can we find those who are going to develop lung cancer?”

Researchers also sought to assess the feasibility of longer screening intervals for those with double-negative baseline CT screens and microRNA, and to reveal the potential damage of postponing CT after 2 or 3 years in terms of stage I detection, resection rates and interval cancers.

The analysis included 4,119 individuals aged 50 to 75 years who had more than 30 pack-years of smoking history and who had stopped smoking 10 or fewer years prior.

Researchers classified participants into three groups according to their testing results: double negative, meaning they had a low-risk microRNA blood test result and a negative CT finding (58%); single positive, meaning they had a positive lesion on CT imaging or an intermediate- or high-risk microRNA blood test result (37%); or double positive, meaning both CT imaging and the blood test were positive (5%).

A lesion of at least 113 mm³ on CT defined a positive result, which Pastorino noted was a “pretty high” threshold.

“Usually the threshold cutoff is much lower but, in fact, the newly published Lung-RADS criteria use exactly the same cutoff,” he said.

Lung cancer incidence at 4 years appeared significantly higher among patients with single-positive results (HR = 5.96; 95% CI, 3.38-10.52) or double-positive results (HR = 36.64; 95% CI, 20.31-66.11) compared with the double-negative group.

“The lung cancer incidence is enormously different among these groups that have the same composition of age, sex and tobacco consumption,” Pastorino said.

Risk for mortality at 4 years followed the same pattern, with much higher risks observed for the single-positive (HR = 4.67; 95% CI, 1.26-17.24) and double-positive (HR = 32.34; 95% CI, 8.55-121.6) groups than the double-negative group.

在肺癌筛查中血液中微小RNA和低剂量螺旋CT（LDCT）减少不必要的重复LDCT检查：前瞻性BioMILD试验结果】是关于肺癌筛查的间隔时间。通常而言，我们采用每年筛查的方式，但是在基线筛查CT阴性的人群中，是否有一部分人群可以采用更长的间隔时间，我们能否结合一些标志物帮助我们筛选这部分人群？这一研究采用CT和miRNA检查相结合的方式，如果LDCT扫描和血液miRNA检测均为阴性的受试者，定义为低风险人群，可以每3年复查一次。