早期胰腺癌血液中蛋白质生物标志物候选物的序贯验证
Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer.
作者信息
Capello Michela, Bantis Leonidas E, Scelo Ghislaine, Zhao Yang, Li Peng, Dhillon Dilsher S, Patel Nikul J, Kundnani Deepali L, Wang Hong, Abbruzzese James L, Maitra Anirban, Tempero Margaret A, Brand Randall, Firpo Matthew A, Mulvihill Sean J, Katz Matthew H, Brennan Paul, Feng Ziding, Taguchi Ayumu, Hanash Samir M
机构信息
Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
出版信息
J Natl Cancer Inst. 2017 Apr 1;109(4). doi: 10.1093/jnci/djw266.
BACKGROUND
CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone.
METHODS
Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided.
RESULTS
Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set).
CONCLUSION
The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.
背景
CA19-9目前作为胰腺导管腺癌（PDAC）生物标志物应用于临床，但在检测早期疾病方面性能有限。我们和其他研究人员已鉴定出有潜力补充CA19-9的蛋白质生物标志物候选物。我们从17种蛋白质生物标志物候选物开始进行了系列验证，以确定与单独使用CA19-9相比，哪些标志物及标志物组合能改善早期疾病的检测。
方法
使用由PDAC病例（n = 187）、良性胰腺疾病患者（n = 93）和健康对照者（n = 169）组成的独立多样本队列，对候选生物标志物进行基于酶联免疫吸附测定的系列验证。基于逻辑回归模型开发了用于早期PDAC的生物标志物组合。以下结果的所有统计检验均为单侧检验。
结果
在由75例PDAC患者、27例健康受试者和19例慢性胰腺炎患者组成的样本集中，对17种生物标志物候选物中的6种以及CA19-9进行了验证。在由73例早期PDAC患者、60例健康受试者和74例良性胰腺疾病患者组成的第二个独立组（联合验证集）中，得到了一个由基质金属蛋白酶组织抑制因子1（TIMP1）、富含亮氨酸α-2糖蛋白1（LRG1）和CA19-9组成的模型。使用来自39例可切除PDAC患者和82例匹配健康受试者的独立血浆样本集（测试集）对该模型进行了额外的盲法测试。在联合验证集和测试集中，该模型在区分早期PDAC与健康受试者时，曲线下面积（AUC）分别为0.949（95%置信区间[CI]=0.917至0.981）和0.887（95%CI = 0.817至0.957），在95%特异性时敏感性分别为0.849和0.667。与单独使用CA19-9相比，该生物标志物组合性能在统计学上有显著改善（联合验证集：P <.001；测试集：P =.008）。
结论
在CA19-9检测中加入TIMP1和LRG1免疫测定在统计学上能显著改善早期PDAC的检测。
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