Influence of intra-individual variability in serial screening samples on clinical decision-making for risk stratification and biopsy by a single PSA and additional markers

通过单一 PSA 和其他标志物进行的系列筛查样本中个体内变异性对风险分层和活检临床决策的影响

• 批准号: 10468509
• 负责人: Sigrid Carlsson
• 金额: $ 46.38万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468509
• 关键词: Affect; Aftercare; Age; Antibiotics; Anxiety; Attention; Attenuated; Biological; Biological Markers; Biopsy; Blood; Blood Tests; Blood specimen; Cancer Detection; Cessation of life; Clinical; Clinical Data; Cohort Studies; Colorectal; Complex; Data; Decision Making; Detection; Disease; Early Diagnosis; Elderly; Ensure; Future; Genes; Genetic Variation; Goals; Guidelines; Head; Human; Image; Individual; Kinetics; Kininogenase; Knowledge; Lead; Ligands; Light; Liquid substance; Lung; MSMB gene; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Monitor; Neoplasm Metastasis; Outcome; Ovarian; PSA level; PSA screening; Patients; Pattern; Peptide Hydrolases; Population; Population Study; Predictive Value; Primary Care Physician; Promoter Regions; Prostate; Prostate Cancer therapy; Prostate specific antigen measurement; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Prostate-Specific Antigen; Prostatic; Proteins; Publishing; Research; Research Personnel; Risk; Role; Sampling; Screening for Prostate Cancer; Single Nucleotide Polymorphism; Specific qualifier value; Specificity; Staging; Statistical Models; Test Result; Testing; Time; United Kingdom; United States; Urology; Variant; alpha 1-Antichymotrypsin; base; blood-based biomarker; cancer biomarkers; cancer risk; cancer therapy; clinical care; clinical decision-making; clinical practice; cohort; cost; diagnostic value; evidence base; head-to-head comparison; improved; individual variation; innovation; insight; men; middle age; molecular marker; multi-ethnic; novel; patient subsets; population based; programs; prospective; prostate biopsy; prostate cancer risk; racial and ethnic; randomized trial; risk prediction model; risk stratification; screening; tool; treatment trial

Testing for prostate-specific antigen (PSA) in blood has enabled early detection of prostate cancer and reduced metastasis and death from disease—but also contributed to overdetection of low-risk cancers. Although no PSA concentration confers zero risk of finding cancer at prostate biopsy, a single PSA measurement at midlife is a remarkably strong predictor of the risk of developing lethal prostate cancer decades later. PSA is a proteolytic enzyme that is non-catalytic in blood, and it occurs in multiple forms. A statistical model based on four kallikrein (4K) markers (free, total, and intact PSA, plus human kallikrein-related peptidase-2 [hK2]) improves specificity in detecting high-grade prostate cancer among men with elevated PSA (reducing unnecessary biopsies) and is also a strong predictor of the risk of lethal prostate cancer decades later. While intra-individual fluctuations in PSA levels are common, an excessive degree of variability is highly problematic, as temporary “false positive” elevations reduce the specificity of PSA as a cancer marker, attenuate the diagnostic value of PSA kinetics, and lead to the use of unnecessary antibiotics. Less studied but similarly abundant in prostatic fluid as PSA, the concentration of microseminoprotein-ß (MSP, MSMB) in blood is inversely associated with prostate cancer risk, and a single nucleotide polymorphism (SNP, rs10993994) in the promoter region of the MSMB gene is also associated with prostate cancer risk, but the role of these markers in clinical decision-making is unclear. Similarly, a SNP in the SERPINA3 gene is significantly associated with blood levels of PSA, and the encoded protein, alpha-1-antichymotrypsin (ACT), is the predominant stable complexing ligand to PSA in the blood. However, the clinical value of these makers is undetermined, and it remains unclear whether ACT levels in blood influence the predictive value of a baseline PSA value or affect intra-individual variation in PSA. Additionally, the intra-individual variation of the 4K-panel is currently unknown but could be determined using high-quality serial samples. As the role of these different molecular markers in combined risk-prediction models of aggressive prostate cancer is not well understood, we plan to delineate the influence of intra-individual variability in serial screening samples on clinical decision- making for risk stratification and biopsy by a single PSA value and additional markers. Using blood samples from the PLCO, Göteborg-1 & -2 trials, and Multiethnic Cohort (MEC), we plan to: 1) quantify the patterns of variation in the 4K markers + MSP in serial measurements; 2) determine the relationship between a statistical model based on 4K markers + MSP and subsequent risk of lethal prostate cancer, then independently validate the clinical utility of the markers in decision-making and risk stratification before treatment decisions in a randomized trial of prostate cancer treatments (ProtecT); and 3) compare head-to-head the clinical utility of pre-biopsy biomarkers versus magnetic resonance imaging on cancer detection rates. The resulting insights will shed light on how to improve the specificity of prostate cancer screening and early detection.

血液中前列腺特异性抗原（PSA）的检测能够早期发现前列腺癌， 减少了转移和疾病死亡，但也导致了低风险癌症的过度检测。 虽然没有PSA浓度在前列腺活检中发现癌症的风险为零，但单一PSA 中年测量是发展致命前列腺癌风险的一个非常强的预测因素 几十年后。PSA是一种蛋白水解酶，在血液中是非催化性的，它以多种形式存在。一 基于四种激肽释放酶（4K）标志物（游离、总和完整PSA，加上人激肽释放酶相关 peptidase-2 [hK 2]）提高了PSA升高男性中检测高级别前列腺癌的特异性 （减少不必要的活检），也是一个强有力的预测风险致命的前列腺癌几十年 后虽然PSA水平的个体内波动是常见的，但过度程度的变异性是高度危险的。 有问题的是，由于暂时的“假阳性”升高降低了PSA作为癌症标志物的特异性， 削弱了PSA动力学的诊断价值，并导致使用不必要的抗生素。研究较少，但 前列腺液中与PSA类似丰富的微量前列腺蛋白-β（MSP，MSMB）浓度， 与前列腺癌风险呈负相关，并且在前列腺癌中存在单核苷酸多态性（SNP，rs 10993994）。 MSMB基因的启动子区域也与前列腺癌风险相关，但这些基因的作用 临床决策中的标志物尚不清楚。类似地，SERPINA 3基因中的SNP显著增加了 与PSA的血液水平相关，编码的蛋白质α-1-抗胰凝乳蛋白酶（ACT）是 在血液中PSA的主要稳定络合配体。然而，这些标记物的临床价值是 目前尚不清楚血液中的ACT水平是否会影响基线的预测值。 PSA值或影响PSA的个体内变异。此外，4K样本组的个体内变异 目前尚不清楚，但可以使用高质量的系列样品来确定。由于这些不同的角色 分子标志物在侵袭性前列腺癌的联合风险预测模型中的作用还不清楚，我们 计划描述系列筛选样本中个体内变异性对临床决策的影响- 通过单个PSA值和其他标志物进行风险分层和活检。使用血液样品 从PLCO，哥德堡-1和-2试验，和多种族队列（MEC），我们计划：1）量化的模式， 在连续测量中4K标记物+ MSP的变化; 2）确定统计学之间的关系， 基于4K标记物+ MSP和随后的致死性前列腺癌风险的模型，然后独立验证 在治疗决定之前，标记物在决策和风险分层中的临床效用 前列腺癌治疗的随机试验（ProtecT）;和3）比较头对头的临床效用， 活检前生物标志物与磁共振成像对癌症检出率的影响。由此产生的见解 将阐明如何提高前列腺癌筛查和早期发现的特异性。