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: 10708766
• 负责人: Sigrid Carlsson
• 金额: $ 38.61万
• 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/10708766
• 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; Diagnosis; Disease; Early Diagnosis; Elderly; Ensure; Ethnic Origin; Future; Genes; Genetic Variation; Goals; Guidelines; Head; Human; Image; Individual; Kinetics; Kininogenase; Knowledge; Ligands; 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; Race; Recommendation; Research; Research Personnel; Risk; Risk Marker; Role; Sampling; Screening for Prostate Cancer; Single Nucleotide Polymorphism; Specific qualifier value; Specificity; Staging; Statistical Models; Technology; Test Result; Testing; Time; United Kingdom; United States; Urology; Variant; alpha 1-Antichymotrypsin; blood-based biomarker; cancer biomarkers; cancer risk; chymotrypsin; 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; randomized trial; risk prediction; 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.

检测血液中的前列腺特异性抗原 (PSA) 能够及早发现前列腺癌和 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。 尽管任何 PSA 浓度都不会导致前列腺活检中发现癌症的风险为零，但单一 PSA 中年时的测量是致命性前列腺癌风险的显着预测指标 几十年后，PSA 是一种在血液中无催化作用的蛋白水解酶，并且以多种形式存在。 基于四种激肽释放酶 (4K) 标记（游离、总和完整 PSA，以及人激肽释放酶相关蛋白）的统计模型 肽酶-2 [hK2]）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）也是几十年来致命前列腺癌风险的有力预测因素 虽然 PSA 水平的个体内部波动很常见，但过度的变异性也很严重。 存在问题，因为暂时的“假阳性”升高会降低 PSA 作为癌症标志物的特异性， 削弱 PSA 动力学的诊断价值，并导致使用不必要的抗生素。 前列腺液中的含量与 PSA 类似，血液中微精蛋白-β（MSP、MSMB）的浓度 与前列腺癌风险呈负相关，并且单核苷酸多态性（SNP，rs10993994） MSMB 基因的启动子区域也与前列腺癌风险相关，但这些区域的作用 类似地，SERPINA3 基因中的 S​​NP 也具有显着影响。 与血液中 PSA 水平相关，其编码蛋白 α-1-抗胰凝乳蛋白酶 (ACT) 是 血液中 PSA 的主要稳定络合配体 然而，这些标志物的临床价值是。 尚未确定，并且尚不清楚血液中的 ACT 水平是否影响基线的预测值 PSA 值或影响 PSA 的个体内变异，另外，4K 面板的个体内变异。 目前尚不清楚，但可以使用高质量的系列样本来确定这些不同的作用。 侵袭性前列腺癌联合风险预测模型中的分子标记尚不清楚，我们 计划描述连续筛查样本中个体内变异对临床决策的影响 使用血液样本通过单一 PSA 值和其他标记进行风险分层和活检。 根据 PLCO、Göteborg-1 和 -2 试验以及多种族队列 (MEC)，我们计划：1) 量化 连续测量中 4K 标记 + MSP 的变化；2) 确定统计数据之间的关系； 基于 4K 标记 + MSP 和随后的致死性前列腺癌风险的模型，然后独立验证 标记物在治疗决策前的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)；以及 3) 比较临床效用 活检前生物标志物与磁共振成像对癌症检出率的影响。 将阐明如何提高前列腺癌筛查和早期检测的特异性。