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.

在血液中对前列腺特异性抗原（PSA）的测试已使前列腺癌和 疾病的转移和死亡减少，但也导致低风险癌症的过度检测。 尽管没有PSA浓度承认在前列腺活检中发现癌症的零风险，但单个PSA 中年的测量是对患致命前列腺癌风险的明显预测指标 几十年后。 PSA是一种蛋白水解酶，血液中非催化性，以多种形式发生。一个 基于四个Kallikrein（4K）标记的统计模型（免费，总和完整的PSA，以及与人类Kallikrein相关的人 肽酶-2 [HK2]）提高了PSA升高男性检测高级前列腺癌的特异性 （减少不必要的活检），也是对致命前列腺癌几十年风险的有力预测指标 之后。尽管PSA级别的个体内部波动很常见，但过多的可变性程度很高 有问题的，因为暂时的“假阳性”高程降低了PSA作为癌症标志物的特异性， 减轻PSA动力学的诊断价值，并导致使用不必要的抗生素。较少研究，但是 类似地在前列腺液中与PSA一样丰富，小糖蛋白 - ß（MSP，MSMB）的浓度在血液中的浓度 与前列腺癌风险和单一核苷酸多态性（SNP，rs10993994）成反比 MSMB基因的启动子区域也与前列腺癌风险有关，但这些作用 临床决策中的标记尚不清楚。同样，serpina3基因中的SNP显着 与PSA的血液水平以及编码蛋白Alpha-1-抗胰蛋白酶蛋白（ACT）相关的是 血液中主要稳定的络合配体与PSA。但是，这些制造商的临床价值是 不确定，尚不清楚血液中的作用水平是否影响基线的预测价值 PSA的PSA值或影响PSA的个体内部变化。另外，4K面板的个体内部变化 目前未知，但可以使用高质量的串行样品确定。作为这些不同的角色 侵略性前列腺癌的合并风险预测模型中的分子标记尚不清楚，我们 计划描述个体内变异性在连续筛查样品对临床决策的影响 - 通过单个PSA值和其他标记进行风险分层和活检。使用血液样本 在PLCO，Göteborg -1和-2试验和多民族队列（MEC）中，我们计划：1）量化 串行测量中4K标记 + MSP的变化； 2）确定统计之间的关系 基于4K标记 + MSP的模型以及随后发生致命前列腺癌的风险，然后独立验证 在治疗决策之前，标记在决策和风险分层中的临床实用性 前列腺癌治疗的随机试验（Protect）； 3）比较正面的临床实用程序 生物预印器与磁共振成像有关癌症检测率的成像。由此产生的见解 将阐明如何改善前列腺癌筛查和早期检测的特异性。