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

血液中前列腺特异性抗原(PSA)检测使前列腺癌和前列腺癌的早期发现成为可能 减少转移和疾病死亡--但也有助于过度检测低风险癌症。 尽管没有PSA浓度可以保证在前列腺活检中发现癌症的风险为零，但单一的PSA 中年时的测量是患致命前列腺癌风险的一个非常有力的预测因素 几十年后。PSA是一种蛋白质水解酶，在血液中是非催化的，它以多种形式存在。一个 基于四个激肽释放酶(4K)标志物(游离、总和完整的PSA，以及人激肽释放酶相关的)的统计模型 多肽酶-2[HK2]可提高检测PSA升高男性中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 后来。虽然PSA水平的个体内部波动是常见的，但过度的变异性是非常严重的 问题在于，暂时性的“假阳性”升高降低了PSA作为癌症标记物的特异性， 削弱了PSA动力学的诊断价值，并导致不必要的抗生素的使用。研究较少，但 与PSA一样，前列腺液中同样丰富的微量精浆蛋白(MSP，MSMB)在血液中的浓度 与前列腺癌的风险呈负相关，并且在 MSMB基因的启动子区域也与前列腺癌风险有关，但这些因素的作用 临床决策中的标志物尚不清楚。同样，SERPINA3基因中的SNP显著地 与血液中PSA水平和编码蛋白α-1-抗糜蛋白酶(ACT)相关的是 血液中主要稳定的PSA络合配体。然而，这些标记物的临床价值是 尚不确定，目前尚不清楚血液中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。此外，4K面板的个人内部变化 目前尚不清楚，但可以使用高质量的系列样品来确定。因为这些不同的角色 分子标志物在侵袭性前列腺癌联合风险预测模型中的作用尚不清楚 计划描述系列筛查样本中个体内变异性对临床决策的影响 通过单个PSA值和附加标记物进行风险分层和活检。使用血液样本 从PLCO、Göteborg-1&2试验和多种族队列(MEC)，我们计划：1)量化 4K标记+MSP在连续测量中的变化；2)确定统计之间的关系 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 标记物在非霍奇金淋巴瘤患者治疗前决策和风险分层中的临床应用 前列腺癌治疗的随机试验(PROTECT)；以及3)面对面比较 活检前生物标记物与磁共振成像对癌症发现率的比较。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。

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.