Long-term prediction of prostate cancer death from kallikreins measured in blood

描述(由申请人提供)：我们将确定在44-50岁的男性中测量的激肽释放酶形式(前列腺特异性抗原[PSA]和激肽释放酶2[HK2])是否预测前列腺癌的后续转移或死亡。以前没有研究评估在健康志愿者人群中分析的生物标记物是否预测多年(通常是15-35年)后的转移或癌症特有的死亡。注册期间(1974-1986)瑞典PSA检测的低发生率和长期随访是我们独特的“自然实验”的先决条件。我们不会问“我们能检测出前列腺癌吗？”但“我们能预测前列腺癌对生活质量或预期寿命有重要影响吗？”我们希望预测前列腺癌转移或死亡的风险，以进行风险分层筛查和化学预防策略，这必须在这些努力开始之前进行，即在44-50岁。我们将首先确定在年龄=50岁时采集的血液中PSA和HK2的高度优化指标是否可以预测以后发生转移或前列腺癌死亡；然后确定第二个样本(6年后收集)中的指标是否会增强这些预测。我们将建立统计模型，使用单一或重复的测量方法来预测一个人在44-55岁的前列腺癌转移或死亡的概率。如果这些模型在R21阶段有足够的准确性，我们将在R33阶段继续在40,000名男性的独立队列中确定它们的准确性。避免了许多常见的问题。其中包括过度诊断：我们知道PSA可以在早期、可治愈的阶段发现前列腺癌，具有很高的敏感性(但特异性很差)，然而，许多PSA检测到的癌症在患者死于其他原因之前永远不会导致发病率或死亡率。研究还受到选择偏差的影响：有家族病史或其他风险因素的男性更有可能参加筛查；以及领先时间偏差，即明显的生存优势只与早期诊断时间有关。关于过度诊断的关键问题，我们的研究终点是死亡或转移性疾病。在我们的研究队列中，由于PSA筛查的发生率较低，因此几乎不会有选择偏差。由于这项研究的回溯性，参与者永远不会受到任何PSA数据的影响，我们也不会受到提前期偏差的影响，因为我们不会比较筛查和未筛查队列之间的存活率。使用20世纪70年代中期至80年代在瑞典采集的血液样本，我们能够证明，44-50岁的一次血液测试可以预测25年后的前列腺癌。由于被诊断患有前列腺癌的男性比死于前列腺癌的男性多得多，目前的建议是延长我们的工作，以确定我们是否可以预测前列腺癌死亡。如果是这样的话，可以使用一次血液测试来确定前列腺癌风险最高的男性，然后可以做出特别努力，对这些人进行密集筛查和化学预防。

DESCRIPTION (provided by applicant): We will determine whether kallikrein forms (prostate-specific antigen [PSA] and kallikrein 2 [hK2]) measured in men aged 44 - 50 predict subsequent metastases or death from prostate cancer. No previous study have evaluated whether a biomarker analyzed in a healthy volunteer population predicts metastases or cancer-specific death many years (typically 15-35 years) later. Low incidence of PSA testing in Sweden during enrollment (1974-1986) and long-term follow-up are prerequisites for our unique "natural experiment". We do not ask "can we detect prostate cancer?" but "can we predict prostate cancers with important impact on quality of life or reduced life expectancy?" We wish to predict risk of metastases or death from prostate cancer to risk-stratify screening and chemoprevention strategies, which must be made before these efforts start; i.e. in age 44- 50. We will first determine whether highly optimized measures of PSA and hK2 in blood collected at age =50 predict later development of metastases or death from prostate cancer; go on to determine whether measures in a 2nd sample (collected 6 years later) enhances these predictions. We will build statistical models to predict an individual man's probability of metastases or death from prostate cancer using single, or repeated measures at ages 44 - 55. If these models have sufficient accuracy in the R21 phase, we will go on in the R33 phase to determine their accuracy on an independent cohort of 40,000 men. Many common problems are avoided. These include over-diagnosis: we know that PSA detects prostate cancer at early, curable stages with high sensitivity (but poor specificity), however, many PSA-detected cancers would never cause morbidity or mortality to the patient before he dies of other causes. Studies are also affected by selection bias: men with family history or other risk factors are more likely to attend screening; and lead-time bias, where apparent survival advantage only relates to early time of diagnosis. Regarding the key issue of over-diagnosis, our study endpoint is death, or metastatic disease. There will be little if any selection bias due to low incidence of PSA screening in our study cohorts. Due to the retrospective nature of the study, the participants are never influenced by any PSA-data, and we will not be subject to lead- time bias as we will not compare survival between screened vs. unscreened cohorts. Using blood samples taken in Sweden in the mid-1970s - 1980s, we were able to show that a single blood test at age 44 - 50 can predict prostate cancer up to 25 years later. As many more men are diagnosed with prostate cancer than who die from the disease, the current proposal is to extend our work to determine if we can predict prostate cancer death. If so, a single blood test could be used to identify men at highest risk from prostate cancer and particular efforts could then be made for intensive screening and chemoprevention for these individuals.