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岁男性中测量的钾化因子形式（前列腺特异性抗原[PSA]和钾化因子2 [hK2]）是否能预测前列腺癌随后的转移或死亡。此前没有研究评估在健康志愿者人群中分析的生物标志物是否能预测多年（通常为15-35年）后的转移或癌症特异性死亡。瑞典在入组期间（1974-1986）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。我们问的不是“我们能不能检测出前列腺癌？”而是“我们能不能预测前列腺癌对生活质量或预期寿命的影响？”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，这些必须在这些努力开始之前制定；即年龄在44- 50岁之间。我们将首先确定50岁时采集的血液中高度优化的PSA和hK2指标是否能预测前列腺癌转移的后期发展或死亡；接下来确定第二个样本（6年后收集）的测量是否增强了这些预测。我们将建立统计模型来预测44 - 55岁男性个体前列腺癌转移或死亡的概率，使用单一或重复测量。如果这些模型在R21阶段具有足够的准确性，我们将继续在R33阶段确定其在40,000名男性的独立队列中的准确性。避免了许多常见的问题。其中包括过度诊断：我们知道PSA在早期可治愈阶段检测前列腺癌，灵敏度高（但特异性差），然而，许多PSA检测到的癌症在患者死于其他原因之前不会引起发病或死亡。研究也受到选择偏差的影响：有家族史或其他风险因素的男性更有可能参加筛查；提前期偏差，即明显的生存优势只与早期诊断有关。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筛查的低发生率，几乎没有选择偏倚。由于该研究的回顾性性质，参与者从未受到任何psa数据的影响，我们不会受到前置时间偏差的影响，因为我们不会比较筛查与未筛查队列之间的生存率。通过使用20世纪70年代中期至80年代在瑞典采集的血液样本，我们能够证明在44岁至50岁之间进行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该疾病的男性多得多，目前的建议是扩展我们的工作，以确定我们是否可以预测前列腺癌的死亡。如果是这样的话，一个单一的血液测试就可以用来识别患前列腺癌风险最高的男性，然后可以做出特别的努力，对这些人进行密集的筛查和化学预防。

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.