Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee.
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
JAMA Oncol. 2024 Jun 1;10(6):726-736. doi: 10.1001/jamaoncol.2024.0455.
Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater).
To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers.
DESIGN, SETTING, AND PARTICIPANTS: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023.
Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy.
Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily.
Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater.
In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.
重要性：单独使用前列腺特异性抗原 (PSA) 进行前列腺癌 (PCa) 筛查的益处，很大程度上被大量的阴性活检和由于 PSA 对高级别 PCa（即 GG2 或更高）的特异性差而导致的惰性癌症的过度检测所抵消。
目的：开发一种用于高级别 PCa 的多重尿液检测面板，并验证其相对于当前指南推荐的生物标志物的外部性能。
设计、设置和参与者：对 58724 个基因进行 RNA 测序分析，确定了 54 个 PCa 标志物，包括 17 个仅由高级别癌症过表达的标志物。在一个新的用于高级别 PCa 的尿液检测中（MyProstateScore 2.0 [MPS2]），对基因表达和临床因素进行建模。在没有前列腺体积的情况下（MPS2）和有前列腺体积的情况下（MPS2+），同时开发了最佳模型。锁定模型在一项前瞻性的美国国立癌症研究所试验队列中进行了盲法外部验证。数据收集于 2008 年 1 月至 2020 年 12 月，数据分析于 2023 年 11 月至 11 月进行。
暴露：方案化的血液和尿液采集以及经直肠超声引导的系统前列腺活检。
主要结果和措施：在验证队列中评估了多种生物标志物检测，包括血清 PSA 单独、前列腺癌预防试验风险计算器、前列腺健康指数（PHI）以及衍生的多重 2 基因和 3 基因模型、原始的 2 基因 MPS 检测和 18 基因 MPS2 模型。在用于 GG2 或更高的 PCa 的 95%敏感性的检测方法下，计算了检测的诊断准确性和临床后果的措施。其次评估了 GG3 或更高的癌症。
结果：在开发队列的 761 名男性中，中位（IQR）年龄为 63（58-68）岁，中位（IQR）PSA 水平为 5.6（4.6-7.2）ng/mL；在验证队列的 743 名男性中，中位（IQR）年龄为 62（57-68）岁，中位（IQR）PSA 水平为 5.6（4.1-8.0）ng/mL。在验证队列中，151 名（20.3%）男性在活检中患有高级别 PCa。单独使用 PSA 的受试者工作特征曲线下面积值为 0.60，使用风险计算器为 0.66，使用 PHI 为 0.77，使用衍生的多重 2 基因模型为 0.76，使用衍生的多重 3 基因模型为 0.72，使用原始 MPS 模型为 0.74，而使用 MPS2 模型为 0.81，使用 MPS2+模型为 0.82。在 95%的敏感性下，MPS2 模型将减少初始活检人群（其他测试范围为 15%至 30%；MPS2 范围为 35%至 42%）和重复活检人群（其他测试范围为 9%至 21%；MPS2 范围为 46%至 51%）中进行的不必要活检。在相关亚组中，MPS2 模型对 GG2 或更高的癌症具有 95%至 99%的阴性预测值，对 GG3 或更高的癌症具有 99%的阴性预测值。
结论和相关性：在这项研究中，一种新的 18 基因 PCa 检测对高级别 PCa 的诊断准确性相对于现有生物标志物检测更高。从临床角度来看，使用该检测将大大减少在保持高级别癌症高度敏感检测的同时进行的不必要的活检。这些数据支持在具有升高的 PSA 水平的患者中使用这种新的 PCa 生物标志物检测，以减少前列腺癌筛查的潜在危害，同时保留其长期益处。
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