Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
JAMA Oncol. 2017 Aug 1;3(8):1085-1093. doi: 10.1001/jamaoncol.2017.0177.
Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease.
To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs.
DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort.
INTERVENTIONS/EXPOSURES: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy.
Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes.
Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men.
Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.
积极治疗（Gleason 评分≥7）早期前列腺癌可能带来生存获益，但前列腺活检的潜在危害和惰性疾病的过度诊断会削弱这种获益。
评估联合检测数字直肠检查后尿液中 PCA3 和 TMPRSS2:ERG（T2:ERG）RNA 的预先假设主要假设，即与单独检测前列腺特异性抗原相比，该方法能否提高检测 Gleason 评分≥7 的癌症的特异性。次要目标是评估这种尿液 RNA 检测对医疗保健成本的潜在影响。
设计、地点和参与者：前瞻性、多中心学术和社区门诊泌尿科临床诊断评估和验证。参与者为首次前列腺活检时无前列腺癌既往史的男性：516 名合格参与者来自于发展队列中的 748 名前瞻性队列参与者，561 名合格参与者来自验证队列中的 928 名参与者。
干预/暴露：前列腺活检前检测尿液 PCA3 和 T2:ERG RNA。
前列腺活检中存在 Gleason 评分≥7 的前列腺癌。病理检测结果对尿液检测结果进行了盲法评估。在发展队列中，使用尿液 RNA 检测构建了一个多重决策算法，以优化特异性，同时保持 95%的敏感性，用于预测初始活检时的侵袭性前列腺癌。通过预设分析，根据前瞻性样本采集、回顾性盲法评估（PRoBE）标准，在另一个多中心队列中对发现进行了验证。通过对观察到的活检结果和以前报告的治疗结果进行建模，评估了尿液检测策略的成本效果。
在发展队列的 516 名男性（平均年龄 62 岁；范围 33-85 岁）中，联合检测尿液 T2:ERG 和 PCA3 的阈值，同时保持 95%的检测侵袭性前列腺癌的敏感性，特异性从 18%提高到 39%。在验证队列的 561 名男性（平均年龄 62 岁；范围 27-86 岁）中，分析结果证实了特异性的提高（从 17%提高到 33%；单侧 95%CI 的下限为 0.73%；预设单侧 P=0.04），同时保持了检测侵袭性前列腺癌的高敏感性（93%）。如果使用尿液检测结果选择进行活检的男性，42%的不必要的前列腺活检可以避免。成本分析表明，这种尿液检测算法限制前列腺活检在年轻男性中具有更大的成本效益。
联合检测尿液 T2:ERG 和 PCA3 可以避免不必要的活检，同时保持检测侵袭性前列腺癌的强大敏感性，从而可能节省医疗保健成本。
