Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Eur Urol. 2017 Sep;72(3):461-469. doi: 10.1016/j.eururo.2017.05.040. Epub 2017 Jun 2.
Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed.
To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study.
DESIGN, SETTING, AND PARTICIPANTS: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values.
We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions.
The progression score was significantly (p<0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p<0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p<0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R=0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients).
The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens.
Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.
非肌肉浸润性膀胱癌（NMIBC）进展为肌肉浸润性膀胱癌（MIBC）是危及生命的，不能仅通过临床和病理危险因素来准确预测。目前非常需要用于分层治疗和监测的生物标志物。
在一项大型、多中心、前瞻性研究中验证先前开发的 12 基因进展评分，以预测进展为 MIBC。
设计、设置和参与者：我们在 2008 年至 2012 年间招募了来自十个欧洲中心的 1224 名患者。共有 750 名患者（851 个肿瘤）符合纳入标准和样本质量标准。患者的平均随访时间为 28 个月（范围 0-76）。对所有肿瘤进行 12 基因实时定量聚合酶链反应检测，并使用预定义公式和截止值计算进展评分。
使用 Cox 回归分析和对数秩检验来测量 MIBC 的进展，发现进展评分与年龄、分期、分级、原位癌、卡介苗治疗、欧洲癌症研究和治疗组织风险评分以及疾病进展显著相关（p<0.001）。单变量 Cox 回归分析显示，分子分类为高危的患者更频繁地发生疾病进展（危险比 5.08，95%置信区间 2.2-11.6；p<0.001）。多变量 Cox 回归模型显示，进展评分在临床和组织病理学危险因素之外提供了独立的预后信息（p<0.001），一致性统计量从 0.82 增加到 0.86。进展评分在新鲜冷冻和福尔马林固定石蜡包埋肿瘤标本之间具有高度相关性（R=0.85），支持在标准临床环境中的转化潜力。局限性在于进展率相对较低（5%，37/750 例患者）。
12 基因进展评分具有独立的预后能力，超过了临床和组织病理学危险因素，可能有助于分层 NMIBC 患者以优化治疗和随访方案。
疾病侵袭性的 12 基因分子检测的临床应用可能有助于分层非肌肉浸润性膀胱癌患者，以获得最佳治疗方案。
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