Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Laboratory of Pleural and Lung Cancer Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford Respiratory Trials Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Lancet Oncol. 2018 Jul;19(7):930-939. doi: 10.1016/S1470-2045(18)30294-8. Epub 2018 Jun 13.
The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival.
In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation.
17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score).
To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies.
European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.
恶性胸腔积液的患病率在全球范围内呈上升趋势，但仍未发现用于规划治疗和了解疾病进展潜在机制的预后生物标志物。PROMISE 研究旨在发现、验证和前瞻性评估恶性胸腔积液中与生存和胸膜固定术反应相关的生物标志物，并构建预测生存的评分。
在这项多队列研究中，我们使用五项来自随机对照试验的独立数据集，研究了与生存和胸膜固定术相关的潜在生物标志物。采用基于质谱的发现方法，对来自不同生存和胸膜固定术结局的发现组患者的胸腔积液样本进行差异蛋白表达分析。将临床、影像学和生物学变量输入最小绝对收缩和选择算子回归中，构建预测 3 个月死亡率的模型。我们使用内部和外部验证来评估该模型。
在发现数据集中共鉴定出 17 个与生存相关和 7 个与胸膜固定术相关的生物标志物候选物。三个独立数据集（n=502）用于生物标志物验证。所有与胸膜固定术相关的生物标志物均未通过验证，而凝胶蛋白、巨噬细胞移动抑制因子、软骨寡聚基质蛋白和金属蛋白酶组织抑制剂 1（TIMP1）成为准确预测生存的标志物。验证了 8 个变量（血红蛋白、C 反应蛋白、白细胞计数、东部肿瘤协作组体能状态、癌症类型、胸腔积液 TIMP1 浓度以及既往化疗或放疗），并利用这些变量开发了一个生存评分。通过 bootstrap 重采样进行内部验证，以及使用来自两个独立数据集的 162 名患者进行外部验证，均显示出良好的区分度（内部验证的临床 PROMISE 评分的 C 统计值为 0.78[95%CI 0.72-0.83]，外部验证为 0.89[0.84-0.93]）。
据我们所知，该评分是首个前瞻性验证的恶性胸腔积液预后模型，它将生物学和临床参数相结合，准确估计 3 个月死亡率。这是一个稳健、具有临床相关性的预后评分，可立即应用，为患者预后提供重要信息，并指导选择适当的管理策略。
欧洲呼吸学会、牛津大学医学研究基金会、斯莱特和戈登研究基金以及牛津郡卫生服务研究委员会研究资助。
