Prospective Validation of Prognostic and Predictive Molecular tests in Mesothelioma

恶性胸膜间皮瘤（MPM）是一种毁灭性的石棉诱发的癌症，5年生存率<10%。 治疗方法很少且有限。侵袭性手术（胸膜外肺切除术（EPP）或 胸膜切除术/剥脱术（PD））后化疗在一部分患者中有效， 5年生存率，但确定谁将受益于这种治疗的患者是一个重大的挑战。手术 任何类型的MPM都与相当大的发病率和一定的死亡率有关。主要目标是 增强和验证预后生物标志物和稳健的风险评分，以仅识别那些将 长期存活者接受手术。我们先前开发并前瞻性验证了4因素 病理分期评分（MPS=MPM预后评分），是手术后最可靠的预后测试， MPM。我们将这一努力扩展到开发一个治疗前临床预后评分，以告知患者他们的 关于治疗的决定。在此，我们建议多中心临床评价该风险评分（MRiS = MPM 风险评分）基于4项简单检查（胸部CT、CBC、2项胸膜活检分子检测）。我们将利用4 独特的前瞻性患者队列（总计：1101例患者），包含拟定工作的临床数据和样本。 这些群体构成了一种独一无二的资源，还可以生成、评估和验证新的 候选生物标志物。在最近发表在《国家遗传学》上的一项研究中，我们定义了4种强大的、独特的和更多的 均质表达簇与上皮向间充质转化一致， 表明表达簇I（由CLDN 15/Vim比率定义）可以是组织学-病理学-病理学的替代物。 亚型诊断的MRI，我们建议将其扩展到其他集群。我们还建造了 验证了一个简单的现有血液检测（中性粒细胞/淋巴细胞比率）的衍生物，它是预后的一部分， MRI代表免疫反应。我们假设：1）增加新的遗传和临床测试 我们目前的预后模型的信息将使MPM患者更准确地分配到更多的 同质的治疗前亚群，允许合理分配治疗; 2）我们新的预后 模型可以成功地转移到FFPE并用于临床。目标是：1.前瞻性地验证 一种新的治疗前预后算法，通过招募所有新患者来预测MPM患者的生存期， MPM纳入临床试验，在治疗前确定MRiS，并通过随访测量结局。 我们还将：a.确定胸膜活检中分子检测的检测和样本特性;以及 B.开发、探索和测试基于表达的MPM新的诊断、预后和预测特征 集群成员资格和对特定疗法的反应。2.将分子检测转移至FFPE保存 胸膜活检样本，并确定一致性，标本和拟议的分子测试的测试特性 (MPT和表达簇成员）。3.验证MRiS以及MPT， 多中心采集的FFPE标本中的MPS。

Malignant pleural mesothelioma (MPM), a devastating asbestos-induced cancer, has <10% 5-yr survival. Treatments are few and limited. Aggressive surgery (extra-pleural pneumonectomy (EPP) or pleurectomy/decortication (PD)) followed by chemotherapy is effective in a subset of patients, yielding 20%-30% 5-yr survival, but identifying the patients who will benefit from this treatment is a significant challenge. Surgery of any type for MPM is associated with considerable morbidity and some mortality. The primary goal is to enhance and validate prognostic biomarkers and a robust risk score to identify only those patients who will be long-term survivors to undergo surgery. We previously developed and prospectively validated a 4-factor pathology staging score (MPS=MPM Prognostic Score) that is the best reliable prognostic test after surgery for MPM. We extended this effort to develop a pre-treatment clinical prognostic score to inform patients in their decisions regarding therapy. Herein we propose for multicenter clinical evaluation this risk score (MRiS = MPM Risk Score) based on 4 simple tests (Chest CT, CBC, 2 molecular tests on pleural biopsy). We will leverage 4 unique prospective patient cohorts (total: 1101 patients) with clinical data and specimens for the proposed work. These cohorts constitute a one-of-a-kind resource that also allows to generate, evaluate and validate new candidate biomarkers. In a recent study published in Nat. Genetics, we defined 4 robust, distinct and more homogeneous expression clusters consistent with the epithelial to mesenchymal transformation and demonstrated that expression cluster I (defined by CLDN15/VIM ratio) can be a surrogate for the histological- subtype-diagnosis in MRiS and we propose to expand this to the other clusters. We also constructed and validated a derivative of a simple existing blood test (neutrophil/lymphocyte ratio) that is prognostic and a part of MRiS representing the immune response. We hypothesize that 1) adding new genetic and clinical test information to our current prognostic models will enable more accurate allocation of MPM patients into more homogeneous pre-treatment subpopulations, allowing for rational assignment of therapies; 2) our new prognostic models can be successfully transferred to FFPE and be used clinically. The Aims are: 1. Prospectively validate a new pre-treatment prognostic algorithm to predict survival for MPM patients, by enrolling all new patients with MPM into a clinical trial where the MRiS is determined prior to treatment and outcome is measured by follow up. We will also: a. Determine test and specimens properties for the molecular tests in pleural biopsies; and b. Develop, explore and test new diagnostic, prognostic and predictive signatures for MPM based on expression clusters membership and response to specific therapies. 2. Transfer the molecular tests to FFPE preserved pleural biopsy samples and determine concordance, specimen and test properties of proposed molecular tests (MPT and expression cluster membership) using RT-PCR. 3. Prospectively validate MRiS as well as MPT and MPS in FFPE specimens from multi-center collections.