Prospective Validation of Prognostic and Predictive Molecular tests in Mesothelioma

间皮瘤预后和预测分子检测的前瞻性验证

• 批准号: 10216184
• 负责人: RAPHAEL BUENO
• 金额: $ 30.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216184
• 关键词: Address; Algorithms; American Joint Committee on Cancer; Asbestos; Asbestos-Related Malignant Neoplasm; Biological Specimen Banks; Biopsy; Biopsy Specimen; Blood Tests; Cerebral Decortication; Cisplatin; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Clinical Trials Design; Collection; Communities; Complete Blood Count; Consensus; Consent; DNA; Data; Diagnosis; Diagnostic; Enrollment; Epithelial; Excision; Formalin; Freezing; Gene Expression; Genetic; Germ Lines; Goals; Grant; Histologic; Histology; Image; Immune response; Link; Long-Term Survivors; Lymphocyte; Malignant Neoplasms; Malignant Pleural Mesothelioma; Measures; Medical; Mesenchymal; Mesothelioma; Molecular; Molecular Diagnostic Testing; Morbidity - disease rate; Nature; Normal tissue morphology; Operative Surgical Procedures; Outcome; PF4 Gene; Paraffin Embedding; Pathologic; Pathological Staging; Pathology; Patient Selection; Patient-Focused Outcomes; Patients; Pemetrexed; Pharmaceutical Preparations; Plasma; Pleural; Pneumonectomy; Prognostic Factor; Prognostic Marker; Property; Prospective cohort; Publishing; Regimen; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Serum; Specimen; Staging; Stratification; Survival Rate; TNM; Testing; Therapeutic; Training; Treatment Protocols; Treatment outcome; Tumor Volume; Unresectable; Validation; Vimentin; Work; base; bevacizumab; candidate marker; chemotherapy; chest computed tomography; cohort; design; exome sequencing; follow-up; genetic testing; improved; improved outcome; individualized medicine; lymph nodes; mortality; multimodality; neutrophil; novel; novel diagnostics; patient stratification; patient subsets; potential biomarker; predictive signature; predictive test; preservation; prognostic; prognostic assays; prognostic model; prognostic signature; prospective; recruit; research clinical testing; response; success; survival prediction; targeted treatment; therapy outcome; tool; transcriptome sequencing; treatment stratification; tumor; validation studies

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.

恶性胸膜间皮瘤(MPM)是一种由石棉引起的破坏性癌症，5年生存率为10%。 治疗方法很少，而且有限。积极手术(胸膜外肺切除术(EPP)或 切除/去皮质(PD)后再化疗对部分患者有效，有效率为20%-30% 5年存活率，但确定将从这种治疗中受益的患者是一个重大挑战。外科手术 任何类型的MPM都与相当大的发病率和一些死亡率有关。主要目标是 增强和验证预后生物标记物和稳健的风险评分，以仅识别那些将 长期幸存者接受手术。我们之前开发并前瞻性地验证了一个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检测 MPM。我们将这一努力扩展到开发一个治疗前的临床预后评分，以告知患者 关于治疗的决定。在此，我们建议对多中心临床评估使用此风险评分(MRIS=MPM 基于4项简单检查(胸部CT、血细胞计数、2项胸膜活检分子检查)。我们将利用4 为拟议的工作提供临床数据和标本的独特的预期患者队列(总计：1101名患者)。 这些队列构成了一种独一无二的资源，还允许生成、评估和验证新的 候选生物标志物。在最近发表在NAT上的一项研究中。遗传学，我们定义了4个健壮、独特和更多的 均一表达簇符合上皮向间充质转化和 证明了表达簇I(由CLDN15/VIM比率定义)可以作为组织学- 核磁共振成像中的亚型诊断，我们建议将其扩展到其他集群。我们还建造了 验证了现有简单血液测试(中性粒细胞/淋巴细胞比率)的派生结果，这是预后的一部分 核磁共振成像代表了免疫反应。我们假设1)增加了新的基因和临床测试 我们目前的预后模型的信息将使MPM患者能够更准确地分配到更多 同质的治疗前亚群，允许合理分配治疗；2)我们的新预后 模型可以成功地移植到FFPE上并应用于临床。目标是：1.前瞻性验证 一种新的预测MPM患者生存的治疗前预后算法，通过登记所有新的 将MPM转化为临床试验，在治疗前确定核磁共振成像，并通过随访测量结果。 我们还将：a.为胸膜活检的分子测试确定测试和样本性质；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 集群成员和对特定治疗的反应。2.将分子检测转移至保存的FFPE 胸膜活检样本并确定建议的分子测试的一致性、样本和测试特性 (MPT和表达簇成员)。3.前瞻性地验证磁共振成像以及MPT和 来自多中心采集的FFPE标本中的MPS。

项目成果

Routine surveillance for diagnosis of venous thromboembolism after pleurectomy for malignant pleural mesothelioma.

恶性胸膜间皮瘤胸膜切除术后静脉血栓栓塞诊断的常规监测。

• DOI: 10.1016/j.jtcvs.2019.12.115
• 发表时间: 2020
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: DeLeón,LuisE;Bravo-Iñiguez,CarlosE;Fox,Sam;Tarascio,Jeffrey;Freyaldenhoven,Samuel;Lapidot,Moshe;Jaklitsch,MichaelT;Bueno,Raphael
• 通讯作者: Bueno,Raphael

Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline.

• DOI: 10.1200/jco.2017.76.6394
• 发表时间: 2018-05-01
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Kindler HL;Ismaila N;Armato SG 3rd;Bueno R;Hesdorffer M;Jahan T;Jones CM;Miettinen M;Pass H;Rimner A;Rusch V;Sterman D;Thomas A;Hassan R
• 通讯作者: Hassan R

Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma.

• DOI: 10.1158/1078-0432.ccr-12-2117
• 发表时间: 2013-05-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: De Rienzo A;Richards WG;Yeap BY;Coleman MH;Sugarbaker PE;Chirieac LR;Wang YE;Quackenbush J;Jensen RV;Bueno R
• 通讯作者: Bueno R

The Molecular Basis of Malignant Pleural Mesothelioma.

• DOI: 10.1016/j.thorsurg.2020.08.005
• 发表时间: 2020-11
• 期刊: Thoracic surgery clinics
• 影响因子: 2.1
• 作者: Wadowski B;De Rienzo A;Bueno R
• 通讯作者: Bueno R

Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients.

胸膜外肺切除术治疗上皮性恶性胸膜间皮瘤：基于529名患者的经验，N1和N2结节介入的新型预后意义。

• DOI: 10.1097/sla.0000000000000903
• 发表时间: 2014-10
• 期刊: Annals of surgery
• 影响因子: 9
• 作者: Sugarbaker DJ;Richards WG;Bueno R
• 通讯作者: Bueno R