Towards identification of prognostic gene sets in breast cancer: The E2197 Trial

鉴定乳腺癌的预后基因集：E2197 试验

• 批准号: 8111749
• 负责人: BRIAN LEYLAND-JONES
• 金额: $ 16.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111749
• 关键词: Adjuvant; Adjuvant Chemotherapy; Biological Assay; Biological Markers; Cancer Patient; Characteristics; Clinical; Clinical Trials; Complementary DNA; Cyclophosphamide; Data; Disease; Doxorubicin; Drug Delivery Systems; Eastern Cooperative Oncology Group; Epidermal Growth Factor Receptor; Estrogen Receptors; Event; Formalin; Gene Expression; Gene Proteins; Genes; Genetic; Genome; Genomics; Hormone Receptor; Human; Individual; Ligation; Malignant Neoplasms; Mediating; Messenger RNA; Molecular Profiling; Multi-Institutional Clinical Trial; Mutation; Outcome; Paraffin Embedding; Patients; Phase; Phenotype; Polymerase Chain Reaction; Population; Positive Lymph Node; Process; Progesterone Receptors; Prognostic Marker; RNA; Randomized; Recurrence; Relapse; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Estimate; Sampling; Signal Pathway; Specimen; Staging; Stratification; Subgroup; Testing; Time; Transcript; Validation; Woman; base; clinical decision-making; cohort; compare effectiveness; design; docetaxel; experience; high risk; lymph nodes; malignant breast neoplasm; prognostic; public health relevance; receptor; tumor

DESCRIPTION (provided by applicant): As we move forward, clinical decision making will rely more heavily on the genetic characteristics of the tumor and less on the clinical characteristics. Thus, identification and subsequent validation of biomarkers that can be used to accurately estimate the recurrence risk of breast cancer is a high priority. To this end, our hypothesis is that breast cancer subtypes, based upon hormone receptor and HER2 status, possess a unique constellation of genomic mutations that manifest in specific alterations in gene expression and protein signaling pathways. We further hypothesize that these major breast cancer phenotypes, contain specific signaling pathway alterations that are class-specific, drive the disease process itself, and most critically serve as candidates for biomarkers for therapy stratification and effective drug targets. Our overall objective is to identify gene sets within different subgroups of patients through molecular profiling of formalin-fixed, paraffin-embedded (FFPE) tumor samples from the E2197 clinical trial that will have prognostic utility in predicting recurrence. The ECOG E2197 clinical trial is a completed Phase III multisite trial that involved the randomization of patients (2,952) with primary breast cancer to compare the effectiveness of doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC), in treating women with node-positive and high risk node-negative breast cancer. Our primary objective is to identify genes based upon their ability to predict recurrence within the different subgroups of E2197 patients. Additional objectives will involve 1) comparing the data generated in the whole genome (WG)-DASL (cDNA-mediated annealing, selection and ligation) assay for the OncotypeDX set of genes with data from the OncotypeDX assay which will serve as a validation of the WG-DASL platform; 2) defining a set of the most significant individual genes as prognostic markers; 3) comparing the prognostic value of the OncotypeDX assay from a previous study with gene sets determined in this study; 4) comparing the prognostic value of genes selected from a set of 371 genes from a previous study with genes determined in this study; and 5) comparing the prognostic value of the PAM50 gene set with genes determined in this study. Toward that end, total RNA will be prepared from 868 FFPE tumor samples from E2197 classified into 4 patient subgroups as follows: 1) HR+, HER2-; 2) HR+, HER2+; 3) HR-, HER2+; 4) HR-, HER2- and . Expression profiling of the extracted RNA will be performed on the WG-DASL platform which will interrogate 24,526 mRNA transcripts. A signature set of genes will be selected based upon their ability to predict the recurrence-free interval (RFI) as the primary endpoint and secondary endpoints of breast cancer-free survival (BCFS), and overall survival (OS). Potential biomarkers will be validated by TaqMan quantitative real-time polymerase chain reaction (qRT-PCR). Prognostic biomarkers will be prospectively validated in a subsequent study. PUBLIC HEALTH RELEVANCE: Available adjuvant chemotherapies, such as doxorubicin, docetaxel and cyclophosphamide, and combinations thereof, are effective adjuvant treatment for the large population of women with node-positive early-stage breast cancer, but many patients still relapse and die of their disease. Thus, identification and subsequent validation of biomarkers that can be used to accurately estimate the risk of recurrence of breast cancer is a high priority. Our hypothesis is that the major breast cancer phenotypes contain specific signaling pathway alterations that are class-specific, drive the disease process itself, and most critically serve as candidates for biomarkers for therapy stratification and effective drug targets.

描述（由申请人提供）：随着我们的发展，临床决策将更多地依赖于肿瘤的遗传特征，而不是临床特征。因此，识别和随后验证可用于准确估计乳腺癌复发风险的生物标志物是一个高度优先事项。为此，我们的假设是，乳腺癌亚型，激素受体和HER 2状态的基础上，拥有一个独特的星座的基因组突变，表现在基因表达和蛋白质信号通路的特定改变。我们进一步假设，这些主要的乳腺癌表型，包含特定的信号通路改变，是类特异性的，驱动疾病过程本身，最重要的是作为候选生物标志物的治疗分层和有效的药物靶点。 我们的总体目标是通过对E2197临床试验中福尔马林固定、石蜡包埋（FFPE）肿瘤样本的分子谱分析，确定不同亚组患者中的基因集，这将在预测复发方面具有预后效用。ECOG E2197临床试验是一项已完成的III期多中心试验，涉及对原发性乳腺癌患者（2，952例）进行随机化，以比较多柔比星/多西他赛（AT）与多柔比星/环磷酰胺（AC）治疗淋巴结阳性和高危淋巴结阴性乳腺癌女性的有效性。我们的主要目的是根据E2197患者不同亚组中预测复发的能力来鉴定基因。其他目标将涉及1）比较全基因组（WG）-DASL中产生的数据使用来自OncotypeDX测定的数据对OncotypeDX基因集进行cDNA介导的退火、选择和连接（cDNA介导的退火、选择和连接）测定，其将用作WG-DASL平台的验证; 2）将一组最显著的个体基因定义为预后标志物; 3）将来自先前研究的OncotypeDX测定法的预后价值与本研究中确定的基因集进行比较; 4）将选自来自先前研究的371个基因集的基因的预后价值与本研究中确定的基因进行比较;和5）比较PAM 50基因集与本研究中确定的基因的预后价值。 为此，将从来自E2197的868份FFPE肿瘤样本制备总RNA，这些样本分为4个患者亚组，如下所示：1）HR+，HER 2-; 2）HR+，HER 2 +; 3）HR-，HER 2 +; 4）HR-，HER 2-和。将在WG-DASL平台上对提取的RNA进行表达谱分析，该平台将询问24，526个mRNA转录物。将基于其预测无复发间期（RFI）作为主要终点和无乳腺癌生存期（BCFS）和总生存期（OS）的次要终点的能力，选择一组特征基因。将通过TaqMan定量实时聚合酶链反应（qRT-PCR）验证潜在生物标志物。预后生物标志物将在后续研究中进行前瞻性验证。 公共卫生相关性：可用的辅助化疗，如多柔比星、多西他赛和环磷酰胺及其组合，是用于患有淋巴结阳性早期乳腺癌的大量妇女的有效辅助治疗，但许多患者仍然复发并死于其疾病。因此，鉴定和随后验证可用于准确估计乳腺癌复发风险的生物标志物是一个高度优先事项。我们的假设是，主要的乳腺癌表型包含特定的信号通路改变，这些改变是类别特异性的，驱动疾病过程本身，最重要的是作为治疗分层和有效药物靶点的生物标志物的候选者。