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）：随着我们的前进，临床决策将更依赖于肿瘤的遗传特征，而较少依赖于临床特征。因此，可用于准确估计乳腺癌复发风险的生物标志物的鉴定和随后验证是一个高度优先级。为此，我们的假设是，基于激素受体和HER2状态的乳腺癌亚型具有独特的基因组突变星座，这些星座体现在基因表达和蛋白质信号传导途径的特定变化中。我们进一步假设，这些主要的乳腺癌表型包含特定阶级的特定信号通路改变，推动疾病过程本身，并且最严重地充当了治疗分层和有效药物靶标生物标志物的候选者。 我们的总体目的是通过对E2197临床试验的福尔马林固定，石蜡填充（FFPE）肿瘤样品的分子分析来鉴定患者不同亚组中的基因集，该试验将在预测重生方面具有预后的效用。 ECOG E2197临床试验是一项完整的III期多站点试验，涉及患者（2,952）与原发性乳腺癌的随机分组，以比较阿霉素/多西昔昔·赛（AT）与阿霉素/环磷酰胺（AC）（AC）的有效性，以治疗恶性阳性和高风险乳腺癌的女性。我们的主要目标是根据其预测E2197患者不同亚组复发的能力来识别基因。其他目标将涉及1）比较整个基因组（WG）-DASL中生成的数据（cDNA介导的退火，选择和连接）分析的OnCoTypEDX基因集和来自OnCoTYPEDX分析的数据，该数据将用作WG-DASL平台的验证； 2）将一组最重要的单个基因定义为预后标记； 3）比较了先前研究的Oncotypedx测定的预后价值与本研究中确定的基因集的预后值； 4）比较本研究中确定的基因从先前的研究中选择的基因的预后价值； 5）将PAM50基因的预后值与本研究确定的基因进行比较。 为此，将从E2197的868个FFPE肿瘤样品中制备总RNA，如下所示：1）HR+，HER2-； 2）HR+，HER2+; 3）hr-，her2+; 4）hr-，her2-和。提取的RNA的表达分析将在WG-DASL平台上进行，该平台将询问24,526个mRNA转录本。将根据其预测无复发间隔（RFI）作为无乳腺癌生存期（BCFS）（BCFS）的主要终点和次要终点的能力以及总体生存（OS）来选择一组签名基因。潜在的生物标志物将通过TAQMAN定量实时聚合酶链反应（QRT-PCR）验证。预后生物标志物将在随后的一项研究中得到前瞻性验证。 公共卫生相关性：可用的辅助化学疗法，例如阿霉素，多西他赛和环磷酰胺及其组合，是针对大量淋巴结阳性早期乳腺癌妇女的有效辅助治疗，但许多患者仍会复发并死于疾病。因此，可用于准确估计乳腺癌复发风险的生物标志物的鉴定和后续验证是高度的重点。我们的假设是，主要的乳腺癌表型包含特定阶级的特定信号通路改变，推动疾病过程本身，并且最严重地充当了治疗分层和有效药物靶标生物标志物的候选者。