Predictive Biomarkers of Adjuvant Trastuzumab in the HER2+N9831 Intergroup Trial

HER2 N9831 组间试验中曲妥珠单抗辅助治疗的预测生物标志物

• 批准号: 8091379
• 负责人: EDITH A. PEREZ
• 金额: $ 19.87万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-20 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091379
• 关键词: Address; Adjuvant; Adverse effects; Antibodies; Biological Assay; Biological Markers; Breast; Breast Cancer Treatment; Cancer Patient; Caring; Chromosomes; Clinical; Clinical Trials; Complementary DNA; Correlative Study; Custom; Cyclophosphamide; DNA; DNA topoisomerase II alpha; Data; Disease; Disease-Free Survival; Doxorubicin; EGF gene; ERBB2 gene; ERBB3 gene; Enrollment; Epidermal Growth Factor Receptor; ErbB4 gene; Family; Fluorescent in Situ Hybridization; Formalin; Gene Expression; Gene Expression Profiling; Gene Proteins; Genes; Genetic; Goals; Human; Immunohistochemistry; Individual; Insulin-Like-Growth Factor I Receptor; Investigation; Ligation; Mammary Neoplasms; Mediating; Medicine; Methods; North Central Cancer Treatment Group; PTEN gene; Paclitaxel; Paraffin Embedding; Paraffin Tissue; Patient Care; Patients; Pattern; Phase; Positive Lymph Node; Primary Neoplasm; Proteins; RNA; Recombinants; Recurrence; Resected; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Signal Pathway; Specimen; System; TOP2A gene; Technology; Testing; Therapeutic Intervention; Time; TimeLine; Tissues; Toxic effect; Trastuzumab; Tumor Markers; Variant; Woman; base; clinical care; design; experience; follow-up; high risk; humanized monoclonal antibodies; improved; malignant breast neoplasm; multidisciplinary; patient population; pre-clinical; protein expression; public health relevance; response; translational study; treatment response; tumor; validation studies

DESCRIPTION (provided by applicant): Successful personalized care of breast cancer patients is critically dependent on accurately applying predictive markers of treatment response. The specific objective of this proposal is to identify reliable biomarkers, derived from proteins, DNA aberrations, and gene expression patterns, in paraffin-embedded primary breast tumors that predict response to adjuvant trastuzumab (an antibody directed against HER2). These patients were enrolled in the landmark NCCTG-sponsored adjuvant N9831intergroup trial (EA Perez-PI) that led to dramatic changes in the clinical care of HER2-positive breast cancer patients. Our overall hypothesis is that tissue markers associated with EGF-family signaling pathways will predict those patients more likely to respond to adjuvant trastuzumab. Our specific aims include three translational studies: 1) To determine the tissue expression of select proteins involved in the mechanisms of trastuzumab activity and resistance using conventional immunohistochemistry and Automated Quantitative Analysis (AQUA); 2) To determine DNA aberrations of specific genes that have been suggested to be associated with trastuzumab response using fluorescence in situ hybridization; and 3) To identify gene expression patterns predictive of trastuzumab benefit using DASL, a gene expression profiling system specifically designed for paraffin tissue. Our multidisciplinary team has the experience to accomplish these important translational protein- and gene-based studies within the proposed timeline. We have collected all relevant specimens to conduct this investigation as well as the clinical follow-up data related to disease free and overall survival. Results from these correlative studies using the well-defined N9831 patient population will provide a better understanding of individual variation of benefit to adjuvant trastuzumab and will identify opportunities for therapeutic intervention for patients at increased risk of recurrence. As this is achieved, it will be possible to more effectively tailor therapy with the greatest efficiency and fewest side effects. Positive results from these proposed correlative studies will also allow us to design further phase II and III clinical trials addressing our overall goal of individualized therapy for patients with breast cancer. PUBLIC HEALTH RELEVANCE: Biomarker identification and validation studies are necessary to successfully achieve personalized medicine. This is critically important in the adjuvant management of patients with resected HER2-positive breast cancer as trastuzumab treatment significantly increases disease free and overall survival, but is associated with potential toxicities. Our study proposes biomarker tissue correlative studies to help identify those patients most likely to benefit from this treatment.

描述（由申请人提供）：乳腺癌患者的成功个性化护理关键取决于准确应用治疗反应的预测标志物。本提案的具体目的是在石蜡包埋的原发性乳腺肿瘤中鉴定来源于蛋白质、DNA畸变和基因表达模式的可靠生物标志物，以预测对辅助曲妥珠单抗（一种针对HER 2的抗体）的反应。这些患者入选了具有里程碑意义的NCCTG申办的辅助N9831组间试验（EA Perez-PI），该试验导致HER 2阳性乳腺癌患者的临床护理发生了巨大变化。我们的总体假设是，与EGF家族信号通路相关的组织标志物将预测这些患者更可能对辅助曲妥珠单抗有反应。我们的具体目标包括三个转化研究：1）使用常规免疫组织化学和自动定量分析（AQUA）确定参与曲妥珠单抗活性和耐药机制的选定蛋白质的组织表达; 2）使用荧光原位杂交确定已被认为与曲妥珠单抗反应相关的特定基因的DNA畸变;和3）使用DASL（一种专为石蜡组织设计的基因表达谱分析系统）鉴定预测曲妥珠单抗益处的基因表达模式。我们的多学科团队有经验在拟议的时间轴内完成这些重要的基于翻译蛋白和基因的研究。我们收集了所有相关标本进行本研究，以及与无病生存期和总生存期相关的临床随访数据。这些使用明确定义的N9831患者人群的相关研究的结果将更好地了解曲妥珠单抗辅助治疗获益的个体差异，并将确定复发风险增加的患者的治疗干预机会。随着这一目标的实现，将有可能更有效地定制具有最大效率和最少副作用的治疗。这些相关研究的积极结果也将使我们能够设计进一步的II期和III期临床试验，以实现我们对乳腺癌患者进行个体化治疗的总体目标。 公共卫生相关性：生物标志物识别和验证研究是成功实现个性化医疗的必要条件。这在切除的HER 2阳性乳腺癌患者的辅助管理中至关重要，因为曲妥珠单抗治疗显著增加了无病生存期和总生存期，但与潜在毒性相关。我们的研究提出了生物标志物组织相关研究，以帮助确定那些最有可能从这种治疗中受益的患者。

项目成果

Expression profiling of formalin-fixed paraffin-embedded primary breast tumors using cancer-specific and whole genome gene panels on the DASL® platform.

• DOI: 10.1186/1755-8794-3-60
• 发表时间: 2010-12-20
• 期刊: BMC medical genomics
• 影响因子: 2.7
• 作者: Reinholz MM;Eckel-Passow JE;Anderson SK;Asmann YW;Zschunke MA;Oberg AL;McCullough AE;Dueck AC;Chen B;April CS;Wickham-Garcia E;Jenkins RB;Cunningham JM;Jen J;Perez EA;Fan JB;Lingle WL
• 通讯作者: Lingle WL