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

描述(申请人提供)：乳腺癌患者成功的个性化护理关键依赖于准确应用治疗反应的预测性标记物。这项建议的具体目标是识别可靠的生物标记物，来自蛋白质、DNA异常和基因表达模式，在石蜡包埋的原发乳腺肿瘤中预测对佐剂曲妥珠单抗(一种针对HER2的抗体)的反应。这些患者参加了NCCTG赞助的具有里程碑意义的N9831佐剂组间试验(EA PEREZ-PI)，该试验导致HER2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那些更有可能对佐剂曲妥珠单抗有反应的患者。我们的具体目标包括三项翻译研究：1)使用常规免疫组织化学和自动定量分析(AquA)来确定与曲妥珠单抗活性和耐药机制相关的特定蛋白的组织表达；2)使用荧光原位杂交来确定已被认为与曲妥珠单抗疗效相关的特定基因的DNA异常；以及3)使用DASL(一种专门为石蜡组织设计的基因表达谱系统)确定预测曲妥珠单抗疗效的基因表达模式。我们的多学科团队有经验在建议的时间表内完成这些重要的基于蛋白质和基因的翻译研究。我们已经收集了所有相关的标本来进行这次调查，以及与无病和总存活率相关的临床随访数据。使用明确定义的N9831患者群体进行的这些相关研究的结果将更好地了解曲妥珠单抗对辅助剂曲妥珠单抗益处的个体差异，并将确定对复发风险增加的患者进行治疗干预的机会。随着这一目标的实现，将有可能以最高的效率和最少的副作用更有效地定制治疗。这些拟议的相关研究的积极结果也将使我们能够设计进一步的II和III期临床试验，以实现我们为乳腺癌患者进行个体化治疗的总体目标。 公共卫生相关性：生物标记物的识别和验证研究是成功实现个性化医疗所必需的。这在切除的HER2阳性乳腺癌患者的辅助治疗中至关重要，因为曲妥珠单抗治疗显著提高了无病生存率和总存活率，但与潜在的毒性相关。我们的研究建议进行生物标记物组织相关研究，以帮助确定哪些患者最有可能从这种治疗中受益。

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.