权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Optimizing HER2-targeting using RNA- and DNA-based predictive algorithms

使用基于 RNA 和 DNA 的预测算法优化 HER2 靶向

基本信息

批准号：
10218096
负责人：
LISA A CAREY
金额：
$ 54.29万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218096
关键词：
Address Affect Aftercare B-Cell Antigen Receptor Biological Markers Biology Breast Cancer Patient Cancer and Leukemia Group B Cells Clinical Clinical Trials Combination Drug Therapy Cytotoxic agent DNA DNA copy number DNA sequencing Data Data Set Death Rate Development Diagnosis Disease Disease-Free Survival Drug Targeting Drug resistance ERBB2 gene Endocrine Financial cost Gene Dosage Gene Expression Gene Expression Profile Genes Genetic Genomics Goals Immune In complete remission Individual Malignant Neoplasms Modeling Mutation National Surgical Adjuvant Breast and Bowel Project Neoadjuvant Therapy Nonmetastatic Outcome Pathologic Pathway Analysis Patients Pharmaceutical Preparations Prognosis RNA Randomized Recurrence Residual Tumors Risk Role Sampling Somatic Mutation Subgroup T-Lymphocyte TP53 gene Testing Treatment Protocols Treatment outcome Woman base cost cost effective design exome genomic aberrations immune activation malignant breast neoplasm molecular subtypes new therapeutic target predicting response prediction algorithm prognostic randomized trial response response biomarker survival outcome targeted agent targeted treatment therapeutic target therapy outcome transcriptome sequencing tumor

项目摘要

ABSTRACT HER2-positive disease, which comprises 20% of all breast cancers, is among the most aggressive but treatable forms. Outcomes for HER2-positive patients have been transformed by the development of several highly effective HER2-targeting agents that are given broadly for stages I-IV HER2+ breast cancer either as single agents or as dual HER2-targeting. These drugs have reduced death rates from this disease by nearly 40%, however come at a high financial cost – all HER2-targeted drugs individually cost at least $100,000 per year. We also clearly overtreat many of the approximately 40,000 non-metastatic patients diagnosed with HER2-positive breast cancers in the U.S. each year. Most of the treatment regimens used in stages I-III HER2- positive breast cancer include polychemotherapy with 2-3 cytotoxic drugs plus 1-2 HER2-targeted drugs given for 1 year. Genomic studies from large randomized trials provide opportunities for improvement. Several studies have found that tumor and microenvironmental influences are major contributors to variability in response and outcome. RNA- and DNA-based studies from CALGB 40601 and other neoadjuvant trials of HER2-targeting agents suggest that tumor intrinsic molecular subtype and immune cell activation are at least as important as treatment type in determining outcome and can identify tumors that respond best to single or dual HER2- targeting. These studies suggest a way to more thoughtfully and rationally treat HER2-positive breast cancer patients, but we must do this collaboratively and comprehensively. We propose to collectively integrate and analyze the clinical, gene expression, gene aberration, response to therapy, and outcomes data from more than 1500 women participating in multiple randomized neoadjuvant clinical trials of HER2-targeted therapy. We will examine the role of tumor and microenvironmental factors in determining response to HER2-targeting, relationship of pathologic complete response to outcome, and the biology of residual disease after dual or single HER2-targeting in HER2-positive breast cancer.

摘要 HER2阳性疾病占所有乳腺癌的20%，是最具侵袭性的疾病之一，但可治疗的形式。HER2阳性患者的结局因几种高效的HER2靶向制剂，广泛用于I-IV期HER2+乳腺癌单一药物或双重HER2靶向。这些药物使这种疾病的死亡率降低了近然而，40%的药物成本很高-所有针对HER2的药物单独成本至少为100,000美元年。我们显然也过度治疗了大约40,000名被诊断为在美国，每年都有HER2阳性的乳腺癌。在第一至第三阶段使用的大多数治疗方案HER2- 阳性乳腺癌包括给予2-3种细胞毒药物和1-2种HER2靶向药物的综合化疗为期1年。来自大型随机试验的基因组研究提供了改进的机会。几项研究已经发现肿瘤和微环境的影响是反应和反应差异的主要因素结果。来自CALGB 40601的基于RNA和DNA的研究以及其他针对HER2靶向的新佐剂试验研究人员认为，肿瘤固有的分子亚型和免疫细胞激活至少与治疗类型决定预后，可以识别对单或双HER2反应最好的肿瘤- 瞄准目标。这些研究提出了一种更周到、更合理地治疗HER2阳性乳腺癌的方法。患者，但我们必须通力合作，全面开展这项工作。我们建议集体整合和分析临床、基因表达、基因异常、对参与多种随机新辅助疗法的1500多名妇女的治疗和结果数据 HER2靶向治疗的临床试验。我们将研究肿瘤和微环境因素在确定对HER2靶向的反应，病理完全反应与结果的关系，以及 HER2阳性乳腺癌双靶向或单靶向治疗后残留病变的生物学研究。