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：
10414912
负责人：
LISA A CAREY
金额：
$ 48.52万
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/10414912
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 RNA Randomized Recurrence Residual Tumors Risk Role Sampling Somatic Mutation Subgroup T-Lymphocyte TP53 gene Testing Treatment Protocols Treatment outcome Woman base clinical prognosis 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 treatment response 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.

抽象的 HER2阳性疾病占所有乳腺癌的20％，是最具侵略性但可治疗形式。 HER2阳性患者的结果已通过几种的发展进行了转化高效的HER2靶向剂，其广泛为I-IV HER2+乳腺癌的阶段赋予单个代理商或双重HER2靶向。这些药物使这种疾病的死亡率降低了几乎但是，有40％的经济成本很高 - 所有靶向HER2靶向药物的单独成本至少为每人100,000美元年。我们也清楚地过度过度了许多被诊断出患有的非转移性患者中的许多每年在美国，HER2阳性乳腺癌。 I-III HER2-阶段使用的大多数治疗方案阳性乳腺癌包括2-3个细胞毒性药物的多化学疗法以及1-2个靶向HER2靶向药物 1年。大型随机试验的基因组研究为改进提供了机会。有几项研究发现肿瘤和微环境影响是导致反应变异性和结果。 CALGB 40601的基于RNA和DNA的研究以及其他HER2靶向的新辅助试验药物表明肿瘤固有的分子亚型和免疫细胞活化至少与确定结果的治疗类型，可以鉴定出对单个或双重HER2-的反应最佳的肿瘤定位。这些研究提出了一种更加周到和理性地治疗HER2阳性乳腺癌的方法患者，但我们必须进行协作，全面地进行此操作。我们建议集体整合和分析临床，基因表达，基因像差，对治疗，以及来自1500多名女性参加多个随机新辅助的妇女的结果 HER2靶向疗法的临床试验。我们将研究肿瘤和微环境因素在确定对HER2靶向的反应，病理完全反应对结果的关系以及在HER2阳性乳腺癌中双重或单一HER2靶向后残留疾病的生物学。