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：
9912734
负责人：
LISA A CAREY
金额：
$ 61.7万
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/9912734
关键词：
Address Affect Aftercare 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 Receptors, Antigen, B-Cell 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 outcome forecast 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.

抽象的 HER2 阳性疾病占所有乳腺癌的 20%，是最具侵袭性但又最具侵袭性的疾病之一。可治疗的形式。 HER2 阳性患者的治疗结果因多种药物的开发而发生了改变高效 HER2 靶向药物，广泛用于治疗 I-IV 期 HER2+ 乳腺癌单一药物或双重 HER2 靶向药物。这些药物使这种疾病的死亡率降低了近 40%，但财务成本很高——所有 HER2 靶向药物的单独成本至少为 100,000 美元年。我们还明显对大约 40,000 名被诊断患有癌症的非转移患者中的许多人进行了过度治疗。美国每年都有 HER2 阳性乳腺癌病例。大多数治疗方案用于 I-III 期 HER2- 阳性乳腺癌包括采用 2-3 种细胞毒性药物加 1-2 种 HER2 靶向药物的联合化疗 1年。大型随机试验的基因组研究提供了改进的机会。多项研究已发现肿瘤和微环境的影响是反应变化的主要原因结果。来自 CALGB 40601 和其他 HER2 靶向新辅助试验的基于 RNA 和 DNA 的研究药物表明肿瘤内在分子亚型和免疫细胞激活至少与确定结果的治疗类型，并可以识别对单一或双重 HER2- 反应最佳的肿瘤瞄准。这些研究提出了一种更深思熟虑、更合理地治疗 HER2 阳性乳腺癌的方法患者，但我们必须合作、全面地做到这一点。我们建议共同整合和分析临床、基因表达、基因畸变、反应超过 1500 名参与多项随机新辅助治疗的女性的治疗和结果数据 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 阳性乳腺癌双重或单一 HER2 靶向后残留疾病的生物学。