Robust Predictor of Breast Cancer Risk

乳腺癌风险的稳健预测因子

• 批准号: 9409030
• 负责人: Harry Ostrer
• 金额: $ 30万
• 依托单位: MORGAN AND MENDEL GENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409030
• 关键词: Age; Assessment tool; BRCA1 Protein; BRCA2 Protein; Biological Assay; Blood Cells; Blood specimen; Cancer Intervention; Cell Nucleus; Cell physiology; Cells; Chemical Agents; Chemicals; Classification; Clinical; Clinical Research; Collaborations; Companions; Cyclins; Cytoplasm; DNA; Defect; Diagnosis; Disease; Double Strand Break Repair; FDA approved; Family; Flow Cytometry; Genes; Genetic Predisposition to Disease; Genetic screening method; Genomics; Germ-Line Mutation; Goals; Health Benefit; Health Personnel; High Risk Woman; Human; Individual; Intervention; Knowledge; Laboratories; Laboratory Research; Learning; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Marketing; Medical; Medicine; Methods; Mutation; Newly Diagnosed; Nuclear; Oncogenes; Oncologist; Onset of illness; Outcome; Ovarian; Pancreas; Pathway interactions; Patient Care; Patient risk; Patients; Performance; Phase; Phosphorylation; Physicians; Proteins; Protocols documentation; Reagent; Recording of previous events; Recruitment Activity; Reporting; Reproducibility; Research Personnel; Risk; Risk Assessment; Route; Sensitivity and Specificity; Siblings; Small Business Technology Transfer Research; TP53 gene; Techniques; Technology; Testing; Time; United States; Ursidae Family; Validation; Variant; Whole Blood; Woman; base; breast cancer family registry; cancer risk; chemotherapy; college; commercial application; commercialization; companion diagnostics; cost; drug use screening; gene panel; genetic counselor; genetic risk assessment; hazard; high risk; inhibitor/antagonist; innovation; lifetime risk; malignant breast neoplasm; member; molecular phenotype; mutation carrier; new technology; next generation; novel diagnostics; personalized medicine; pre-clinical; prevent; repaired; research clinical testing; tool; treatment response; validation studies; variant of unknown significance

Summary Approximately 1.5 million women in the United States are at high-risk for developing breast cancer, based on inheritance of a germline mutation in a gene in the double strand-break (DSB) repair and cyclin-checkpoint pathways. Many are unaware of their genetic predispositions, because their family history is uninformative or unknown. Genetic testing is important for identifying mutations in these genes, but in ~75% of cases no mutation or a variant of uncertain significance will be identified, leading to ambiguous, unsatisfactory results. Identifying women at high risk prior to the onset of disease is an important challenge for personalized medicine, because disease can be prevented or treated at the earliest stage when cure is more likely. As more women are seeking genetic testing to identify their risk of breast cancer, accurate alternatives to sequencing are needed to predict the molecular phenotypic effects of mutations in genes in breast cancer-predisposing pathways. Risk classification scores based on flow variant assays (FVAs) are a new technology that can accurately identify women with heterozygous germline mutations in these pathways. In response to treatment with radiomimetic chemicals, FVAs identify decreased nuclear localization of BRCA1 and BRCA2 proteins and decreased phosphorylation of p53 in cells that bear mutations in these genes. FVAs are rapid, inexpensive and highly reproducible and can be performed on circulating and cultured human blood cells, thus lending themselves to becoming a Next Generation, non-sequencing, standalone test for assessing cancer risks. The goal of this STTR project is to develop a, simple, rapid and inexpensive clinical test that will accurately identify those at high risk for breast cancers. Phase I hypothesis. The standalone FVA test using whole blood samples will identify those at high-risk with 95% accuracy. Specific aim 1. Achieve risk classification score results for 99% of subjects with at least 95% accuracy on 180 subjects from well-characterized risk groups. Specific Aim 2. Achieve risk classification score results for all subjects from Aim 1 with comparable accuracy using an automated analysis protocol and newly created commercial kit. Having demonstrated analytical validity in Phase I, MMG will demonstrate clinical utility in Phase II by calculating and validating 10-year hazard ratios for breast cancer by age decade for 1,800 women followed by up to 20 years by the NCI's Breast Cancer Family Registry. This product will be sold to clinical laboratories in collaboration with a designated good manufacturing practices facility commercial partner, initially as a laboratory developed test and then as an FDA approved test. Several factors will drive this commercialization into the $1B market cancer risk assessment market: 1. low entry and performance costs, 2. greater accuracy than sequencing, 3. application to understanding risks for ovarian, pancreatic and prostate cancers, and 4. companion diagnostic for the new class of targeted chemotherapy, called “PARP inhibitors.” The creation of simplified, commercial FVA kits will be a game changer for assessing cancer risks.

摘要 根据以下数据，美国约有150万女性有罹患乳腺癌的高风险 双链断裂修复和细胞周期蛋白检查点基因种系突变的遗传 小路。许多人没有意识到他们的遗传倾向，因为他们的家族史没有提供信息或 未知。基因检测对于识别这些基因的突变很重要，但在约75%的情况下没有 不确定意义的突变或变种将被识别，导致模棱两可的、不令人满意的结果。 在疾病发作前识别高危女性是个性化的一个重要挑战 医学，因为疾病可以在更有可能治愈的最早阶段被预防或治疗。作为更多 女性正在寻求基因测试来确定她们患乳腺癌的风险，这是测序的准确替代方案 需要用来预测乳腺癌易感基因突变的分子表型效应 小路。基于流量变量分析(FVA)的风险分类评分是一种新技术，可以 准确识别在这些途径中具有杂合生殖系突变的女性。对治疗的反应 利用仿射化学物质，FVA发现BRCA1和BRCA2蛋白的核定位降低，并 在携带这些基因突变的细胞中，P53的磷酸化减少。FVA快速、廉价、 高度可重复性，可以在循环和培养的人类血细胞上进行，从而借出 成为下一代、无测序、独立的癌症风险评估测试。这个 这个STTR项目的目标是开发一种简单、快速和廉价的临床测试，它将准确地识别 那些乳腺癌的高危人群。第一阶段假设。全血标本FVA单项检测 将以95%的准确率识别高危人群。具体目标1.实现风险分类评分结果 99%的受试者对180名受试者具有至少95%的准确率，这些受试者来自具有良好特征的风险组。特定目标 2.目标1中所有受试者的风险分类评分结果均可使用 自动分析方案和新创建的商业试剂盒。在证明了分析的有效性之后 第一阶段，MMG将在第二阶段通过计算和验证以下项目的10年风险比来展示临床实用性 1800名女性患乳腺癌的年龄为10年，NCI的乳腺癌家族最多为20年 注册表。本产品将与指定的产品制造商合作销售给临床实验室 实践设施的商业合作伙伴，最初作为实验室开发的测试，然后作为FDA批准的测试。 几个因素将推动这种商业化进入10亿美元的市场癌症风险评估市场：1.低 入门和性能成本，2.比测序更准确，3.应用于了解风险 卵巢癌、胰腺癌和前列腺癌，以及4.针对新的目标类别的伴随诊断 化疗，称为“PARP抑制剂”。简化的商业FVA试剂盒的创建将是一场游戏 用于评估癌症风险的转换器。