Robust Predictor of Breast Cancer Risk

乳腺癌风险的稳健预测因子

• 批准号: 10079935
• 负责人: Harry Ostrer
• 金额: $ 99.18万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079935
• 关键词: Affect; Age; Antibodies; Assessment tool; BARD1 gene; BRCA1 gene; BRCA2 gene; Biological; Biological Assay; Blood; Blood Cells; Blood specimen; Breast Cancer Risk Factor; CHEK2 gene; Cells; Chemicals; Classification; Clinical; Collaborations; Companions; Counseling; Cyclins; Cytotoxic Chemotherapy; DNA Double Strand Break; Defect; Development; Diagnostic; Disease; Double Strand Break Repair; Exposure to; FDA approved; Family; Flow Cytometry; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Germ-Line Mutation; Goals; Health Personnel; High Risk Woman; Human; In Vitro; Individual; Intervention; Knowledge; Laboratories; Life; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Measures; Methods; Monitor; Monoclonal Antibodies; Mutation; Oncogenes; Onset of illness; Outcome; Pathway interactions; Patients; Pattern; Penetrance; Performance; Peripheral Blood Mononuclear Cell; Phase; Probability; Process; Protocols documentation; Reagent; Recording of previous events; Reporting; Reproducibility; Research Personnel; Residual state; Risk; Risk Assessment; Role; Sampling; Sensitivity and Specificity; Site; Small Business Technology Transfer Research; Temperature; Testing; Time; Translating; United States; Variant; Whole Blood; Woman; age related; automated analysis; base; breast cancer family registry; cancer risk; chemotherapy; cohort; commercial application; commercialization; companion diagnostics; cost; gene panel; gene repair; genetic testing; hazard; high risk; inhibitor/antagonist; malignant breast neoplasm; molecular phenotype; mortality; new technology; next generation; novel; novel diagnostics; personalized medicine; pre-clinical; predicting response; prevent; repaired; research clinical testing; response; technological innovation; tool; trait; treatment response; variant of unknown significance

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 ~80% of cases no mutation is 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. 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. 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 the 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. In addition, MMG will demonstrate the analytical validity of this test analytical validity and reproducibility of FVA test kits in-house and at collaborating laboratories, demonstrate the roles of mutations in high and moderate-penetrance DSB repair genes in modifying FVA traits, and demonstrate the stability of FVA traits over time and whether these are affected by exposure to chemotherapy. This product will be sold to clinical laboratories in collaboration with a designated good manufacturing practices facility commercial partner 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.

根据研究，美国约有 150 万女性面临患乳腺癌的高风险 双链断裂 (DSB) 修复和细胞周期检查点基因中种系突变的遗传 途径。许多人不知道自己的遗传倾向，因为他们的家族史信息不多，或者 未知。基因检测对于识别这些基因的突变很重要，但在约 80% 的情况下，没有突变 突变被识别，导致模糊的、不令人满意的结果。在手术前识别出高危女性 疾病的发作是个性化医疗的一个重要挑战，因为疾病可以预防或 在治愈可能性更大的最早阶段进行治疗。随着越来越多的女性寻求基因检测来识别 由于她们患乳腺癌的风险，需要准确的测序替代方法来预测分子表型 乳腺癌诱发途径中基因突变的影响。基于流量的风险分类评分 变异检测（FVA）是一项新技术，可以准确识别具有杂合种系的女性 这些途径的突变。 FVA 快速、廉价且高度可重复，并且可以在 循环和培养人类血细胞，从而使其成为下一代、非 测序，独立测试。 STTR 项目的目标是开发一种简单、快速且廉价的 临床测试将准确识别乳腺癌高危人群。第一阶段假设： 使用全血样本的独立 FVA 测试将识别高风险人群，准确率达 95%。具体目标 1. 获得 99% 受试者的风险分类评分结果，其中 180 名受试者的准确率至少为 95% 明确的风险群体。具体目标 2. 获得 Aim 中所有受试者的风险分类评分结果 1 使用自动分析协议和新创建的商业套件具有相当的准确性。拥有 证明了第一阶段的分析有效性，MMG 将通过计算来证明第二阶段的临床实用性 并验证 1,800 名女性的 10 年乳腺癌风险比，随后最多 20 名女性 NCI 乳腺癌家族登记处的年记录。此外，MMG 将证明分析的有效性 该测试在内部和合作实验室中测试 FVA 测试套件的分析有效性和再现性， 证明高和中等外显率 DSB 修复基因突变在修饰 FVA 中的作用 性状，并证明 FVA 性状随时间的稳定性以及这些性状是否受到暴露的影响 化疗。该产品将与指定商品合作销售给临床实验室 制造实践设施商业合作伙伴作为 FDA 批准的测试。有几个因素将推动这一趋势 进入 10 亿美元市场癌症风险评估市场的商业化：1. 低进入和绩效成本，2. 比测序更准确，3.应用于了解卵巢、胰腺和前列腺的风险 4. 新型靶向化疗（称为“PARP 抑制剂”）的伴随诊断。 简化的商业 FVA 试剂盒的创建将改变癌症风险评估的游戏规则。