Robust Predictor of Breast Cancer Risk

乳腺癌风险的稳健预测因子

• 批准号: 10319323
• 负责人: Harry Ostrer
• 金额: $ 16万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319323
• 关键词: Affect; Age; Assessment tool; BARD1 gene; BRCA1 gene; BRCA2 gene; Biological; Biological Assay; Blood; Blood Cells; Blood specimen; Breast Cancer Risk Factor; CHEK2 gene; Chemicals; Classification; Clinical; Collaborations; Companions; Counseling; Cyclins; Cytotoxic Chemotherapy; DNA Double Strand Break; DNA sequencing; Data; Defect; Development; Diagnostic Reagent Kits; Disease; Double Strand Break Repair; Exposure to; FDA approved; Family; Flow Cytometry; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic testing for cancer risk; Genomics; Germ-Line Mutation; Goals; Health Personnel; High Risk Woman; Human; Individual; Intervention; Knowledge; Laboratories; Life; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Methods; Monitor; Mutation; Oncogenes; Onset of illness; PALB2 gene; Pathway interactions; Patients; Pattern; Penetrance; Performance; 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; Testing; Time; Translating; United States; Variant; Whole Blood; Woman; age related; automated analysis; base; breast cancer family registry; cancer genomics; cancer risk; chemotherapy; cohort; commercialization; companion diagnostics; cost; gene panel; gene repair; genetic testing; hazard; high risk; inhibitor; malignant breast neoplasm; molecular phenotype; mortality; new technology; next generation; novel; novel diagnostics; personalized medicine; phase 2 study; pre-clinical; prevent; rapid test; repaired; research clinical testing; response; risk prediction; technological innovation; tool; trait; treatment response; 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 ~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.

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80%的情况下没有 突变被识别出来，导致模糊的、不令人满意的结果。在发现高危妇女之前确定 疾病的发病是个性化医学的一个重要挑战，因为疾病可以预防或 在更有可能治愈的最早阶段进行治疗。随着越来越多的女性寻求基因测试来识别 他们患乳腺癌的风险，需要准确的测序替代方案来预测分子表型 乳腺癌易感途径中基因突变的影响。基于流量的风险分类分数 变异分析(FVA)是一种可以准确识别具有杂合子生殖系的女性的新技术 这些途径中的突变。FVA快速、廉价、重复性高，可以在 循环和培养人类血细胞，从而使自己成为下一代，非 测序，独立测试。该项目的目标是开发一种简单、快速、廉价的 将准确识别乳腺癌高危人群的临床测试。第一阶段假设： 使用全血样本的独立FVA测试将识别高危人群，准确率为95%。特定目标 1.获得99%的对象的风险分类评分结果，其中180个对象的风险分类准确率至少为95% 具有良好特征的风险群体。具体目标2.从AIM获得所有对象的风险分类评分结果 1使用自动分析方案和新创建的商业试剂盒，具有相当的准确性。拥有 在第一阶段证明了分析的有效性，MMG将在第二阶段通过计算证明临床实用 并验证了1800名女性10年来患乳腺癌的风险比率，随后是20岁以下 被NCI的乳腺癌家庭登记处登记了多年。此外，MMG将证明分析的有效性 这项测试分析了内部和合作实验室FVA试剂盒的分析有效性和重复性， 证明高、中外显性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接触的影响 化疗。该产品将与指定的产品合作销售给临床实验室 作为FDA批准的测试的制造实践设施商业合作伙伴。有几个因素将推动这一趋势 进入10亿美元市场的癌症风险评估市场商业化：1.低进入和性能成本，2. 比测序更准确，3.应用于了解卵巢、胰腺和前列腺的风险 癌症，以及4.被称为“PARP抑制剂”的新型靶向化疗的辅助诊断。 简化的商业FVA试剂盒的创建将改变评估癌症风险的游戏规则。

项目成果

Health care professionals' attitudes toward cancer gene panel testing.

• DOI: 10.1111/tbj.14210
• 发表时间: 2021-05
• 期刊: BREAST JOURNAL
• 影响因子: 2.1
• 作者: Klugman, Susan;Schnabel, Freya;Alim, Ishraq;Loke, Johnny;Arun, Banu;Chun Kim, Jennifer;Ostrer, Harry
• 通讯作者: Ostrer, Harry

Prediction of breast cancer risk based on flow variant analysis of circulating peripheral blood mononuclear cells.

• DOI: 10.1016/j.xhgg.2022.100085
• 发表时间: 2022-04-14
• 期刊: HGG advances
• 作者: Loke J;Alim I;Yam S;Klugman S;Xia LC;Gruber D;Tegay D;LaBella A;Onel K;Ostrer H
• 通讯作者: Ostrer H