Robust Predictor of Breast Cancer Risk

美国约有150万妇女处于患乳腺癌的高风险中， 在双链断裂（DSB）修复和细胞周期蛋白检查点中基因的种系突变的遗传 途径。许多人不知道自己的遗传倾向，因为他们的家族史缺乏信息，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%的病例中， 突变被识别，导致模糊的、不令人满意的结果。确定妇女在高风险之前， 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， 在最早的阶段治疗，治愈的可能性更大。随着越来越多的女性寻求基因检测来识别 他们患乳腺癌的风险，需要准确的替代测序来预测分子表型 乳腺癌易感途径中基因突变的影响。基于流量的风险分类评分 变异检测（FVA）是一种新的技术，可以准确地识别妇女与杂合子生殖系 这些路径的突变。FVA是快速、廉价和高度可重复的，并且可以在 循环和培养的人类血细胞，从而使自己成为下一代， 测序，独立测试。该STTR项目的目标是开发一种简单、快速和廉价的 临床测试，将准确地确定那些在高风险的乳腺癌。第一阶段假设： 使用全血样本的独立FVA测试将以95%的准确度识别高风险人群。具体目标 1. 99%的受试者获得风险分类评分结果，180例受试者的准确率至少为95%， 特征明确的风险群体。具体目标2。获得Aim所有受试者的风险分类评分结果 1，使用自动化分析方案和新创建的商业试剂盒具有可比的准确度。具有 在I期试验中证明了分析有效性，MMG将在II期试验中证明临床效用， 并验证了1,800名女性在10岁时患乳腺癌的10年风险比， NCI的乳腺癌家族登记处。此外，MMG将证明以下分析的有效性： 本试验分析了FVA检测试剂盒内部和合作实验室的有效性和重现性， 证明了高和中突变率DSB修复基因在修饰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于 化疗本产品将与指定商品合作销售给临床实验室 生产实践机构商业合作伙伴作为FDA批准的测试。几个因素将推动这一点 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. 比测序更精确，3.应用于了解卵巢、胰腺和前列腺的风险 癌症，4。这是一种新的靶向化疗的伴随诊断，称为“PARP抑制剂”。 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。

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.