Robust Predictor of Breast Cancer Risk

Summary Approximatelymillion women in the United States are at high risk for developing breast cancerbased on inheritance of a germline mutation in a gene in the double strand breakDSBrepair and cyclin checkpoint pathwaysMany are unaware of their genetic predispositionsbecause their family history is uninformative or unknownGenetic testing is important for identifying mutations in these genesbut inof cases no mutation or a variant of uncertain significance will be identifiedleading to ambiguousunsatisfactory resultsIdentifying women at high risk prior to the onset of disease is an important challenge for personalized medicinebecause disease can be prevented or treated at the earliest stage when cure is more likelyAs more women are seeking genetic testing to identify their risk of breast canceraccurate alternatives to sequencing are needed to predict the molecular phenotypic effects of mutations in genes in breast cancer predisposing pathwaysRisk classification scores based on flow variant assaysFVAsare a new technology that can accurately identify women with heterozygous germline mutations in these pathwaysIn response to treatment with radiomimetic chemicalsFVAs identify decreased nuclear localization of BRCAand BRCAproteins and decreased phosphorylation of pin cells that bear mutations in these genesFVAs are rapidinexpensive and highly reproducible and can be performed on circulating and cultured human blood cellsthus lending themselves to becoming a Next Generationnon sequencingstandalone test for assessing cancer risksThe goal of this STTR project is to develop asimplerapid and inexpensive clinical test that will accurately identify those at high risk for breast cancersPhase I hypothesisThe standalone FVA test using whole blood samples will identify those at high risk withaccuracySpecific aimAchieve risk classification score results forof subjects with at leastaccuracy onsubjects from well characterized risk groupsSpecific AimAchieve risk classification score results for all subjects from Aimwith comparable accuracy using an automated analysis protocol and newly created commercial kitHaving demonstrated analytical validity in Phase IMMG will demonstrate clinical utility in Phase II by calculating and validatingyear hazard ratios for breast cancer by age decade forwomen followed by up toyears by the NCI s Breast Cancer Family RegistryThis product will be sold to clinical laboratories in collaboration with a designated good manufacturing practices facility commercial partnerinitially as a laboratory developed test and then as an FDA approved testSeveral factors will drive this commercialization into the $ B market cancer risk assessment marketlow entry and performance costsgreater accuracy than sequencingapplication to understanding risks for ovarianpancreatic and prostate cancersandcompanion diagnostic for the new class of targeted chemotherapycalledPARP inhibitorsThe creation of simplifiedcommercial FVA kits will be a game changer for assessing cancer risks