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