Mayo Clinic Breast Cancer SPORE

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Program Summary/Abstract This third renewal application of the Mayo Clinic Breast Cancer SPORE is being submitted with the vision that the burden of breast cancer (BC) can be reduced through the performance of innovative translational research addressing issues of high significance for women. The science of the SPORE includes three translational research projects. Project 1: “The influence of variants in ER-positive BC predisposition genes on BC risk and response to therapy”. This project builds upon the work from the prior funding period, where the principal investigators (PIs) identified that certain BC predisposition genes (ATM, CHEK2 and PALB2) were associated mainly with the risk of ER+ BC. The Pis will assess pathogenic variants in ATM, BRCA2, CHEK2, PALB2 and determine a) age-related risks, the risks of contralateral BC and second cancers (ovarian, colorectal, pancreatic etc.), b) the prognostic effects of these PV and c) the clinical relevance of variants of uncertain significance in ATM, CHEK2, and PALB2. Project 2: “Improving the endocrine management of premenopausal ER+/HER2- BC” brings forward a new ER-targeting drug, Z-endoxifen (ENDX), for premenopausal ER+ BC based on new data that ENDX dually targets both ERα and PKCβ1, with potent protein downregulation of ERα, Cyclin D1, and E2F1. This dual targeting is not only unique to ENDX, but at the dosing proposed in the clinical trial, ENDX is able to completely block the stimulatory effects of premenopausal levels of estrogen. Project 3: “Development of a novel multi-antigen BC prevention vaccine for women with premalignant disease” is based on pioneering work of Mayo investigators to develop a novel vaccine that targets six antigens collectively expressed by all BC subtypes. The work in this project will provide critical information that will allow the investigators to a) understand the expression of target antigens during progression from normal breast tissue to BC; and, b) in the phase I study, evaluate blood and breast tissue biomarkers of immune response. Successful completion of this project will establish the parameters for a phase III clinical trial of the vaccine for BC prevention in women with benign breast disease (BBD), with the enormous potential to drive significant reductions in overall BC incidence and mortality. These research projects are supported by three highly interactive cores: Core A: Administrative Core, Core B: Biospecimen and Pathology Core, and Core C: Biostatistics, Bioinformatics, and Patient Registry Core. A Developmental Research Program will continue to identify and develop research projects that hold the greatest promise to advance to full SPORE projects, and a Career Enhancement Program will continue to identify and support faculty investigators in BC translational research that have the greatest potential to become future SPORE leaders. The investigators, cores, and the research programs in the SPORE are all integrated in the Mayo Clinic Cancer Center. Collectively, our SPORE will make discoveries and translate them into the clinic for the benefit of women with, or at risk of BC.