Project 2

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) remains the most commonly diagnosed cancer in premenopausal women (pre-MW) worldwide and its incidence is increasing in developed countries. BCs in pre-MW are more likely to be of an aggressive intrinsic subtype, higher grade, and advanced stage compared to BCs in post-MW. Pre-MW with ER+/HER2- BC are commonly treated with chemotherapy (CT), endocrine therapy (ET) and ovarian function suppression (OFS). Long-term data from the SOFT and TEXT adjuvant trials demonstrated that aromatase inhibitors (AI)+OFS improved disease free survival but have yet to improve overall survival (OS), compared to tamoxifen (TAM) or TAM+OFS. Furthermore, in one study (ABCSG 12), AI+OFS led to worse OS compared to TAM+OFS. The lack of a survival benefit in these studies may relate to the detrimental side-effects of premature menopause (PM), known to be associated with higher rates of cardiac disease, hypertension, diabetes, hyperlipidemia, osteoporosis and death. Therefore, alternative endocrine strategies for pre-MW with ER+/HER2- BC are critically needed, especially for pre-MW who cannot tolerate OFS. Endoxifen (ENDX) is an active TAM metabolite, and the PI’s have led the development of ENDX as a novel ET for BC. Through completion of phase I and II trials, we have demonstrated that ENDX is safe, well-tolerated, has substantial oral bioavailability and is superior to TAM in endocrine therapy (ET) resistant BC. Furthermore, the PI’s have identified a novel mechanistic basis for the superior anti-cancer effects of ENDX; namely, the novel ENDX target, PKCβI. Here, we build upon this foundation by performing a prospective neoadjuvant endocrine study comparing ENDX without OFS vs AI+OFS in the neoadjuvant treatment of pre-MW with ER+/HER2- BC. We will also extensively study the roles of PKCβI in mediating ENDX efficacy, given our preliminary data demonstrating that ENDX uniquely binds PKCβI and targets it for proteasomal degradation, resulting in downregulation of ERα, cyclin D1, and E2F1 protein levels concurrent with marked inhibition of BC cell proliferation. Importantly, these effects are not observed with PKCβI kinase inhibitors, suggesting novel non-kinase related functions of PKCβI. Furthermore, they are not observed with TAM or AI. Based on these data, the central hypothesis of this proposal is that ENDX is a superior ET in part due to its ability to dually target both ER and PKCβI. We further hypothesize that the optimal treatment of pre-MW with ER+/HER2- BC can be achieved using ENDX monotherapy without the need for OFS. To test our hypotheses, we will 1) develop ENDX for pre-MW with ER+/HER2- BC; 2) elucidate the mechanisms by which PKCβI contributes to ENDX responsiveness in endocrine sensitive disease; and 3) determine the predictive and prognostic value of PKCβI in ER+/HER2- BC patients treated with TAM and ENDX. Given the increasing incidence of BC in pre-MW, along with the known morbidity associated with OFS, the proposed studies are of critical importance towards improving the endocrine management of ER+/HER2- BC in pre-MW.