Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients responding sub-optimally to tamoxifen.

Patient-derived xenografts (PDX) are generated in immune deficient mice and demonstrate histologic and molecular features similar to their corresponding human tumors. However, murine tumors (non-human) spontaneously occur in these models. 120 consecutive patients with high-risk primary breast cancer enrolled in the prospective neoadjuvant BEAUTY study had tumor tissue obtained at the time of diagnosis. These tumor cells, including initial tissue and subsequent generations, were injected into either NSG (n = 365) or NOD-SCID (n = 396) female mice. Mice with initial tumor growth sufficient for transfer to the 2nd generation underwent histologic review by pathologists, including Ki67 staining. After passaging the tumors for up to 4 generations, at least one primary mouse tumor was detected from 24 of the 54 PDX-lines, for a frequency of 3.2% (24 mice out of 761 mice), including murine lymphomas (n = 13), mammary tumors (n = 7), osteosarcomas (n = 2), and hemangiosarcomas (n = 2). While true PDX showed scattered strong staining with Ki67, murine tumors were Ki67 negative. No significant differences (p = 0.062) were observed comparing development of murine tumors in NOD-SCID (n = 8) vs NSG mice (n = 16). While PDX are a useful tool in cancer research, there is a potential for spontaneous murine tumors to arise, which could alter results of studies utilizing PDX. Morphologic review by a pathologist, potentially along with Ki67 staining, is necessary to ensure that tumor growth represents the desired PDX prior to use in downstream studies. This study is the first prospective study evaluating the frequency, type, and time frame for development of non-human tumors.

Triple negative breast cancer (TNBC), which comprises approximately 15% of all primary breast cancer diagnoses, lacks estrogen receptor alpha, progesterone receptor and human epidermal growth factor receptor 2 expression. However, we, and others, have demonstrated that approximately 30% of TNBCs express estrogen receptor beta (ERβ), a nuclear hormone receptor and potential drug target. Treatment of ERβ expressing MDA-MB-231 cells with estrogen or the ERβ selective agonist, LY500307, was shown to result in suppression of cell proliferation. This inhibitory effect was due to blockade of cell cycle progression. In vivo, estrogen treatment significantly repressed the growth of ERβ expressing MDA-MB-231 cell line xenografts. Gene expression studies and ingenuity pathway analysis identified a network of ERβ down-regulated genes involved in cell cycle progression including CDK1, cyclin B and cyclin H. siRNA mediated knockdown or drug inhibition of CDK1 and CDK7 in TNBC cells resulted in substantial decreases in proliferation regardless of ERβ expression. These data suggest that the tumor suppressive effects of ERβ in TNBC result from inhibition of cell cycle progression, effects that are in part mediated by suppression of CDK1/7. Furthermore, these data indicate that blockade of CDK1/7 activity in TNBC may be of therapeutic benefit, an area of study that has yet to be explored.