#407 Introduction:
 The PI3K/Akt/mTOR pathway is often constitutively activated in BC, making inhibition of this pathway an attractive treatment strategy. Temsirolimus (TEM) is an inhibitor of mammalian target of rapamycin (mTOR) inhibitor. A phase II trial of TEM was conducted to determine its activity in MBC and TEM's activity in tumors with PIK3CA mutations.
 Methods:
 An open-label, single-arm, phase II study in patients (pts) with metastatic breast cancer (MBC) was performed at two institutions. TEM (25mg) was intravenously administered weekly. Eligible pts had ECOG performance status (PS) 0 or 1, and albumin > 3.0 mg/dL. Tumor expression of ER, PR, and/or Her2 was required. Prior therapy was not limited. Pts were evaluated for response every 8 weeks of TEM. The primary endpoint was overall response rate, defined as a complete or partial response or stable disease (SD) for ≥ 24 weeks by RECIST. Tumor PIK3CA mutations and immunohistochemical (IHC) expression of PI3K/Akt/mTOR pathway components were evaluated.
 Results:
 Thirty-one pts were enrolled (median age 59; range: 37-80). Pts received a median of 4 prior chemotherapy regimens (range 1-8); pts had ECOG PS 0 (n=14), 1 (n=14), and unknown (n=3). A total of 111 cycles were administered. (median: 2 cycles; range 1-16). Three pts (9.7 %) had prolonged SD for ≥ 24 weeks. Two pts with SD at ≥ 24 weeks had ER+ tumor; all three pts were Her2/neu negative. Seven additional pts had a best response of SD at 16 weeks. One patient achieving SD remains on treatment after 16 cycles.
 The most common adverse events (grades 1-4) include fatigue (n=21), mucositis (n=18), anemia (n=14), increased LFTs (n=14), thrombocytopenia (n=13), rash (n=12), leukopenia (n=12), hypertriglyceridemia (n=11), and hyperglycemia (n=11). Twenty-three pts required a dose reduction or interruption; 3 pts discontinued therapy due to drug toxicity.
 Twenty-three tumors were available for sequencing of PIK3CA helical (HD) and kinase (KD) domains and 24 tumors underwent IHC analysis. Of the three pts with prolonged SD, two pts had tumor with a wildtype PIK3CA sequence in both domains (sequencing on 3rd pt is pending). Four pts had tumor PIK3CA mutations ( 2 pts with HD mutation; 1 with KD; 1 with both HD and KD); these 4 pts had a trend towards decreased progression-free survival versus pts with tumors with wild type PIK3CA (5.3 vs 7.8 weeks). IHC included analysis of pan and phosphorylated: AKT1, S6K1, mTOR, PTEN, and Cyclin D1. Nuclear pAKT308 expression was weakly associated with prolonged PFS (p=0.03).
 Conclusions:
 TEM has limited activity as a single agent in pts with pretreated MBC, and the study did not progress to the planned second stage. Preliminary data suggest that tumors with a mutation in hotspot domains of PIK3CA do not have enhanced sensitivity to TEM.
 This trial was supported by the Avon Foundation and NCI (P30 CA 1459931 S1). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 407.
#6011 Background: Understanding the natural history of breast cancer is important for effective patient management and treatment. For example, some evidence suggests that preinvasive ductal carcinoma in situ (DCIS) may be over-treated, since not all will progress to invasive cancer. Unfortunately, due to obligate surgical excision of newly diagnosed breast cancers, the natural history of disease is difficult to study in women. However, mouse models of breast cancer can serve as an alternative; the purpose of this study was to use magnetic resonance imaging (MRI) to investigate the progression of DCIS into invasive cancer in a transgenic model.
 Methods:12 SV40 Tag mice were imaged every 2-3 weeks (wks) starting at 10 wks of age. SV40 mice develop mammary cancer similar to DCIS and IDC, and usually live to 22 wks when they succumb to breast cancer. T1-weighted gradient echo images of inguinal mammary glands were obtained. DCIS lesions and invasive tumors were identified and volumes were measured over time. For each lesion we measured: the time at initial development (TDCIS and Ttumor), the growth rate of DCIS and invasive tumors (calculated from 'V=V0exp(αt)'), and for DCIS lesions that progressed to invasive tumors the progression time Tprog was measured.
 Results:DCIS (n=21) and invasive (n=16) tumors developed, at an average initial age of TDCIS =12.7±2.6 wks and Ttumor =16.3±3.1 wks, and at an initial volume of 0.3±0.2 mm3 and 1.7 mm3, respectively. The average growth rate for DCIS lesions was αDCIS= 0.08±0.23 wk-1, significantly smaller than that of invasive tumors (αtumor= 0.55±0.35 wk-1, p =0.001). 9/21 DCIS lesions progressed to invasive cancers in an average time of Tprog=4.56 ± 1.9 wks(Figure 1a). 11/21 DCIS did not progress within the study window and 5/21 were stable for over 8 wks (Figure 1b).
 
 The volume of DCIS was not a predictor of progression, but there was a trend for DCIS growth rate to be related to eventual development of invasiveness.
 Discussion:To our knowledge, the results reported here are the first direct measurements of the timescales and characteristics of progression from in situ to invasive carcinoma. Surprisingly, even in transgenic mice that are strongly pre-disposed to develop cancer, some DCIS lesions did not progress to invasive cancer. Interestingly, DCIS volume did not predict future progression to invasive tumors, but growth rate may have been a predictor. The methods and data here provide a foundation for using MRI in pre-clinical studies of early cancer progression, prevention and targeted treatment. Extensions of this pilot study may yield image-based biomarkers of progressing vs. indolent DCIS. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6011.
Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2. A subset of primary TNBCs (at least 30%) expresses moderate to strong glucocorticoid receptor (GR) in greater than 10% of invasive tumor cells; in addition, we have reported that increased GR signaling promotes TNBC cell survival. Furthermore, our laboratory recently observed that patients with early stage/high-GR-expressing TNBCs have a relatively poor prognosis. Therefore, GR is being explored as a target for improving outcome in TNBC. Indeed, mifepristone, a well-characterized non-selective steroidal GR/PR antagonist, has shown promise in reversing GR-mediated tumor cell-survival signaling in TNBC. In vivo, increased TNBC xenograft chemosensitivity was observed when mifepristone was added to chemotherapy treatment. Most recently, a Phase I clinical trial demonstrated the safety and potential efficacy of mifepristone added to nab-paclitaxel chemotherapy in Stage IV TNBC patients. Three highly selective non-steroidal GR antagonists (GRAs) have been investigated, CORT108297. CORT125134 (two aryl pyrazole-fused azadecalins) and CORT118335 (a pyrimidine dione). These new GRAs have 1) far less cross-reactivity than mifepristone with other nuclear receptor family members and 2) lower interaction profiles for drug metabolizing CYP enzymes. We hypothesized that selective GRAs would not only inhibit GR-induced pro-survival gene expression, but also increase TNBC chemosensitivity, and may eventually be a valuable adjunct therapy for treating chemotherapy-resistant TNBC. To understand how GR modulators interact with the GR ligand-binding domain (LBD), we are employing two approaches: 1) computational modeling of the GRA-GR LBD based on published crystal structures of the GR LBD with mifepristone (in collaboration with UIUC), and 2) crystal structure analysis of the GR LBD with GR modulators. Preliminary computational results indicate that CORT108297 docks into the LBD and antagonizes GR activity by indirectly disordering Helix 12. Experiments are ongoing using various buffer conditions to produce crystals of the GR LBD with CORT108297 and CORT118335 for x-ray crystallography. Secondly, we are functionally characterizing CORT108297, CORT125134, and CORT118335 for their ability to inhibit glucocorticoid induction of key GR-mediated target genes. Over the course of eight hours, we observed that the compounds exhibited temporal antagonism of the expression of GR target genes encoding anti-apoptotic proteins such as SGK-1, MCL-1, and MKP-1/DUSP1. Lastly, we are examining the selective GRAs' ability to enhance tumor cell cytotoxicity from paclitaxel in cell culture and in TNBC xenograft models. Preliminary results indicate that CORT125134 and CORT108297 significantly increase GR+ TNBC sensitivity to paclitaxel, and are well-tolerated in our in vivo models. Citation Format: West DC, Hosfield DJ, Mayne CG, Skor MN, Styke SC, Pierce CF, Kocherginsky M, Hunt H, Fleming GF, Szmulewitz RZ, Tajkhorshid E, Greene GL, Conzen SD. Second-generation selective glucocorticoid receptor modulators in triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-02.
In normal physiology, glucocorticoid receptor (GR) activity regulates thousand of genes whose products modulate metabolism, inflammation, cell cycle and apoptosis/cell survival pathways. Synthetic GR agonists, or glucocorticoids (GCs), are often used to treat hematologic malignancies because of GR's ability to induce proapoptotic gene expression, inhibit nuclear factor – κB, and induce cell cycle arrest. In contrast, recent examination of GR expression and activity in human breast cancer models and clinical specimens has suggested that GR expression has remarkably diverse roles in breast cancer subtypes. In ER+ breast cancer, GR appears to modulate ER-regulated transcriptional activity through ER/GR receptor crosstalk resulting in antagonism of ER-associated proliferation. However, in ER-negative breast cancer (including TNBC), high tumor GR expression is associated with poor prognosis, anti-apoptotic signaling, and chemotherapy resistance. In addition, high GR activity in the tumor microenvironment is predicted to be immunosuppressive. Recently described selective GR modulators are expected to help dissect divergent GR mechanisms present in breast cancer subtypes. Citation Format: Conzen SD. Androgen, progesterone and glucocorticoid receptors: Drivers of breast tumor progression or reprogramming of steroid receptors during breast tumor progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES9-3.
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