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Purpose: This review compared the real-world effectiveness of everolimus-based therapy versus endocrine monotherapy or chemotherapy in postmenopausal hormone receptor positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) patients with multiple metastatic sites., Methods: This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2- mBC women with ≥2 non-lymph-node metastatic sites. Patients must have initiated everolimus-based therapy (monotherapy or combination therapy including everolimus), endocrine monotherapy (any endocrine agent), or chemotherapy (monotherapy or combination with another chemotherapeutic or endocrine agent) for mBC between July 1, 2012 and August 15, 2013 after nonsteroidal aromatase inhibitor failure. Progression-free survival and time on treatment were compared using Kaplan-Meier analysis and Cox proportional hazard models, adjusting for line of therapy and baseline characteristics., Findings: One hundred patients received everolimus-based therapy, 79 received endocrine monotherapy, and 86 received chemotherapy. Everolimus-based therapy was associated with significantly longer progression-free survival and time on treatment than endocrine monotherapy and chemotherapy., Implications: Among HR+/HER2- mBC patients with multiple metastatic sites, everolimus-based therapy was associated with better real-world effectiveness than endocrine monotherapy or chemotherapy., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Aims: Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI)., Data & Methods: Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics., Results & Conclusion: 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

Background: Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents., Methods: This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan-Meier analyses and Cox proportional hazards models adjusting for baseline characteristics., Results: A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51-0.87) and PFS (HR = 0.75, 95% CI: 0.57-0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52-1.27). Results stratified by line of therapy were generally consistent with the overall results., Limitations: Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review., Conclusions: Among a nationwide sample of postmenopausal HR+/HER2- mBC patients treated in community oncology settings, treatment with everolimus-based therapy was associated with significantly longer TOT and PFS compared to endocrine monotherapy.

Background: Clinical guidelines prefer endocrine therapy (ET) as initial treatment for post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC). Chemotherapy (CT) should be reserved for patients who develop symptomatic visceral disease or have no clinical benefit after three sequential ET regimens. It is unclear if real-world clinical practice reflects these guidelines., Objective: To describe treatment patterns and treatment durations by lines of therapy for ET and CT among post-menopausal HR+/HER2- mBC patients., Methods: Charts were reviewed from a network of community-based oncology practices of eligible patients who had progressed after initiating adjuvant or first-line treatment for mBC between 1 January 2004 and 30 September 2010. Extracted chart data included demographics, treatment histories, and outcomes. Treatment duration was estimated using Kaplan-Meier estimators., Results: A total of 144 patients were studied. Patients received a median of two lines of ET, and <10% had three or more lines of ET before receiving CT. From first line to second line, the median treatment duration was 11.6 to 4.9 months for ET overall; 13.8 to 10.5 months for anastrozole; 18.6 to 7.0 months for letrozole; and 5.1 to 2.9 months for fulvestrant. For CT, the median duration was 5.1 months in the first line and 3.7 months and below in subsequent lines., Conclusion: During the study period (1 January 2004 - 30 September 2012), most patients received <3 lines of ET before receiving CT. The drop in median duration of ET from first to second line suggests that single agent ETs might not be as effective beyond the first line. A key limitation of this study was the small sample size. In addition, more research is needed to further investigate the short treatment duration of fulvestrant across early lines of therapy (which could indicate lack of efficacy).

Objective: This study investigated the comparative effectiveness of everolimus-based therapy (EVE) versus endocrine monotherapy (ET) and chemotherapy (CT) in the treatment of hormone-receptor-positive human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients with liver metastasis., Methods: Medical charts of patients treated by community oncologists were examined. Eligible patients included postmenopausal women with HR+/HER2- mBC with liver metastasis who received EVE, ET or CT between 1 July 2012 and 15 April 2013 after non-steroidal aromatase inhibitor use. Time on treatment (TOT) and progression-free survival (PFS) were compared between EVE and ET or CT using Kaplan-Meier analyses and Cox proportional hazards models., Results: Among the 202 patients in the study, 82 received EVE, 49 ET, and 71 CT. After adjusting for baseline characteristics, EVE was associated with significantly longer TOT than ET (hazard ratio [HR]: 0.49; 95% CI: 0.28 - 0.86) or CT (HR: 0.35; 95% CI: 0.22 - 0.55), and significantly longer PFS than ET (HR: 0.48; 95% CI: 0.27 - 0.87). PFS was not significantly different with EVE versus CT (HR: 0.76; 95% CI: 0.44 - 1.32)., Conclusions: EVE had significantly longer TOT and PFS than ET and longer TOT than CT among postmenopausal HR+/HER2- mBC patients with liver metastasis.

Iodide uptake in the thyroid and breast is mediated by the sodium/iodide symporter (NIS). NIS activation is used for radioiodide imaging and therapeutic ablation of thyroid carcinoma. NIS is expressed in >70% of breast cancers but at a level insufficient for radioiodine treatment. All-trans retinoic acid (tRA) induces NIS gene expression and functional iodide uptake in human breast cancer cell lines and mouse breast cancer models. tRA usually regulates gene expression by direct interaction of RA receptor (RAR) with a target gene, but it can also act through nongenomic pathways. We report a direct influence of tRA treatment on the phosphoinositide 3-kinase (PI3K) signal transduction pathway that mediates tRA-induced NIS expression in MCF-7 breast cancer cells. MCF-7 cells express all three RAR isoforms, alpha, beta, and gamma, and RXRalpha. We previously identified RARbeta and RXRalpha as important for NIS induction by tRA. Treatment with LY294002, the PI3K inhibitor, or p85alpha knockdown with siRNA abolished tRA-induced NIS expression. Immunoprecipitation experiments and glutathione S-transferase pull-down assay showed a direct interaction between RARbeta2, RXRalpha, and p85alpha. RA also induced rapid activation of Akt in MCF-7 cells. Treatment with an Akt inhibitor or Akt knockdown with siRNA reduced NIS expression. These findings indicate that RA induction of NIS in MCF-7 cells is mediated by rapid activation of the PI3K pathway and involves direct interaction with RAR and retinoid X receptor. Defining these mechanisms should lead to methods to further enhance NIS expression, as well as retinoid targets that influence growth and differentiation of breast cancer.

Context: All-trans retinoic acid (tRA) induces differentiation in MCF-7 breast cancer cells, stimulates sodium/iodide symporter (NIS) gene expression, and inhibits cell proliferation. Radioiodine administration after systemic tRA treatment has been proposed as an approach to image and treat some differentiated breast cancer., Objective: The objective of this work was to study the relative role of genomic and nongenomic pathways in tRA stimulation of NIS expression in MCF-7 cells., Design: We inspected the human NIS gene locus for retinoic acid-responsive elements and tested them for function. The effects of signal transduction pathway inhibitors were also tested in tRA-treated MCF-7 cells and TSH-stimulated FRTL-5 rat thyroid cells, followed by iodide uptake assay, quantitative RT-PCR of NIS, and cell cycle phase analysis., Results: Multiple retinoic acid response elements around the NIS locus were identified by sequence inspection, but none of them was a functional tRA-induced element in MCF-7 cells. Inhibitors of the IGF-I receptor, Janus kinase, and phosphatidylinositol 3-kinase (PI3K), significantly reduced NIS mRNA expression and iodide uptake in tRA-stimulated MCF-7 cells but not FRTL-5 cells. An inhibitor of p38 MAPK significantly reduced iodide uptake in both tRA-stimulated MCF-7 cells and TSH-stimulated FRTL-5 cells. IGF-I and PI3K inhibitors did not significantly reduce the basal NIS mRNA expression in MCF-7 cells. Despite the chronic inhibitory effects on cell proliferation, tRA did not reduce the S-phase distribution of MCF-7 cells during the period of NIS induction., Conclusion: The IGF-I receptor/PI3K pathway mediates tRA-stimulated NIS expression in MCF-7 but not FRTL-5 thyroid cells.

The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of beta-emitting radioiodide-131 ((131)I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance (131)I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) beta/gamma produced marked NIS induction; and selective stimulation of RARalpha, RARgamma, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR beta/gamma-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC(50) of tRA for NIS stimulation to approximately 7%, such that 10(-7) m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of (131)I greater than 10(-6) m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of (131)I after combination treatment.