Efficacy and safety of everolimus plus exemestane in patients with hormone receptor-positive, HER-2-negative advanced breast cancer: Results from the open-label, multicentre, non-interventional BRAWO study.

BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.

Superior suppression of serum estrogens during neoadjuvant breast cancer treatment with letrozole compared to exemestane.

PURPOSE: The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking. METHODS: Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC-MS/MS method established in our laboratory. RESULTS: Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women. CONCLUSION: To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.

The Antioxidant and HDAC-Inhibitor α-Lipoic Acid Is Synergistic with Exemestane in Estrogen Receptor-Positive Breast Cancer Cells.

Anti-estrogenic therapy is established in the management of estrogen receptor (ER)-positive breast cancer. However, to overcome resistance and improve therapeutic outcome, novel strategies are needed such as targeting widely recognized aberrant epigenetics. The study aims to investigate the combination of the aromatase inhibitor exemestane and the histone deacetylase (HDAC) inhibitor and antioxidant α-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of α-lipoic acid, and rac-dihydro-lipoic acid were investigated for HDAC inhibition. We found HDAC inhibitory activity in the 1-3-digit micromolar range with a preference for HDAC6. Rac-dihydro-lipoic acid is slightly more potent than rac-α-lipoic acid. The antiproliferative IC50 value of α-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and α-lipoic acid resulted in synergistic behavior under various incubation times (24 h to 10 d) and readouts (MTT, live-cell fluorescence microscopy, caspase activation) analyzed by the Chou-Talalay method. α-lipoic acid increases mitochondrial fusion and the expression of apoptosis-related proteins p21, APAF-1, BIM, FOXO1, and decreases expression of anti-apoptotic proteins survivin, BCL-2, and c-myc. In conclusion, combining exemestane with α-lipoic acid is a promising novel treatment option for ER-positive breast cancer.

XENERA-1: a randomised double-blind Phase II trial of xentuzumab in combination with everolimus and exemestane versus everolimus and exemestane in patients with hormone receptor-positive/HER2-negative metastatic breast cancer and non-visceral disease.

BACKGROUND: Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease. METHODS: This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review. RESULTS: A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8-29.3) months with xentuzumab and 11.0 (7.7-19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55-2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8-9.7) months with xentuzumab and 9.2 (5.6-14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69-2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3-56.0%), fatigue (33.3-44.0%) and headache (21.6-40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms. CONCLUSIONS: While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018.

Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer: phase II randomized controlled trial.

BACKGROUND: We aimed to confirm the efficacy and safety of the oral histone deacetylase inhibitor entinostat in Japanese patients with hormone receptor-positive advanced/recurrent breast cancer and to explore potential biomarkers. METHODS: This phase II, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT03291886) was conducted at 28 Japanese sites (September 2017-July 2020; interim analysis cutoff: April 2019). Patients with progression/relapse following non-steroidal aromatase inhibitors were randomized 1:1 to entinostat (5 mg/week) or placebo, plus exemestane (25 mg/day). Primary endpoint was progression-free survival; secondary endpoints included overall survival and safety. Exploratory biomarker outcomes included lysine acetylation, immune cell profiles, estrogen receptor 1 mutations and plasma chemokines. RESULTS: Of 133 randomized patients, 131 (65 entinostat, 66 placebo) who received study drug were analyzed. Median (95% confidence interval) progression-free survival was 5.8 (3.2-7.8) months for entinostat and 3.3 (3.1-5.8) months for placebo (hazard ratio [95% confidence interval]: 0.75 [0.50 - 1.14]; P = 0.189). Median overall survival was not reached in either group. Entinostat tended to prolong progression-free survival in patients aged ≥65 years, not endocrine resistant, or with estrogen receptor 1 Y537S mutation. Candidate biomarkers of efficacy (progression-free survival) included lysine acetylation in CD3+ cells, plasma interferon gamma-induced protein 10, dendritic cell CD86 expression, and CD4+ cell expression of human leukocyte antigen-DR and inducible T-cell co-stimulator. Safety was similar to non-Japanese populations; however, seven entinostat-treated patients (10.8%) had reversible lung injury. CONCLUSIONS: In Japanese patients, the safety of entinostat plus exemestane was acceptable and progression-free survival was prolonged, although not significantly. Exploratory analyses identified potential biomarkers, including lysine acetylation, of efficacy.

QbD-assisted development of lipidic nanocapsules for antiestrogenic activity of exemestane in breast cancer.

Some breast cancers are caused by hormonal imbalances, such as estrogen and progesterone. These hormones play a function in directing the growth of cancer cells. The hormone receptors in hormone receptor-positive breast cancer lead breast cells to proliferate out of control. Cancer therapy such as hormonal, targeted, radiation is still unsatisfactory because of these challenges namely multiple drug resistance (MDR), off-targeting, severe adverse effects. A novel aromatase inhibitor exemestane (Exe) exhibits promising therapy in breast cancer. This study aims to develop and optimize Exe-loaded lipid nanocapsules (LNCs) by using DSPC, PF68 and olive oil as lipid, surfactant and oil phase, respectively and to characterize the same. The prepared nanocapsules were investigated via in vitro cell culture and in vivo animal models. The LNCs exhibited cytotoxicity in MCF-7 cell lines and enhanced anti-cancer activity and reduced cardiotoxicity in DMBA-induced animal model when compared to the drug. Additionally, in vivo pharmacokinetics revealed a 4.2-fold increased oral bioavailability when compared with Exe suspension. This study demonstrated that oral administration of Exe-loaded LNCs holds promise for the antiestrogenic activity of exemestane in breast cancer.

Lyophilized mixed micelles of exemestane: A novel paradigm to improve its absorption and anticancer activity.

The objective of the present investigation was to prepare and optimize lyophilized mixed micelles (Lyp-EXE-MMs) of exemestane (EXE) with improved solubility, bioavailability, in vivo anticancer activity, and physical stability, by using various cryoprotectants. The prepared lyophilized mixed micelles were characterized by various techniques, including dynamic light scattering, zeta potential, powdered X-ray diffraction, differential scanning calorimetry (DSC), nuclear magnetic resonance (1 H NMR), transmission electron microscopy (TEM), and so on. Thereafter, the lyophilized micelles were evaluated for ex vivo permeation, in vitro drug release and gene/protein expression (RT-PCR and Western blot analysis) in MCF-7 breast cancer cells. The developed formulation was also investigated for its in vivo anticancer study in BALB/c mice with induced breast cancer. The use of trehalose (10% w/w) was proven to be a suitable cryoprotectant for these micelles. Lyp-EXE-MMs were spherical, with a particle size of 42.9 ± 3.8 nm and a polydispersity index of 0.307 ± 0.122. Furthermore, % drug loading and % entrapment efficiency were found to be 5.8 ± 1.4 and 89.1 ± 1.1, respectively. Lyp-EXE-MMs showed sustained release behavior as compared to EXE-suspensions in SGF/SIF (pH 1.2 and 6.8) and phosphate buffer saline (pH 7.4). The micelles induced apoptosis through the regulation of BAX, BCL2, Caspase-3, p53, and CYP19A1 in MCF-7 cells, which was correlated to enhanced ex vivo drug permeation. Animals receiving EXE micelle formulations showed reduced tumor volume and improved survivability and pharmacokinetic parameters as compared to pure EXE. Lyp-EXE-MMs were found to withstand simulated harsh conditions of SGF/SIF during stability studies. The fabricated EXE micellar preparations hold a promising approach for breast cancer treatment.

In Vitro Effects of Combining Genistein with Aromatase Inhibitors: Concerns Regarding Its Consumption during Breast Cancer Treatment.

INTRODUCTION: The third-generation of aromatase inhibitors (AIs)-Exemestane (Exe), Letrozole (Let), and Anastrozole (Ana)-is the main therapeutic approach applied for estrogen receptor-positive (ER+) breast cancer (BC), the most common neoplasm in women worldwide. Despite their success, the development of resistance limits their efficacy. Genistein (G), a phytoestrogen present in soybean, has promising anticancer properties in ER+ BC cells, even when combined with anticancer drugs. Thus, the potential beneficial effects of combining G with AIs were investigated in sensitive (MCF7-aro) and resistant (LTEDaro) BC cells. METHODS: The effects on cell proliferation and expression of aromatase, ERα/ERß, and AR receptors were evaluated. RESULTS: Unlike the combination of G with Ana or Let, which negatively affects the Ais' therapeutic efficacy, G enhanced the anticancer properties of the steroidal AI Exe, increasing the antiproliferative effect and apoptosis relative to Exe. The hormone targets studied were not affected by this combination when compared with Exe. CONCLUSIONS: This is the first in vitro study that highlights the potential benefit of G as an adjuvant therapy with Exe, emphasizing, however, that soy derivatives widely used in the diet or applied as auxiliary medicines may increase the risk of adverse interactions with nonsteroidal AIs used in therapy.

An Exemestane Derivative, Oxymestane-D1, as a New Multi-Target Steroidal Aromatase Inhibitor for Estrogen Receptor-Positive (ER+) Breast Cancer: Effects on Sensitive and Resistant Cell Lines.

Around 70-85% of all breast cancer (BC) cases are estrogen receptor-positive (ER+). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (Oxy), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER+ BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERß and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic.

Effect of variables on exemestane-loaded albumin nanoparticles: statistical optimization and anti-cancer activity in MCF-7 cell lines.

This research aimed to evaluate the effect of variables on exemestane-loaded bovine serum albumin nanoparticles (EXE-BSA NPs) to improve anti-breast cancer activity. EXE-BSA NPs were optimized using 32 factorial design, wherein the concentration of BSA (X1) and sonication time (X2) were independent variables and particle size (Y1) and %w/w entrapment efficiency (Y2) were dependent variables. The statistical optimization revealed a significant effect of BSA concentration on both variables, whereas sonication time affected only particle size. The optimized EXE-BSA NPs were spherical with 124.1 ± 2.62 nm particle size, 83.95 ± 1.06% w/w drug entrapment, and exhibited a biphasic release of 100% (w/w) drug over 72 h. The optimized formulation induced cytotoxicity in MCF-7 cell lines with an IC50 value of 21.46 µg/mL by MTT assay, almost half the free drug (54.87 µg/mL). Thus, statistically optimized EXE-BSA NPs were effective in MCF-7 cell lines and can be explored to treat estrogen receptor-positive breast cancer.

Incorporation of exemestane into ternary nanosponge system for enhanced anti-tumor potential in breast cancer.

The present investigation reports the potential of exemestane loaded cyclodextrin based nanosponges for the treatment of breast cancer. Fourier transform infrared, and nuclear magnetic resonance (NMR) spectroscopic analysis confirmed the encapsulation of ring B, C, and D of exemestane in the nanosponge cavity. In vitro studies demonstrated a 6.58-folds increase in the aqueous solubility and a 1.76-folds increase in the dissolution of exemestane in the optimized nanosponge formulation EF2. It also exhibited enhanced cytotoxicity in MCF-7 cell line. Pharmacokinetic studies revealed a 1.37-fold increase in Cmax and a 2.10-fold increase in oral bioavailability of EF2, as compared to its marketed product Aromasin®. Concomitantly, this nano-formulation reduced the tumor burden to 45.71% in a DMBA-induced breast cancer rat model. This EF2-treatment also improved the hematological parameters of the animals. Histopathology of breast tissue also presented reduction in characteristic cytoarchitectural features of breast tumor. In vivo toxicity studies demonstrated reduced hepatotoxicity of the nanosponge formulation when compared with Aromasin®. These results were further supported by histological studies of excised liver tissues, where the size of hepatocytes in EF2-treated animals was like the normal hepatocyte size. In conclusion, the encapsulation of exemestane in ß-cyclodextrin nanosponge along-with HPMC E5 improved its aqueous solubility, bioavailability, and ultimately therapeutic efficacy for the treatment of breast cancer.

Real-Life Analysis of Efficacy and Safety of Everolimus Plus Exemestane in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Patients: A Turkish Oncology Group (TOG) Study.

PURPOSE: This study evaluated the efficacy and safety of everolimus (EVE) plus exemestane (EXE) in hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) patients in real-life settings. METHODS: Overall, 204 HR+, HER2- MBC patients treated with EVE + EXE after progressing following prior endocrine treatment were included. Overall survival (OS) and progression-free survival (PFS) and safety data were analyzed. RESULTS: The objective response rate, median PFS, and median OS were 33.4%, 8.9 months, and 23.4 months, respectively. Multivariate analysis revealed that negative progesterone receptor status was a significant determinant of poor treatment response (p = 0.035) and PFS (p = 0.024). The presence of bone-only metastasis was associated with better treatment response (p = 0.002), PFS (p < 0.001), and OS (p = 0.001). CONCLUSION: We confirmed the favorable efficacy and safety profile of EVE + EXE for HR+, HER - MBC patients.

Adjuvant tamoxifen switched to exemestane treatment in postmenopausal women with estrogen receptor-positive early breast cancer: A pragmatic, multicenter, and prospective clinical trial in China.

Objective: This post-approval safety study assessed the efficacy and safety of exemestane after 2-3 years of tamoxifen treatment among postmenopausal women with estrogen receptor-positive (ER+) early breast cancer in China. Methods: Enrolled patients had received 2-3 years of tamoxifen and were then switched to exemestane for completion of 5 consecutive years of adjuvant endocrine therapy. The primary endpoint was the time from enrollment to the first occurrence of locoregional/distant recurrence of the primary breast cancer, appearance of a second primary or contralateral breast cancer, or death due to any cause. Other endpoints included the proportion of patients experiencing each event, incidence rate per annum, relationships between human epidermal growth factor receptor 2 status and time to event, and relationship between disease history variables and time to event. Results: Overall, 558 patients were included in the full analysis set: 397 (71.1%) completed the study, 20 experienced an event, and 141 discontinued [47 owing to an adverse event (AE); 37 no longer willing to participate]. Median duration of treatment was 29.5 (range, 0.1-57.7) months. Median time to event was not reached. Event-free survival probability at 36 months was 91.4% (95% CI, 87.7%-95.1%). The event incidence over the total exposure time of exemestane therapy was 3.5 events/100 person-years (20/565). Multivariate analysis showed an association between tumor, lymph node, and metastasis stage at initial diagnosis and time to event [hazard ratio: 1.532 (95% CI, 1.129-2.080); P=0.006]. Most AEs were grade 1 or 2 in severity, with arthralgia (7.7%) being the most common treatment-related AE. Conclusions: This study supports the efficacy and safety of exemestane in postmenopausal Chinese women with ER+ breast cancer previously treated with adjuvant tamoxifen for 2-3 years. No new safety signals were identified in the Chinese population.

Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy.

BACKGROUND: There is currently no clinical trial data regarding the efficacy of everolimus exemestane (EE) following prior treatment with CDK4/6 inhibitors (CDK4/6i). This study assesses the use and efficacy of everolimus exemestane in patients with metastatic HR+ HER2- breast cancer previously treated with endocrine therapy (ET) or endocrine therapy + CDK4/6i. METHODS: Retrospective analysis of electronic health record-derived data for HR+ HER2- metastatic breast cancer from 2012 to 2018. The proportion of patients receiving EE first-line, second-line, or third-line, and the median duration of EE prior to next line of treatment (TTNT) by line of therapy was calculated. OS for patients receiving EE first-line, second-line, or third-line, indexed to the date of first-line therapy initiation and stratified by prior treatment received, was calculated with Kaplan-Meier method with multivariable Cox proportional hazards regression analysis. RESULTS: Six hundred twenty-two patients received EE first-line (n = 104, 16.7%), second-line (n = 273, 43.9%) or third-line (n = 245, 39.4%). Median TTNT was 8.3 months, 5.5 months, and 4.8 months respectively. Median TTNT of EE second-line was longer following prior ET alone compared to prior ET + CDK4/6i (6.2 months (95% CI 5.2, 7.3) vs 4.3 months (95% CI 3.2, 5.7) respectively, p = 0.03). Similarly, EE third-line following ET alone vs ET + CDK4/6i in first- or second-line resulted in median TTNT 5.6 months (95% CI 4.4, 6.9) vs 4.1 months (95% CI 3.6, 6.1) respectively, although this was not statistically significant (p = 0.08). Median OS was longer for patients who received EE following prior ET + CDK4/6i. EE second-line following ET + CDK 4/6i vs ET alone resulted in median OS 37.7 months vs. 32.7 months (p = 0.449). EE third-line following ET + CDK4/6i vs prior ET alone resulted in median OS 59.2 months vs. 40.8 months (p < 0.010). This difference in OS was not statistically significant when indexed to the start of EE therapy. CONCLUSION: This study suggests that EE remains an effective treatment option after prior ET or ET + CDK4/6i use. Median TTNT of EE was longer for patients who received prior ET, whereas median OS was longer for patients who received prior ET + CDK4/6i. However, this improvement in OS was not statistically significant when indexed to the start of EE therapy suggesting that OS benefit is primarily driven by prior CDK4/6i use. EE remains an effective treatment option regardless of prior treatment option.

Everolimus Plus Exemestane Treatment in Patients with Metastatic Hormone Receptor-Positive Breast Cancer Previously Treated with CDK4/6 Inhibitor Therapy.

BACKGROUND: The combination of everolimus (EVE) and exemestane (EXE) is approved for the treatment of patients with metastatic hormone receptor-positive breast cancer (mHRBC) who progress on nonsteroidal aromatase inhibitor (NSAI) therapy. However, none of the patients enrolled in the trial that led to this approval (BOLERO-2) had previously received CDK4/6 inhibitors (CDK4/6is), which have since become a frontline standard of care for mHRBC. As such, the clinical benefit of EVE plus EXE in patients who have previously received CDK4/6is remains unknown. MATERIALS AND METHODS: Adult patients with mHRBC at our institution who progressed on an NSAI plus CDK4/6i or NSAI therapy alone and were treated with at least one cycle of EVE plus EXE between 2012 and 2018 were analyzed. Collected data included patient demographics, treatment history, adverse events, and clinical outcomes. Primary objectives were to compare progression-free survival (PFS) and overall survival (OS) between patients who received prior NSAI plus CDK4/6i therapy versus an NSAI alone. RESULTS: Among 43 patients, 17 had prior CDK4/6i exposure. With the exception of de novo metastatic disease, patient and disease characteristics were comparable across treatment cohorts. There was no significant difference in PFS (median, 3.6 vs. 4.2 months) or OS (median, 15.6 vs. 11.3 months) between patients who had received prior CDK4/6is and those who had not, respectively. CONCLUSION: Prior exposure to CDK4/6i therapy did not impact survival outcomes for patients with mHRBC taking EVE plus EXE. However, there was a trend toward improved OS in the CDK4/6i cohort that should be evaluated in larger cohorts. IMPLICATIONS FOR PRACTICE: The use of CDK4/6 inhibitors in combination with a nonsteroidal aromatase inhibitor has become a standard frontline therapy in metastatic hormone receptor-positive breast cancer. An approved subsequent line of therapy is everolimus plus exemestane; however, the original data supporting this therapy predated approval of CDK4/6 inhibitors. As such, the clinical benefit of everolimus and exemestane in patients previously treated with a CDK4/6 inhibitor was unknown. This retrospective cohort study offers real-world data demonstrating prior CDK4/6 inhibitor exposure does not impact survival outcomes for everolimus plus exemestane.

Lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients: the potential role of the adipokine leptin.

PURPOSE: The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known "lack of cross-resistance". METHODS: Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using Luminex xMAP technology (multiple ELISA). RESULTS: Serum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo. CONCLUSIONS: Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with the non-steroidal aromatase inhibitor letrozole. Our findings provide new insights into the influence of clinically important aromatase inhibitors on cytokine levels in vivo that contribute to the understanding of the clinically observed lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients. TRIAL REGISTRATION: Registered on March 23rd 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).

Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial.

PURPOSE: To correlate MRI morphological response patterns with histopathological tumor regression grading system based on tumor cellularity in locally advanced breast cancer (LABC)-treated neoadjuvant with third-generation aromatase inhibitors. METHODS: Fifty postmenopausal patients with ER-positive/HER-2-negative LABC treated with neoadjuvant letrozole and exemestane given sequentially in an intra-patient cross-over regimen for at least 4 months with MRI response monitoring at baseline as well as after at least 2 and 4 months on treatment. The MRI morphological response pattern was classified into 6 categories: 0/complete imaging response; I/concentric shrinkage; II/fragmentation; III/diffuse; IV/stable; and V/progressive. Histopathological tumor regression was assessed based on the recommendations from The Royal College of Pathologists regarding tumor cellularity. RESULTS: Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (24/50 and 21/50, respectively). After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (21/50). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and histopathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53). CONCLUSION: The type II MRI pattern "fragmentation" was more frequent in the histopathological responder group; and types I and IV in the non-responder group. Type II pattern showed the best endocrine responsiveness and a relatively moderate correlation between sizes obtained from MRI and histology, whereas type IV pattern indicated endocrine resistance but the strongest correlation between MRI and histology.

Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES.

BACKGROUND: This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). METHODS: The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10 mg/day) + EXE (25 mg/day) orally. RESULTS: A total of 235 patients received ≥ 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (≥ 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3 months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. CONCLUSION: The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region.

Estrogen and sex-dependent loss of the vocal learning system in female zebra finches.

Sex hormones alter the organization of the brain during early development and coordinate various behaviors throughout life. In zebra finches, song learning is limited to males, with the associated song learning brain pathways only maturing in males and atrophying in females. While this atrophy can be prevented by treating females with exogenous estrogen during early post-hatch development, the requirement of estrogen during normal male song system development is uncertain. For the first time in songbirds, we administered exemestane, a potent third generation estrogen synthesis inhibitor, from the day of hatching until adulthood in order to reassess the role of estrogen in song circuit development. We examined the behavior, brain anatomy, and transcriptomes of individual song nuclei in these pharmacologically manipulated animals. We found that males with long-term exemestane treatment had diminished male-specific plumage and impaired song learning, but minimal effect on song nuclei sizes and their specialized transcriptome. Consistent with prior findings, females with long-term estrogen treatment retained a functional song system with song nuclei that had specialized gene expression similar, but not identical to males. We also observed that different song nuclei responded to estrogen manipulation differently, with Area X in the striatum being the most altered by estrogen modulation. These findings support the hypothesis that song learning is an ancestral trait in both sexes that was subsequently suppressed in females of some species and that estrogen has come to play a critical role in modulating this suppression as well as refinement of song learning.

Exemestane encapsulated polymer-lipid hybrid nanoparticles for improved efficacy against breast cancer: optimization,in vitrocharacterization and cell culture studies.

Polymer-lipid hybrid nanoparticles (PLHNPs) are novel nanoplatforms for the effective delivery of a lipophilic drug in the management of a variety of solid tumors. The present work was designed to develop exemestane (EXE) encapsulated D-alpha-tocopheryl polyethylene glycol succinate (TPGS) based PLHNPs (EXE-TPGS-PLHNPs) for controlled delivery of EXE for breast cancer management. EXE-TPGS-PLHNPs were formulated by single-step nano-precipitation technique and statistically optimized by a 33Box-Behnken design using Design expert®software. The polycaprolactone (PCL;X1), phospholipon 90 G (PL-90G;X2), and surfactant (X3) were selected as independent factors while particles size (PS;Y1), polydispersity index (PDI;Y2), and %entrapment efficiency (%EE;Y3) were chosen as dependent factors. The average PS, PDI, and %EE of the optimized EXE-TPGS-PLHNPs was observed to be 136.37 ± 3.27 nm, 0.110 ± 0.013, and 88.56 ± 2.15% respectively. The physical state of entrapped EXE was further validated by Fourier-transform infrared spectroscopy, differential scanning calorimetry, and powder x-ray diffraction that revealed complete encapsulation of EXE in the hybrid matrix of PLHNPs with no sign of significant interaction between drug and excipients.In vitrorelease study in simulated gastrointestinal fluids revealed initial fast release for 2 h after that controlled release profile up to 24 h of study. Moreover, optimized EXE-TPGS-PLHNPs exhibited excellent stability in gastrointestinal fluids as well as colloidal stability in different storage concentrations. Furthermore, EXE-TPGS-PLHNPs exhibited distinctively higher cellular uptake and time and dose-dependent cytotoxicity against MCF-7 breast tumor cells compared to EXE-PLHNPs without TPGS and free EXE. The obtained results suggested that EXE-TPGS-PLHNPs can be a promising platform for the controlled delivery of EXE for the effective treatment of breast cancer.