Effect Of Exemestane Research Articles

Enhancing exemestane delivery: Solid lipid nanoparticles formulation and pharmacokinetic evaluation

This research investigates the development of exemestane (EXM) solid lipid nanoparticles (SLNs) for the purpose of improving drug delivery. To prepare EXM SLNs, glycerol monostearate was used as the lipid and Tween 80 as the surfactant and solvent injection followed by high-pressure homogenization as a method of preparation. The formulation parameters were optimized, leading to the development of a promising formula. The formula has a particle size of 188.72 ± 5.62 nm, a polydispersity index (PDI) of 0.215 ± 0.023, and an %EE of 65.39 ± 2.54 %. The formulation's robustness was indicated by minimal changes in particle size and %EE over 30 days, as revealed by stability studies. The bioavailability of EXM SLNs was found to be significantly improved in Wistar rats compared to conventional EXM suspension, as shown by pharmacokinetic studies. The formula that was optimized showed a higher maximum plasma concentration (Cmax) of 168.92 ± 2.40 ng/mL, a delayed time to reach Cmax (Tmax) of 4 hours, and significantly higher area under the curve (AUC) values. These results highlight the effectiveness of the optimized formula in improving drug absorption and bioavailability. The findings indicate that EXM SLNs show potential for enhancing the delivery and effectiveness of EXM, specifically in the treatment of breast cancer.

Abstract P5-04-16: Total estrogenic activity during neoadjuvant therapy with letrozole and exemestane – An intra-patient cross-over comparison using the AroER tri-screen

Abstract Background. Aromatase inhibitors (AIs), letrozole (Femarâ / Femaraâ) and exemestane (Aromasinâ), are widely used anti-hormonal drugs for breast cancer. Both compounds strongly reduce circulating estradiol levels in postmenopausal women. In the setting of metastatic breast cancer, these drugs may be used after another, causing new responses in selected patients by switching to the alternative drug after progressing on the first choice. This well-known ”lack of cross resistance” has been recognized for some time and is documented by several clinical trials. However, the precise explanation for this clinical observation is still unknown. The availability of mechanistic information may lead to an improved strategy against hormone-sensitive breast cancer. Patients and methods. NEO-LET-EXE was a neoadjuvant, randomized, open-label, intra-patient cross-over trial. Postmenopausal patients with estrogen receptor (ER) positive (>50%), HER-2 negative, locally advanced breast cancer were enrolled. Sequential blood samples (obtained at baseline, after 2 months and 4 months of treatment) were available from 29 patients. All patients were randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d) for 2 months followed by another 2 months on the alternative compound. The total estrogenic activities in the collected blood samples were determined using AroER tri-screen assay developed by the Chen laboratory. The assay utilizes MCF-7aro ERE cells which contain both aromatase and ER. The samples were assayed in the presence as well as the absence of letrozole, to estimate relative contributions of estrogen and estrogen+androgen to the activities, respectively. Results. Using the highly sensitive AroER tri-screen assay, estrogenic activity were detected at three time points in all blood samples. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 23 out of 26 patients. Only in three patients, the activity was higher during therapy with letrozole compared to exemestane. When letrozole was included in the assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgen were present in samples from exemestane treatment. Four samples collected after exemestane treatment and three after letrozole treatment had higher activities than baseline samples when assay was carried out with letrozole. Discussion. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples. Significant higher levels of estrogenic activity in human serum were observed during exemestane than those during letrozole treatment. Our observations, that additional letrozole could reduce further the estrogen activity in the exemestane-treated samples, demonstrate probably residual aromatase activity during therapy with exemestane alone.In addition to distinguish the effects of exemestane and letrozole, our results also demonstrate that the assay can also potentially detect the effects of estrogenic mimics. Citation Format: Bahrami N, Chang G, Kanaya N, Sauer T, Gravdehaug B, Chen S, Geisler J. Total estrogenic activity during neoadjuvant therapy with letrozole and exemestane – An intra-patient cross-over comparison using the AroER tri-screen [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-16.

A real-life study on the implementation and effectiveness of exemestane plus everolimus per hospital type in patients with advanced breast cancer. A study of the Southeast Netherlands Advanced Breast Cancer registry.

PurposeWe aimed to assess the implementation and effectiveness of exemestane plus everolimus treatment per hospital type in real-life, shortly after approval of everolimus. MethodsAdvanced breast cancer patients treated with exemestane plus everolimus in 2012–2014 were included from the SONABRE registry. Progression-free survival (PFS) and a 12-week conditional PFS (post-hoc) were estimated by Kaplan-Meier method. The multivariable Cox proportional hazards model was performed by type of hospital and adjusted for patient, tumour and treatment characteristics. ResultsWe included 122 patients, comprising 48 patients treated in academic (N = 1), 56 in teaching (N = 4), and 18 in non-teaching (N = 2) hospitals. The median PFS was 6.3 months (95% Confidence Interval (CI) 4.0–8.6) overall, and 8.5 months (95% CI 7.7–9.3), 4.2 months (95% CI 2.0–6.3), and 5.5 months (95% CI 4.2–6.7) for the patients treated in academic, teaching and non-teaching hospitals, respectively. The adjusted Hazard Ratio (HR) for PFS-events was 1.5 (95% CI 1.0–2.2) and 1.0 (95% CI 0.5–1.9) respectively for patients treated at teaching and non-teaching hospitals versus the academic hospital. The adjusted HR for 12-week conditional PFS-events was not different between hospital types. In the first 12-week treatment period, treatment was discontinued due to early progression in one out of 48 patients in the academic versus nine out of 74 patients in the non-academic hospitals, confirmed by imaging in one and two patients, respectively. ConclusionsIn our study, the median PFS was borderline significantly different between hospital types, possibly the result of a different assessment approach in the first 12-week treatment period.

Prediction of exemestane benefit in patients with advanced breast cancer based on diagnostic biopsy mRNA analysis.

e12532 Background: Exemestaneis a steroidal aromatase inhibitor used in the treatment of postmenopausal patients with estrogen receptor(ER)-positive adjuvant and advanced breast cancer. We aimed to determine the predictive value of a multigene mRNA-based mathematical algorithm (Drug Response Predictor (DRP)) for benefit of exemestane. The DRP is founded on measuring the full cancer transcriptome in sensitive and drug resistant cell lines compared with expression patterns in tumors and broadly validated in several studies (Wang et al. JNCI (2013) 105 (17): 1284-1291.) (Knudsen, S. et al. PLoS One (2014) 9(2): e87415.) (Christensen, TD et al. J Clin Oncol (2016) 34: suppl; abstr e12056.) (Kappel, IB et al. J Clin Oncol (2016) 34: suppl; abstr e20007.). Methods: Among 838 consecutive patients from a DBCG cohort with advanced breast cancer treated at 10 participating sites we identified 163 patients who between November 2008 and November 2015 initiated exemestane. All but one patient were ER-positive. Patients were evaluated every 3 to 4 months using CT scans and clinical examination. After patient informed consent mRNA was extracted and assayed on Affymetrix Gene Chip U133p2 arrays from formalin fixed paraffin embedded diagnostic biopsies. The primary endpoint was progression free survival (PFS). Analysis of the DRP’s ability to predict PFS was performed using a Cox regression model adjusted for treatment line. Results: Median PFS was 8.5 months. Of the 163 patients, 101 received prior adjuvant antihormone therapy and 60 did not. Data regarding adjuvant therapy was inaccessible for two patients. Hazard ratios for patients with predicted good vs. poor effect of exemestane are shown in the table. Conclusions: In a clinical setting, a mathematical algorithm using mRNA from a diagnostic biopsy can in patients unexposed to previous adjuvant endocrine therapy with statistical significance predict who will benefit from exemestane. [Table: see text]

Exemestane Attenuates Hepatic Fibrosis in Rats by Inhibiting Activation of Hepatic Stellate Cells and Promoting the Secretion of Interleukin 10.

Exemestane (EXE) is an irreversible steroidal aromatase inhibitor mainly used as an adjuvant endocrine therapy for postmenopausal women suffering from breast cancer. Besides inhibiting aromatase activity, EXE has multiple biological functions, such as antiproliferation, anti-inflammatory, and antioxidant activities which are all involved in hepatic fibrosis. Therefore, we investigated the role of EXE during the progress of hepatic fibrosis. The effect of EXE on liver injury and fibrosis were assessed in two hepatic fibrosis rat models, which were induced by either carbon tetrachloride (CCl4) or bile duct ligation (BDL). The influence of EXE treatment on activation and proliferation of primary rat hepatic stellate cells (HSCs) was observed in vitro. The results showed that EXE attenuated the liver fibrosis by decreasing the collagen deposition and α-SMA expression in vivo and inhibited the activation and proliferation of primary rat HSCs in vitro. Additionally, EXE promoted the secretion of antifibrotic and anti-inflammatory cytokine IL-10 in vivo and in HSC-T6 culture media. In conclusion, our findings reveal a new function of EXE on hepatic fibrosis and prompted its latent application in liver fibrotic-related disease.

Abstract B46: The influence of exemestane on breast density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial

Abstract Background: Endogenous estradiol blood levels and high breast density are both associated with an increased risk for breast cancer (BC), but, there is conflicting evidence about whether or not they influence breast cancer risk through a shared pathway. Exemestane is an aromatase inhibitor that blocks the synthesis of estrogen and has been demonstrated to reduce the incidence of breast cancer in postmenopausal women by 65%. However the effects of exemestane on breast density remain unclear. Objectives: The primary objective of this research was to prospectively examine the relationship between exemestane versus placebo and changes in mammographic breast density (BD) in postmenopausal women during 3 or more years of treatment. Methods: The NCIC Clinical Trials Group conducted a phase III randomized controlled trial (RCT) comparing exemestane (E), with placebo (P) in postmenopausal women at higher than average risk for BC (MAP.3). This study was nested within the MAP.3 RCT using data from 568 participants across Canada and Buffalo, New York. Information on treatment allocation and established risk factors for BC was previously collected and data on the outcome measures was obtained from mammograms. Baseline and follow-up mammograms were collected from participating centres and were measured (percent density) using Cumulus software by our team radiologist (DJ). Multivariable linear regression was used to estimate the effect of exemestane treatment on >=3 year change in percent BD from randomization controlling for potential confounding variables. Results: Percent BD was measured for 386 participants (E=200, P=186) with a baseline and >=3 year follow-up mammogram that was matching in format (i.e. film or digital). The average age of women at study entry was 63 years and the average Gail score was 2.8%. The mean BD was similar in both arms at baseline (P: 12.9% (SD: 14.5) and E: 13.7% (SD: 14.4)). Similarly, the annual mean change in percent BD was not significantly different between the two treatment arms (P: 0.63% (SD: 1.82) vs E: .077% (SD: 1.80); p=0.90). After controlling for potential confounders (age, body mass index, first degree family history of BC and prior use of HRT), exemestane was not predictive of change in percent BD (p-value=0.641). Neither age (<60 vs. >=60 yrs) nor BMI modified the exemestane-breast density relationship significantly. Conclusion: We found no association between >=3 years of exemestane use and change in percent BD among a subset of postmenopausal women participating in MAP.3. These results suggest that estrogen and breast density may have independent pathways in breast cancer etiology. Citation Format: Harriet Richardson, Paul E. Goss, Melanie Walker, Doris Jabs, Will King. The influence of exemestane on breast density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B46.

Abstract P3-06-43: A genetic deletion in the uridine diphosphate glucuronosyltransferase 2B17 affects the pharmacokinetics of exemestane

Abstract Background Exemestane (EXE) is an aromatase inactivator used in the prevention and treatment of breast cancer (BC). The majority of EXE and its active metabolite 17-dihydroEXE are excreted as glucuronide conjugates by uridine diphosphate glucuronosyltransferase (UGT). The UGT2B17 enzyme is the most expressed in human liver. A deletion spanning the entire UGT2B17 gene (*2) decreased the EXE glucuronidation process by 14-fold in human liver microsomes (HLM) from UGT2B17(*2/*2) genotype subjects compared to wild-type UGT2B17(*1/*1) HLMs. Aim The aim of this study was to investigate whether the UGT2B17 deletion is associated with increased serum levels of EXE and 17-dihydroEXE and to assess if this deletion predicts the anti-proliferative effect of EXE in BC tissue as measured by Ki67 changes 6 weeks apart. Methods In a phase II pre-surgical trial, 50 postmenopausal women with histologically-confirmed ER positive BC; stage T1-2, N0-1, M0 were assigned to EXE 25 mg/d for 6 weeks before surgery. Morning fasting blood was collected at baseline (B) and after 6 weeks and stored at -80° C until assayed. Time of last drug intake was collected at blood draw. DNA was extracted from whole blood (Qiagen, Italy). We used Taqman copy number variation assay (Life Technologies, Monza, Italy) for the UGT2B17 genotyping. EXE and 17-dihydroEXE concentrations were determined by mass spectrometry (MS) using Waters® Xevo™ TQ MS in electrospray positive ionization mode (Waters, Manchester, UK), optimized by multiple reaction monitoring mode. We used Zorbax Eclipse Plus C18 columns and mobile phase MeOH/H2O with 0.1% formic acid. EXE pure substance was provided by Pfizer Inc.,17β-hydroxy EXE and EXE-19-d3 purchased from Toronto Research Chemicals (Toronto, Ontario, Canada). Wilcoxon Signed Rank Test was used to assess differences in serum concentrations of EXE, its metabolites, and post-pretreatment tissue Ki67 changes according to UGT2B17 genotypes. Results Median age and BMI were 62 years and 26 kg/m2, respectively. The UGT2B17 genotype (n=50) was 24 homozygote wt (*1/*1), 20 heterozygote (*1/*2) and 6 homozygote variant (*2/*2). Minor allele frequency = 0.32. Hardy-Weinberg Equilibrium (P=0.57) was respected. Median and interquartile ranges (IQRs) of EXE and 17-dihydroEXE at 6 weeks, by time elapsed since last drug intakeTime since last drugEXE (nM)17-dihydroEXE (nM)≤24 hours (n=32)10.25 (5.55, 17.25)2.75 (1.85, 3.6)>24 hours (n=15)2.10 (1.20, 2.20)*1.50 (1.20, 2.00)*** P=.0001 vs ≤24h; **P=.0003 vs ≤24h ; Median and IQRs of EXE, 17-dihydroEXE and Ki67 change from B by UGT2B17 genotypesGenotypeEXE (nM)17-dihydroEXE (nM)Ki67 changeBMIUGT2B17 *1/*1 (n=22)5.3 (2.2, 11.4)1.85 (1.4, 3.06)-9 (-16, -5)28 (24, 32)UGT2B17 *1/*2, *2/*2 (n=25)9.3 (2.6, 17.6)*2.5 (2.0, 3.6)**-11 (-19, -3)♦26 (23, 30)♦♦P-values between genotype groups:*P=.28; **P=.04; ♦P=.82; ♦♦P=.41 Conclusions Our study demonstrates a significant association of the UGT2B17 deletion with increased serum concentrations of 17-dihydroEXE, irrespective of time since last drug intake. Neither 17-dihydroEXE, nor genotype explained the significant anti-proliferative effect of EXE on BC tissue. Larger studies should determine the clinical implications of this gene on EXE efficacy. Citation Format: Harriet Johansson, Valentina Aristarco, Jennifer Gjerde, Sara Gandini, Aliana Guerrieri-Gonzaga, Matteo Lazzeroni, Serena Mora, Debora Macis, Davide Serrano, Antonio Toesca, Luca Bottiglieri, Gunnar Mellgren, Giuseppe Viale, Andrea DeCensi, Bernardo Bonanni. A genetic deletion in the uridine diphosphate glucuronosyltransferase 2B17 affects the pharmacokinetics of exemestane [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-43.

Minimal impact of adjuvant exemestane or tamoxifen treatment on mammographic breast density in postmenopausal breast cancer patients: A Dutch TEAM trial analysis

Background. Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.Material and methods. Analogue mammograms of selected TEAM participants before start, and after one and two (and if available after three) years of adjuvant endocrine therapy were collected centrally and reviewed. Study endpoints were change in breast density over time, and correlations between breast density and locoregional recurrence (LRR), distance recurrence (DR), and contralateral breast cancer (CBC).Results. Mammograms of 378 patients (181 tamoxifen, 197 exemestane) were included in the current per protocol analyses. Baseline breast density was low (breast density score < 50% in 75% of patients) and not different between patients randomised to exemestane or tamoxifen (coefficient 0.16, standard error 0.17). Breast density did not change during treatment in exemestane (p = 0.25) or tamoxifen users (p = 0.59). No relation was observed between breast density and the occurrence of a LRR [hazards ratio (HR) 0.87, 95% CI 0.45–1.68, p = 0.67], a DR (HR 1.02, 95% CI 0.77–1.35, p = 0.90), or CBC (HR 1.31, 95% CI 0.63–2.72, p = 0.48).Conclusion. The in general low breast density score in early postmenopausal breast cancer patients did not substantially change over time, and this pattern was not different between tamoxifen and exemestane users. Breast density was not a predictive marker for efficacy of adjuvant endocrine therapy.

Effect of exemestane plus everolimus on CTC counts and Ki-67 expression on CTCs in patients with advanced hormone receptor-positive, HER2-negative breast cancer.

11042 Background: The utility of CTCs in predicting patient (pt) outcome has been demonstrated in metastatic breast cancer treated with chemotherapy or endocrine therapy. In this trial we evaluated...

The combination of antitumor drugs, exemestane and erlotinib, induced resistance mechanism in H358 and A549 non-small cell lung cancer (NSCLC) cell lines

Context: Estrogens in non-small-cell lung cancer (NSCLC) are important, and their interaction with epidermal growth factor receptor (EGFR) might be crucial.Objective: This study investigates the effect of exemestane, an aromatase inhibitor, and erlotinib, an EGFR inhibitor, on human NSCLC cell lines; H23, H358 and A549.Materials and methods: A cell proliferation assay was used for measuring cell number, apoptosis assay for detecting apoptosis and necrosis and immunoblotting for beclin-1 and Bcl-2 proteins detection. An immunofluorescence assay was used for EGFR localization. A migration assay and zymography were used for cell motility and metalloproteinases (MMPs) expression, respectively.Results: Exemestane, erlotinib or their combination decreased cell proliferation and increased apoptosis. Exemestane’s half maximal inhibitory concentration (IC50) was 50 μM for H23 and H358 cells and 20 μM for A549. The IC50 of erlotinib was 25 μM for all cell lines. Apoptosis increase induced by exemestane was 58.0 (H23), 186.3 (H358) and 34.7% (A549) and by erlotinib was 16.7 (H23), 65.3 (H358) and 66.3% (A549). A synergy effect was observed only in H23 cells. Noteworthy, the combination of exemestane and erlotinib decreased beclin-1 protein levels (32.3 ± 19.2%), an indicator of autophagy, in H23 cells. The combination of exemestane and erlotinib partially reversed the EGFR translocation to mitochondria and decreased MMP levels and migration.Discussion and conclusions: The benefit from a dual targeting of aromatase and EGFR seems to be regulated by NSCLC cell content. The diverse responses of cells to agents might be influenced by the dominance of certain molecular pathways.

Phase II Trial of Exemestane in Combination With Fulvestrant in Postmenopausal Women With Advanced, Hormone-Responsive Breast Cancer

IntroductionExemestane, the irreversible steroidal aromatase inhibitor, and fulvestrant, the pure estrogen antagonist, are active as single drugs in postmenopausal women with advanced hormone-responsive breast cancer. We designed a phase II study with the purpose of determining whether combining these 2 drugs with different and potentially complementary mechanisms of action will improve the clinical benefit. Patients and MethodsForty postmenopausal women with hormone-responsive advanced breast cancer received intramuscular injection of fulvestrant 250 mg every 28 days in combination with daily exemestane 25 mg until disease progression. We examined the influence of fulvestrant on exemestane pharmacokinetics and the effect of exemestane and fulvestrant on serum IGF-1 (insulin-like growth factor 1) and IGFBP-3 (IGF-binding protein 3) levels. ResultsThe observed proportion of patients free of progressive disease at 6 months after the initiation of treatment with exemestane and fulvestrant was 50%, a rate similar to that achieved with single-agent exemestane or fulvestrant in the first- or second-line setting. Pharmacokinetics parameters showed that coadministration of fulvestrant did not result in clinically relevant changes in exemestane plasma concentrations. A comparison of IGF-1 and IGFBP-3 levels demonstrated the increase of 35% and 12%, respectively, in mean levels from baseline to day 120. ConclusionsThe combination of exemestane and fulvestrant did not improve clinical benefit. The observed lack of improved efficacy was not related to altered drug exposure.

Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) Trial: results of a German substudy

ABSTRACTAim The aim of this study was to compare the effects of exemestane and tamoxifen on hormone levels in postmenopausal patients with hormone receptor-positive breast cancer within a Germany substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.Methods Within the TEAM trial, patients were randomized to receive adjuvant treatment with exemestane for 5 years or tamoxifen for 2.5–3 years followed by exemestane for 2–2.5 years. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)-intact were measured at screening and after 3, 6 and 12 months of treatment.Results Data on hormone levels were available from 63 patients in the tamoxifen arm and 68 patients in the exemestane arm. Treatment with exemestane resulted in decreases from baseline in SHBG and PTH-intact levels, and increases from baseline in testosterone, DHEAS and FSH levels. Tamoxifen treatment resulted in increases from baseline in SHBG and PTH-intact, whereas levels of testosterone and FSH decreased and DHEAS levels did not change. At all time points assessed, the absolute change from baseline was significantly different between tamoxifen and exemestane for testosterone, SHBG, FSH and PTH-intact (all p < 0.0001).Conclusions Exemestane and tamoxifen had statistically significantly different effects on hormone levels, including testosterone, SHBG, FSH and PTH-intact.

P4-11-13: Influence of Two Years of Exemestane on Bone Mineral Density in Postmenopausal Women at Increased Risk of Developing Breast Cancer; a Companion Study to the NCIC CTG MAP.3 Trial.

Abstract Background Exemestane significantly reduced invasive and preinvasive breast cancers in postmenopausal women at increased risk for breast cancer in the NCIC CTG MAP3 trial with no serious toxicities, including excess fractures or osteoporosis. Purpose: To provide additional information on the effect of exemestane on bone loss in women at high risk for breast cancer, within a subset of women participating on the NCIC CTG MAP.3B study. The primary hypothesis is that exemestane does not induce clinically significant bone loss in postmenopausal women at increased risk of developing breast cancer at 2 years. The primary objective of this companion study is to examine the effect of exemestane on lumbar spine and total hip BMD by DEXA at 2 years in women participating in the MAP3 trial. Methods: The MAP.3B bone sub-study registered women from the main MAP. 3 trial from May 2008 to March 2010. Eligible women had to have an acceptable quality BMD scan by DEXA taken within 12 months prior to randomization to MAP.3. A BMD T-score &amp;gt;-2.0 SD (i.e. better than 2 standard deviations below the average peak BMD of a young adult woman) was established as the study population cutoff. A questionnaire including information on height, falls, fractures, lifestyle information including physical activity, tobacco and alcohol use was completed at baseline, 12 months, 24 months and at last visit. Fasting serum for bone biomarkers was collected at 12 months and total hip and L1-L4 (postero-anterior) spine BMD were measured 2 years after randomization on the same Lunar or Hologic scanner. The primary objective was to determine differences in hip and spine BMD at 2 years. Secondary outcomes include number of skeletal fractures and development of osteoporosis 2 years after randomization and changes in bone biomarkers at 1 year after randomization. For the analysis of the primary endpoints, the upper limit of a one sided 95% confidence interval for the difference in mean percentage changes between placebo and exemestane will be calculated for the BMD by DEXA at each site. We will conclude that exemestane does not induce significant bone loss in postmenopausal women at increased risk of developing breast cancer at 2 years when the upper limit is less than 3% for both sites. Similar confidence interval approach will be used to analyze the secondary endpoints. Results: Between May 2008 and March 2010, 238 postmenopausal women were recruited. Median age was 61.8 years, and the majority of women were Caucasian (91%), with approximately 20% of the participants reporting a recent fall (within past 12 months) and another 13% reporting a recent fracture prior to randomization. We will report results from the primary as well as the secondary endpoints at the SABCS meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-13.

P3-15-02: The Change of Bone Turnover Markers during Neoadjuvant Anastrozole Versus Exemestane: A Randomized Single-Center Study.

Abstract Background: Non-steroidal aromatase inhibitors including anastrozole and letrozole have been reported to increase the rate of bone turnover, accelerate loss of bone, and increase the incidence of fractures. Although steroidal inactivator exemestane has similar inhibitory effect on the aromatization, animal studies have shown a weak but potentially important anabolic effect of exemestane metabolites, which might lead to decreased bone resorption. This randomized trial was conducted to compare the effect of exemestane and anastorozole on bone turnover markers. Patients and Methods: Fifty-two postmenopausal women with ER-positive, HER2−negative, invasive, nonmetastatic, and operable breast cancer were randomly assigned to neoadjuvant exemestane (25 mg daily) or anastrozole (1 mg daily) for 4 months. The primary endpoint was change in bone turnover markers including resorption markers urinary and serum N-telopeptide (NTX) and the formation markers serum bone alkaline phosphatase (BAP). The secondary endpoint was tumor objective response (OR) assessed by both caliper and ultrasound. Comparisons were also made of breast conservation rate and adverse events. Results: The changes in serum NTX from baseline to week 16 were not statistically different between anastrozole and exemestane. The changes in urinary NTX from baseline to week 16 were also not statistically different between both groups .BAP did not show any significant increase in the exemestane group (10.8%; p=0.21), whereas the increase in BAP from baseline to week 16 in the anastrozole group was 15.0% and marginally significant (p=0.05). There were no significant differences in OR in the intent-to-treat population between patients receiving anastrozole or exemestane (45.8% vs. 39.2%; p=0.63). The OR was similar between the patients with a baseline Ki67 index of ≥15% and &amp;lt;15% in exemestane group (37.5% vs. 41.2%; p=0.86). In anastrozole group the OR in patients with a baseline Ki67 index of ≥15% and &amp;lt;15% was 44.4% and 53.8%, respectively(p=0.66). Breast conservation rate was similar between anastrozole and exemestane (62.5% vs. 67.9%; p=0.68). Treatment was well tolerated and much the same for both groups. Conclusions: There is no significant differences of the change in bone turnover markers between anastrozole and exemestane. These results indicate exemestane had no anabolic effects which would lead to fewer adverse effects on bone. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-15-02.

S6-1: Menopause-Specific and Health-Related Qualities of Life among Post-Menopausal Women Taking Exemestane for Prevention of Breast Cancer: Results from the NCIC CTG MAP.3 Placebo-Controlled Randomized Controlled Trial.

Abstract Background: Exemestane, a steroidal aromatase inhibitor, reduced the incidence of invasive breast cancers by 65% among 4560 post-menopausal randomized to exemestane or placebo for 5 years on MAP.3. Differences in quality of life (QOL) were judged to be minimal, but only summary information was reported. Purpose: To provide more detailed information about effects of exemestane on menopause-specific and health-related qualities of life. Method: Participation in quality of life assessment was an eligibility criterion. Menopause-specific and health-related qualities of life were assessed using the MENQOL (4 scales; physical, vasomotor, psychosocial, sexual) and SF-36 (8 scales; physical health, role function — physical, bodily pain, general health, vitality, social function, role function — emotional, mental health, and 2 summary scales) instruments, respectively at baseline, 6 months and then yearly after randomization. Compliance with QOL questionnaire completion at each follow-up visit ranged from 93–98%, and did not differ by group. Change scores for each MENQOL and SF-36 scale, calculated for each assessment time relative to baseline, were compared using the Wilcoxon Rank-Sum test. Summary scores were used to summarize the QOL scores observed at each time point for each SF-36 dimension and overall mental (MCS) and physical component summaries (PCS) and MENQOL domains. Clinically important worsening of MENQOL change scores was defined as an increase of ≥0.5/8 points. SF-36 change scores were considered worsened if scores decreased by ≥ 5 points from baseline. Results: Both groups were balanced on scores for MENQOL and SF-36 at baseline. Median follow-up was 35 months and the proportion of women who stopped study medication early for toxicity reasons was 15% in the exemestane arm and 11% in the placebo arm. There was a statistically significant difference in change scores for vasomotor symptoms among women on exemestane during the first 4 years (p-values &amp;lt;0.01), compared to placebo. However, no between-group differences in vasomotor change met the criterion for clinical importance. Women on exemestane had statistically poorer sexual functioning (mean change = −0.02, SD=1.37) compared to placebo (mean change = −0.12, SD=1.32) during the first 6 months on study (p-value = 0.03) but the differences were not statistically significant thereafter or clinically important at any time. Among the 8 SF-36 scales, only bodily pain was statistically different between exemestane and placebo for the first 24 months on study medication (p-value &amp;lt;0.01), but no between-group difference in change scores exceeded 5 points. Overall SF-36 PCS and MCS assessing changes in overall physical and mental health-related QOL did not differ significantly by group at any assessment. Conclusion: Our assessment that early differences in vasomotor symptoms and pain were probably not clinically important is supported by the observation of no between-group differences when overall physical and mental health-related QOL changes were compared. Exemestane does not appear to have a major negative impact on the quality of life among these women. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S6-1.

The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study

BackgroundIn this Tamoxifen Exemestane Adjuvant Multinational Japan sub-study, we evaluated the time course of changes in serum lipids in postmenopausal women with hormone-sensitive early breast cancer treated with exemestane, anastrozole, or tamoxifen for postoperative adjuvant therapy. Patients and methodsA total of 154 breast cancer patients were assigned to receive exemestane, anastrozole, or tamoxifen in this randomized open-label study. Serum lipid parameters including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during 1 year of treatment. ResultsTC and LDL-C rapidly decreased in patients treated with tamoxifen at 3 months. Compared with anastrozole and exemestane patients, TC and LDL-C were significantly lower at all assessment time points in tamoxifen patients (P<0.05). TG increased in tamoxifen patients; it was significantly higher compared with exemestane patients at all assessment time points (P<0.05). HDL-C slightly decreased in exemestane patients; it was significantly lower compared with anastrozole patients at 3 months and 1 year (P=0.0179 and 0.0013, respectively). ConclusionChanges of lipid profiles in Japanese postmenopausal women treated with tamoxifen were relatively favorable, while exemestane and anastrozole had no clinically significant effect on the serum lipids.

Comparison of the effects of exemestane versus letrozole on bone loss: A cohort study

Comparison of the effects of exemestane versus letrozole on bone loss: A cohort study

Effects of Exemestane, Anastrozole and Tamoxifen on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Early Breast Cancer Patients: Results of N-SAS BC 04, the TEAM Japan Substudy

Background: Use of aromatase inhibitors in women with postmenopausal breast cancer accompanies risks of bone loss. We evaluated changes in bone mineral density (BMD) and bone turnover markers in patients treated with exemestane, anastrozole or tamoxifen for hormone-sensitive postmenopausal early breast cancer. Patients and Methods: Sixty-eight patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational Japan bone substudy were randomly assigned to receive tamoxifen, exemestane or anastrozole. During a 2-year study period, lumbar spine BMD was measured using dual-energy X-ray absorptiometry, and urinary type I collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP) were also measured. Results: BMD at 2 years of treatment was higher in tamoxifen patients compared with exemestane and anastrozole patients; however, the intergroup difference was not significant (p = 0.2521 and p = 0.0753, respectively). BMD was higher in exemestane patients compared with anastrozole patients; however, the intergroup difference was not significant (p = 0.7059 and p = 0.8134, respectively). NTX and BAP were significantly lower in tamoxifen patients compared with exemestane and anastrozole patients at 1 and 2 years of treatment (p < 0.05). Conclusion: Tamoxifen may provide better bone protection compared with exemestane or anastrozole. The effect of exemestane and anastrozole on bone loss may be comparable in Japanese postmenopausal women.

Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: Results of a prospective gynecological ultrasound substudy

Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: Results of a prospective gynecological ultrasound substudy

Abstract P1-07-03: Effect of Exemestane on Mammographic Density in Postmenopausal Women at Risk for Breast Cancer

Abstract Background: A reduction in mammographic density(MD) has been associated with the reduction in breast cancer risk among those taking tamoxifen. Aromatase inhibitors (AIs) show promise for breast cancer prevention in postmenopausal women. We are conducting a phase II trial of exemestane in women at increased risk for breast cancer. The primary endpoint for this study is change in MD. Methods: Subjects were screened and enrolled at two sites: Center for Cancer Research, National Cancer Institute and Lombardi Comprehensive Cancer Center, Georgetown University Hospital. Eligible participants are at increased risk for breast cancer by virtue of: Gail model risk ≥1. 7% over 5 years; high risk pathological lesion (e.g. lobular neoplasia, ductal carcinoma in situ); known BRCA1/2 deleterious mutation or prior stage I/II breast cancer at least 2 years from breast cancer treatment and not treated with AIs. Women were excluded if AP spine T-score was &amp;lt;-2.5 (osteoporosis). Study participants received exemestane 25 mg, calcium carbonate 1200 mg and vitamin D 400 IU daily for two years. Mammograms were conducted at baseline, 1 and 2 years. MD was calculated using the semi-automated Cumulus software. The cranio-caudal view of one breast was selected for analysis. For patients who had had no prior surgery or radiation, the side with greater density at baseline was selected. For patients who had undergone significant breast surgery or radiation, mammograms of the unaffected side were selected. Percent MD was determined by one investigator (C.B.) who read each image twice and was masked to the subject's time on exemestane. The mean change in paired images was tested for a mean change of zero using the Wilcoxon signed rank test. As of June 2010, 42 women have enrolled in the trial and we have analyzed change in MD at one year in the first 22 subjects. Results:For the 22 subjects included in this analysis 15 were eligible due to a high risk pathological lesion, 4 by Gail Model and 3 by prior breast cancers. 18 had film screen mammograms at baseline and 12 months, 4 had film screen mammograms at baseline and digital mammogram at 12 months. Mammographic density declined 7% (p=0.0006, 95% CI −11% to −3%) at one year. The change in MD ranged from −26% to +14% and the standard deviation was 9%. In regard to the four subjects who had film screen mammograms at baseline and digital at follow up, the baseline percent dense areas were slightly higher than average but this did not reach statistical significance (p=0.32 by the Wilcoxon rank sum test). The 12 month MD comparison was similar to the 18 subjects with film images (p=0.90). Conclusions: Exemestane use was associated with a statistically significant decrease in MD at one year. Prior evaluations of AI therapy in high risk women have not shown a significant decline in MD, however time on treatment was shorter and other third generation AIs were used. Although the number of subjects is small, MD did not differ significantly between film screen and digital mammograms. We will further evaluate change in MD in the entire cohort at 1 and 2 years and between film screen and digital mammography. Phase III trials are on-going to evaluate the effect of exemestane on breast cancer prevention. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-03.