The impact of Anastrazole and Letrozole on the metabolic profile in an experimental animal model

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Abstract

Anastrazole and Letrozole are used as endocrine therapy for breast cancer patients. Previous studies suggested a possible association with metabolic and liver adverse effects. Their results are conflicting. Fifty-five 4-week-old female Wistar rats were allocated in 4 groups 1) ovariectomy control (OC), 2) ovariectomy-Anastrazole (OA) 3) ovariectomy -Letrozole (OL), 4) control. Serum glucose, cholesterol, triglycerides, HDL-c and LDL-c were measured at baseline, 2 and 4 months. At the end, the animals‘ liver were dissected for pathology. At 4 months, total cholesterol differed among the OC and OL groups ( p = 0.15) and the control and OL groups ( p = 0.12). LDL-C differed between the control and OC groups ( p = 0.015) as well as between the control and OA ( p =0 .015) and OL groups ( p = 0.002). OC group triglycerides, differed from those of the OL group ( p =0 .002) and the control group ( p = 0.007). The OA also significantly differed from the OL ( p = 0.50). Liver pathology analysis revealed differences among groups with favored mild steatosis and ballooning. Anastrazole and Letrozole seem to negatively influence the lipid profile in our experimental model. This information should be taken in caution by medical oncologists when addressing patients with altered lipid metabolism.

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Most cited references 33

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A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.

Beat Thürlimann, Aparna Keshaviah, Alan S Coates … (2005)

The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen. We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women. The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five years of treatment with various adjuvant endocrine therapy regimens in postmenopausal women with hormone-receptor-positive breast cancer: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. This analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched. A total of 8010 women with data that could be assessed were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen group. After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia. In postmenopausal women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites. (ClinicalTrials.gov number, NCT00004205.) Copyright 2005 Massachusetts Medical Society.

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Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Eitan Amir, Saroj Niraula, Alberto Ocana … (2011)

Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding. We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided. Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09). The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.

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Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

H Sleeboom, M L Gershanovich, H. Mouridsen … (2001)

To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

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Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 01 December 2015

Publication date Collection: 2015

Volume: 5

Electronic Location Identifier: 17493

Affiliations

[1 ]Second Department of Obstetrics and Gynecology, University of Athens , Vas. Sofias 76, Athens, 11528, Greece

[2 ]Laboratory of Experimental Surgery and Surgical Research “N.S. Christeas”, Athens Medical School , Agiou Thoma 15B, Athens, 11527, Greece

[3 ]First Department of Pathology, School of Medicine, National University of Athens , Mikras Asias 75str, Athens, 11527, Greece.

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[a ] ioannis.boutas@ 123456gmail.com

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Publisher Item ID: srep17493

DOI: 10.1038/srep17493

PMC ID: 4664924

PubMed ID: 26620133

SO-VID: bc8fb474-40ad-4ae1-967f-6c690020e5e3

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The impact of Anastrazole and Letrozole on the metabolic profile in an experimental animal model

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Most cited references 33

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.

Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

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