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      The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer

      review-article
      International Journal of Clinical Practice
      Blackwell Publishing Ltd

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          Abstract

          The third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor – positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs. In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI-associated adverse events. The primary purpose of this review is to help internists with these two tasks.

          Review Criteria

          Expert opinion based on review of literature on relevant clinical trials.

          Message for the Clinic

          Both tamoxifen and AIs are effective for the adjuvant and neoadjuvant treatment of postmenopausal breast cancer; the optimal choice of drug is dependent on the characteristics of the patient and tumour. Adverse events with both drug classes are manageable. Adverse events associated with tamoxifen include increased risk of uterine cancers and thromboembolic events vs. an increased incidence of vaginal dryness, loss of libido, musculoskeletal pain and bone mineral density loss with AIs. Promising studies of AIs in the breast cancer prevention setting are ongoing.

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          Most cited references89

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          Breast cancer and hormone-replacement therapy in the Million Women Study.

          Current use of hormone-replacement therapy (HRT) increases the incidence of breast cancer. The Million Women Study was set up to investigate the effects of specific types of HRT on incident and fatal breast cancer. 1084110 UK women aged 50-64 years were recruited into the Million Women Study between 1996 and 2001, provided information about their use of HRT and other personal details, and were followed up for cancer incidence and death. Half the women had used HRT; 9364 incident invasive breast cancers and 637 breast cancer deaths were registered after an average of 2.6 and 4.1 years of follow-up, respectively. Current users of HRT at recruitment were more likely than never users to develop breast cancer (adjusted relative risk 1.66 [95% CI 1.58-1.75], p<0.0001) and die from it (1.22 [1.00-1.48], p=0.05). Past users of HRT were, however, not at an increased risk of incident or fatal disease (1.01 [0.94-1.09] and 1.05 [0.82-1.34], respectively). Incidence was significantly increased for current users of preparations containing oestrogen only (1.30 [1.21-1.40], p<0.0001), oestrogen-progestagen (2.00 [1.88-2.12], p<0.0001), and tibolone (1.45 [1.25-1.68], p<0.0001), but the magnitude of the associated risk was substantially greater for oestrogen-progestagen than for other types of HRT (p<0.0001). Results varied little between specific oestrogens and progestagens or their doses; or between continuous and sequential regimens. The relative risks were significantly increased separately for oral, transdermal, and implanted oestrogen-only formulations (1.32 [1.21-1.45]; 1.24 [1.11-1.39]; and 1.65 [1.26-2.16], respectively; all p<0.0001). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. 10 years' use of HRT is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 users of oestrogen-only preparations and 19 (15-23) additional cancers per 1000 users of oestrogen-progestagen combinations. Use of HRT by women aged 50-64 years in the UK over the past decade has resulted in an estimated 20000 extra breast cancers, 15000 associated with oestrogen-progestagen; the extra deaths cannot yet be reliably estimated. Current use of HRT is associated with an increased risk of incident and fatal breast cancer; the effect is substantially greater for oestrogen-progestagen combinations than for other types of HRT.
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            A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.

            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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              Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial.

              The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) trial was designed to test the hypothesis that the clinical and/or biologic effects of neoadjuvant tamoxifen compared with anastrozole and with the combination of tamoxifen and anastrozole before surgery in postmenopausal women with estrogen receptor (ER) -positive, invasive, nonmetastatic breast cancer might predict for outcome in the Arimidex, Tamoxifen Alone or in Combination (ATAC) adjuvant therapy trial. Postmenopausal women with ER-positive, invasive, nonmetastatic, and operable or locally advanced potentially operable breast cancer were randomly assigned to neoadjuvant tamoxifen (20 mg daily), anastrozole (1 mg daily), or a combination of tamoxifen and anastrozole for 3 months. The tumor objective response (OR) was assessed by both caliper and ultrasound. Comparisons were also made of clinical response with ultrasound response, actual and feasible surgery with feasible surgery at baseline, OR in human epidermal growth factor receptor 2 (HER2)-positive cancers, and tolerability. There were no significant differences in OR in the intent-to-treat population between patients receiving tamoxifen, anastrozole, or the combination. In patients who were assessed as requiring mastectomy at baseline (n = 124), 44% of patients received breast-conserving surgery (BCS) after anastrozole compared with 31% of patients after tamoxifen (P = .23); this difference became significant for patients who were deemed feasible for BCS by their surgeon (46% v 22%, respectively; P = .03). The OR for patients with HER2-positive cancer (n = 34) was 58% for anastrozole compared with 22% for tamoxifen (P = .18). All treatments were well tolerated. Neoadjuvant anastrozole is as effective and well tolerated as tamoxifen in ER-positive operable breast cancer in postmenopausal women, but the hypothesis that clinical outcome might predict for long-term outcome in adjuvant therapy was not fulfilled.
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                Author and article information

                Journal
                Int J Clin Pract
                ijcp
                International Journal of Clinical Practice
                Blackwell Publishing Ltd
                1368-5031
                1742-1241
                December 2007
                : 61
                : 12
                : 2051-2063
                Affiliations
                Breast Cancer Prevention Center, Division of Clinical Oncology, Department of Internal Medicine, University of Kansas Medical Center Kansas City, KS, USA
                Author notes
                Correspondence to: Carol J. Fabian, MD, University of Kansas Medical Center, 1347 KU Hospital, Mail Stop 3003, 3901 Rainbow Boulevard, Kansas City, KS 66160-7418, USA Tel.: + 1 913 588 7791 Fax: + 1 913 588 3679 Email: cfabian@ 123456kumc.edu

                Disclosures The author has received funding from Novartis for two investigator-initiated prevention studies using letrozole in women receiving hormone replacement therapy, as well as funding for two investigator-initiated studies from Pfizer (manufacturers exemestane) for investigator-initiated prevention studies using celecoxib. The author has also received unrestricted educational grants from AstraZeneca (manufacturers anastrozole) and have served on advisory boards for Novartis and Pfizer.

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Article
                10.1111/j.1742-1241.2007.01587.x
                2228389
                17892469
                5508f06f-9deb-4b68-99f9-3e2cdc4190f8
                © 2007 The Author Journal compilation © 2007 Blackwell Publishing Ltd
                History
                : May 2007
                : August 2007
                Categories
                Review Article

                Medicine
                Medicine

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