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      The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum

      review-article
      *
      Annals of Oncology
      Oxford University Press
      anastrozole, aromatase inhibitor, breast cancer, estrogen, exemestane, letrozole

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          Abstract

          The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2–3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1–98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology.

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          Most cited references135

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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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            Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.

            In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side-effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years. Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. The primary endpoints were disease-free survival and occurrence of adverse events. Analysis for efficacy was by intention to treat. 9366 patients were recruited, of whom 3125 were randomly assigned anastrozole, 3116 tamoxifen, and 3125 combination. Median follow-up was 33.3 months. 7839 (84%) patients were known to be hormone-receptor-positive. Disease-free survival at 3 years was 89.4% on anastrozole and 87.4% on tamoxifen (hazard ratio 0.83 [95% CI 0.71-0.96], p=0.013). Results with the combination were not significantly different from those with tamoxifen alone (87.2%, 1.02 [0.89-1.18], p=0.8). The improvement in disease-free survival with anastrozole was seen in the subgroup of hormone-receptor-positive patients, but not the receptor-negative patients. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio 0.42 [0.22-0.79], p=0.007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer (p=0.02), vaginal bleeding and discharge (p<0.0001 for both), cerebrovascular events (p=0.0006), venous thromboembolic events (p=0.0006), and hot flushes (p<0.0001). Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (p<0.0001 for both). Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Longer follow-up is required before a final benefit:risk assessment can be made.
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              Mortality after osteoporotic fractures.

              The aim of this study was to examine the pattern of mortality following osteoporotic fractures at the spine, shoulder, hip, and forearm. We studied 2,847 patients with fractures at these sites identified from the radiology department in Malmö, Sweden. Poisson regression was used to compute mortality immediately after the fracture and with time. Mortality immediately after fracture was significantly higher in fracture cases than in the general population except for forearm fractures in both men and women. Mortality was higher in men than in women, but not different when adjusted for sex-specific population risks. For spine, shoulder, and hip fracture, mortality fell after the 1st year, an effect that was most marked for patients with spine fractures. The decrease in mortality risk with time was significant for hip, vertebral, and shoulder fracture. We conclude that the risk of death is increased in patients with osteoporotic fractures and that the highest risk is found immediately after the fracture event. The decreasing mortality with time after fracture may be due in part to a decrease in deaths causally related to the fracture. The extent to which early intervention for osteoporosis might avoid some of these deaths is unknown.
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                Author and article information

                Journal
                Ann Oncol
                annonc
                annonc
                Annals of Oncology
                Oxford University Press
                0923-7534
                1569-8041
                March 2011
                8 July 2010
                8 July 2010
                : 22
                : 3
                : 503-514
                Affiliations
                Section of Oncology, Institute of Medicine, University of Bergen, and Department of Oncology, Haukeland University Hospital, Bergen, Norway
                Author notes
                [* ] Correspondence to: Dr P. E. Lønning, Section of Oncology, Haukeland University Hospital, University of Bergen, Jonas Lies vei 26, N-5021 Bergen, Norway. Tel: +47-55-97-50-00/+47-55-97-20-10; Fax: +47-55-97-35-99/+47-55-97-20-46; E-mail: per.lonning@ 123456helse-bergen.no
                Article
                10.1093/annonc/mdq337
                3042921
                20616198
                a42c16fc-7dbe-498a-9a28-b5c692521257
                © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 February 2010
                : 5 May 2010
                : 6 May 2010
                : 6 May 2010
                Categories
                Reviews

                Oncology & Radiotherapy
                aromatase inhibitor,letrozole,exemestane,anastrozole,breast cancer,estrogen
                Oncology & Radiotherapy
                aromatase inhibitor, letrozole, exemestane, anastrozole, breast cancer, estrogen

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