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Safety profiles of aromatase inhibitors and selective estrogen-receptor modulators in the treatment of early breast cancer

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Abstract

For the medical treatment of early breast cancer, aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane are more effective than selective estrogen-receptor modulators (SERMs) such as tamoxifen (TAM). However, the adverse events associated with AIs are different from those associated with SERMs. Hot flushes, gynecological disorders, and thrombosis are more frequent in patients treated with TAM than in those treated with AIs. Conversely, osteoporosis, fractures, joint symptoms, and myalgia are more common in patients receiving AIs. Osteoporosis and bone fractures resulting from osteoporosis are important issues for patients treated with AIs. The precise management of bone health, in strict accordance with clinical guidelines, is vital in patients receiving AIs. AI-related joint symptoms are also one of the most important considerations for patients taking AIs. AI-related joint symptoms are the most common reason for the discontinuation of AIs. Confirmed management strategies for AI-related joint symptoms are unavailable at present. In patients receiving AIs, long-term adverse events (for example, those occurring as a result of changing lipid metabolism) remain unclear. There is a clear need to elucidate AI-related adverse events over the long term and to establish management strategies for AI-related adverse events, such that AIs can be used safely in patients with breast cancer over long periods of time.

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References

  1. Early Breast Cancer Trialist’ Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  CAS  Google Scholar 

  2. Howell A, Cuzick J, Baum M, et al. (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62

    Article  PubMed  CAS  Google Scholar 

  3. Buzdar A, Howell A, Cuzick J, et al. (2006) Comprehensive sideeffect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 7:633–643

    Article  PubMed  CAS  Google Scholar 

  4. Coates AS, Keshaviah A, Thurlimann B, et al. (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. J Clin Oncol 25:486–492

    Article  PubMed  CAS  Google Scholar 

  5. Crivellari D, Sun Z, Coates AS, et al. (2008) Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol 26:1972–1979

    Article  PubMed  CAS  Google Scholar 

  6. Coombes RC, Hall E, Gibson LJ, et al. (2004) A randomized trial of exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092

    Article  PubMed  CAS  Google Scholar 

  7. Coombes RC, Kilburn LS, Snowdon CF, et al. (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369:559–570

    Article  PubMed  CAS  Google Scholar 

  8. Jakesz R, Jonat W, Gnant M, et al. (2005) Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455–462

    Article  PubMed  CAS  Google Scholar 

  9. Boccardo F, Rubagotti A, Guglielmini P, et al. (2006) Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian Tamoxifen Anastrozole (ITA) trial. Ann Oncol 17(Suppl 7):vii 10–14

    Google Scholar 

  10. Goss PE, Ingle JN, Martino S, et al. (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271

    Article  PubMed  CAS  Google Scholar 

  11. Goss PE, Ingle, JN, Pater JL, et al. (2008) Late extended adjuvant treatment with letrozole improves outcome in women with earlystage breast cancer who complete 5 years of tamoxifen. J Clin Oncol 26:1948–1955

    Article  PubMed  CAS  Google Scholar 

  12. Jakesz R, Greil R, Gnant M, et al. (2007) Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst 99:1845–1853

    Article  PubMed  CAS  Google Scholar 

  13. Mamounas EP, Jeong JH, Wickerham DL, et al. (2008) Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Sur gical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol 26:1965–1971

    Article  PubMed  CAS  Google Scholar 

  14. Saika M, Inoue D, Kido S, et al. (2001) 17 Beta-estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-alpha. Endocrinology 142:2205–2212

    Article  PubMed  CAS  Google Scholar 

  15. Shevde NK, Bendixen AC, Dienger KM, et al. (2000) Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci U S A 97:7829–7834

    Article  PubMed  CAS  Google Scholar 

  16. Kousteni S, Bellido T, Plotkin LI, et al. (2003) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730

    Google Scholar 

  17. Anonymous (2000) Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement. 17:1–45

  18. Eastell R, Adams JE, Coleman RE, et al. (2008) Effect of anastrozole on bone mineral density: 5-year results from the Anastrozole, Tamoxifen, Alone or in Combination trial 18233230. J Clin Oncol 26:1051–1057

    Article  PubMed  CAS  Google Scholar 

  19. Forbes JF, Cuzick J, Buzdar A, et al. (2008) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45–53

    Article  PubMed  CAS  Google Scholar 

  20. Coleman RE on behalf of ATAC Trialist’ Group (2008) Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. J Clin Oncol 26: (May suppl; abstr act 587)

  21. Coleman RE, Banks LM, Girgis SI, et al. (2007) Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol 8:119–127

    Article  PubMed  CAS  Google Scholar 

  22. Perez EA, Josse RG, Pritchard KI, et al. (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 24: 3629–3635

    Article  PubMed  CAS  Google Scholar 

  23. Lonning PE, Geisler J, Krag LE, et al. (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126–5137

    Article  PubMed  CAS  Google Scholar 

  24. Geisler J, Lonning PE, Krag LE, et al. (2006) Changes in bone and lipid metabolism in postmenopausal women with early breast cancer after terminating 2-year treatment with exemestane: a randomised, placebo-controlled study. Eur J Cancer 42:2968–2975

    Article  PubMed  CAS  Google Scholar 

  25. Hillner BE, Ingle JN, Chlebowski RT, et al. (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4057

    Article  PubMed  CAS  Google Scholar 

  26. Donnellan PP, Douglas SL, Cameron DA, et al. (2001) Aromatase inhibitors and arthralgia. J Clin Oncol 19:2767

    PubMed  CAS  Google Scholar 

  27. Crew KD, Greenlee H, Capodice J, et al. (2007) Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25:3877–3883

    Article  PubMed  Google Scholar 

  28. Buzdar A, on behalf of the ATAC Trialist’ Group (2006) Clinical features of joint symptoms observed in the ‘Arimidex’ Tamoxifen, Alone or in Combination (ATAC) trial. J Clin Oncol 2006 Annual Meeting Proceedings Part I 124:551

    Google Scholar 

  29. Morales L, Pans S, Paridaens R, et al. (2007) Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat 104:87–91

    Article  PubMed  CAS  Google Scholar 

  30. Morales L, Pans S, Verschueren K, et al. (2008) Prospective study to assess short-term intra-articular and tenosynovial changes in the aromatase inhibitor-associated arthralgia syndrome. J Clin Oncol 26:3147–3152

    Article  PubMed  Google Scholar 

  31. Dietrich W, Haitel A, Holzer G, et al. (2006) Estrogen receptorbeta is the predominant estrogen receptor subtype in normal human synovia. J Soc Gynecol Investig 13:512–517

    PubMed  CAS  Google Scholar 

  32. Chagin AS, Chrysis D, Takigawa M, et al. (2006) Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis. J Endocrinol 188:193–203

    Article  PubMed  CAS  Google Scholar 

  33. Hoegh-Andersen P, Tanko LB, Andersen TL, et al. (2004) Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res Ther 6:R169–180

    Article  PubMed  CAS  Google Scholar 

  34. Pansini F, Albertazzi P, Bonaccorsi G, et al. (1994) The menopausal transition: a dynamic approach to the pathogenesis of neurovegetative complaints. Eur J Obstet Gynecol Reprod Biol 57:103–109

    Article  PubMed  CAS  Google Scholar 

  35. Fontaine C, Meulemans A, Huizing M, et al. (2008) Tolerance of adjuvant letrozole outside of clinical trials. Breast

  36. Hozumi Y, Hakamata Y, Sasanuma H, et al. (2002) Effects of anastrozole on lipid metabolism compared with tamoxifen in rats. Breast Cancer Res Treat 76:131–136

    Article  PubMed  CAS  Google Scholar 

  37. Goss PE, Qi S, Cheung AM, et al. (2004) Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res 10:5717–5723

    Article  PubMed  CAS  Google Scholar 

  38. Goss PE, Qi S, Josse RG, et al. (2004) The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 34:384–392

    Article  PubMed  CAS  Google Scholar 

  39. Banerjee S, Smith IE, Folkerd L, et al. (2005) Comparative effects of anastrozole, tamoxifen alone and in combination on plasma lipids and bone-derived resorption during neoadjuvant therapy in the IMPACT trial. Ann Oncol 16:1632–168

    Article  PubMed  CAS  Google Scholar 

  40. Sawada S, Sato K, Kusuhara M, et al. (2005) Effect of anastrozole and tamoxifen on lipid metabolism in Japanese postmenopausal women with early breast cancer. Acta Oncol 44:134–141

    Article  PubMed  CAS  Google Scholar 

  41. Elisaf MS, Bairaktari ET, Nicolaides C, et al. (2001) Effect of letrozole on the lipid profile in postmenopausal women with breast cancer. Eur J Cancer 37:1510–1513

    Article  PubMed  CAS  Google Scholar 

  42. Wasan KM, Goss PE, Pritchard PH, et al. (2005) The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 16:707–715

    Article  PubMed  CAS  Google Scholar 

  43. Atalay G, Dirix L, Biganzoli L, et al. (2004) The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, “Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients”. Ann Oncol 15:211–217

    Article  PubMed  CAS  Google Scholar 

  44. Markopoulos C, Polychronis A, Zobolas V, et al. (2005) The effect of exemestane on the lipidemic profile of postmenopausal early breast cancer patients: preliminary results of the TEAM Greek sub-study. Breast Cancer Res Treat 93:61–66

    Article  PubMed  CAS  Google Scholar 

  45. Breast International Group (BIG) 1-98 Collaborative Group (2005) A Comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. New Engl J Med 353: 2747–2757

    Article  Google Scholar 

  46. Thurlimann B, Keshaviah A, Coates AS, et al. (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757

    Article  PubMed  Google Scholar 

  47. Bender CM, Sereika SM, Brufsky AM, et al. (2007) Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer. Menopause 14:995–998

    Article  PubMed  Google Scholar 

  48. Gerber B, Krause A, Reimer T, et al. (2006) Anastrozole versus tamoxifen treatment in postmenopausal women with endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology. Clin Cancer Res 12:1245–1250

    Article  PubMed  CAS  Google Scholar 

  49. Fallowfield L, Cella D, Cuzick J, et al. (2004) Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial. J Clin Oncol 22:4261–4271

    Article  PubMed  CAS  Google Scholar 

  50. Cella D, Fallowfield L, Barker P, et al. (2006) Quality of life of postmenopausal women in the ATAC (“Arimidex”, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for early breast cancer. Breast Cancer Res Treat 100:273–284

    Article  PubMed  Google Scholar 

  51. Fallowfield LJ, Bliss JM, Porter LS, et al. (2006) Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 24:910–917

    Article  PubMed  CAS  Google Scholar 

  52. Whelan TJ, Goss PE, Ingle JN, et al. (2005) Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23:6931–6940

    Article  PubMed  CAS  Google Scholar 

  53. Thomas R, Williams M, Marshall C, et al. (2008) Switching to letrozole or exemestane improves hot flushes, mood and quality of life in tamoxifen intolerant women. Br J Cancer 98:1494–1499

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Breast and Endocrine Surgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Yutaka Yamamoto & Hirotaka Iwase

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  1. Yutaka Yamamoto
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  2. Hirotaka Iwase
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Correspondence to Yutaka Yamamoto.

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Yamamoto, Y., Iwase, H. Safety profiles of aromatase inhibitors and selective estrogen-receptor modulators in the treatment of early breast cancer. Int J Clin Oncol 13, 384–394 (2008). https://doi.org/10.1007/s10147-008-0828-5

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  • DOI: https://doi.org/10.1007/s10147-008-0828-5

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