Hellenic Journal of Surgery

, Volume 88, Issue 4, pp 245–251 | Cite as

Aromatase inhibitors: A comprehensive review in mechanisms of action, side effects and treatment in postmenopausal early breast cancer patients

  • Dimitrios MantasEmail author
  • J. D. Kostakis
  • C. Markopoulos
Review Article


The best adjuvant treatment for hormone receptor-positive breast cancer, especially in the postmenopausal population, is not an unexceptionable decision and depends on several and many times unequal parameters. Apart from the mechanisms of action which are more or less the same among different agents, the two major factors for consideration are the potential side effects and treatment benefits of the selected drug. The last fifteen years have clearly shown that aromatase inhibitors (AIs) are significantly more effective than tamoxifen in preventing recurrence in this group of patients, but they seem to have no beneficial effect on overall survival. The analysis and results of major controlled randomized trials are taken into consideration every time we are called upon to select the best effective adjuvant treatment for well surgically-controlled early breast cancer in a postmenopausal woman. In the present review, we attempt a comprehensive review of the recent English literature in order to unfold the potent aspects for this decision.


Aromatase inhibitors postmenopausal early breast cancer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Patani N, Martin LA. Understanding response and resistance to oestrogen deprivation in ER-positive breast cancer. Mol Cell Endocrinol 2014; 382: 683–94CrossRefPubMedGoogle Scholar
  2. 2.
    Chumsri S, Howes T, Bao T, et al. Aromatase, AIs, and breast cancer. J Steroid Biochem Mol Biol 2011; 125: 13–22CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Chen S. An “omics” approach to determine the mechanisms of acquired aromatase inhibitor resistance. OMICS 2011; 15: 347–52CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Miller WR, Larionov AA, Renshaw L, et al. Changes in breast cancer transcriptional profiles after treatment with aromatase inhibitor, letrozole. Pharmacogenet Genomics 2007; 17: 813–26CrossRefPubMedGoogle Scholar
  5. 5.
    Mackay A, Urruticoechea A, Dixon JM, et al. Molecular response to aromatase inhibitor treatment in primary breast cancer. Breast Cancer Res 2007; 9:R37CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lu Y, You M, Ghazoui Z, et al. Concordant effects of AIs on gene expression in ER+ Rat and human mammary cancers and modulation of the proteins coded by these genes. Cancer Prev Res (Phila) 2013; 6: 1151–61CrossRefGoogle Scholar
  7. 7.
    Miller WR, Larionov A, Anderson TJ, et al. Sequential changes in gene expression profiles in breast cancers during treatment with the aromatase inhibitor, letrozole. Pharmacogenomics J 2012; 12: 10–21CrossRefPubMedGoogle Scholar
  8. 8.
    Miller WR, Larionov A. Changes in expression of oestrogen regulated and proliferation genes with neo-adjuvant treatment highlight heterogeneity of clinical resistance to the aromatase inhibitor, letrozole. Breast Cancer Res 2010; 12:R52CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Iwata H, Masuda N, Ohno S, et al. A randomized, double blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer. Breast Cancer Res Treat 2013; 139: 441–51CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Takei H, Ohsumi S, Shimozuma K, et al. Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04). Breast Cancer Res Treat 2012; 133: 227–36CrossRefPubMedGoogle Scholar
  11. 11.
    Fujiwara Y, Takatsuka Y, Imoto S, et al. Outcomes of Japanese breast cancer patients treated with pre-operative and post-operative anastrozole or tamoxifen. Cancer Sci 2012; 103: 491–6CrossRefPubMedGoogle Scholar
  12. 12.
    Dixon JM, Renshaw L, Langridge C, et al. Anastrozole and letrozole: an investigation and comparison of quality of life and tolerability. Breast Cancer Res Treat 2011; 125: 741–9CrossRefPubMedGoogle Scholar
  13. 13.
    Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo inpostmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 2010; 16: 1904–14CrossRefPubMedGoogle Scholar
  14. 14.
    Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27: 5529–37CrossRefPubMedGoogle Scholar
  15. 15.
    Beck JT, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane as first-line therapy in HR+, HER2- advanced breast cancer in BOLERO-2. Breast Cancer Res Treat 2014; 143: 459–67CrossRefPubMedGoogle Scholar
  16. 16.
    Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) in breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 2013; 30: 870–84CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone on non-steroidal AIs in postmenopausal patients with hormone-receptorpositive locally advanced or metastatic breast cancer (SoFEA): a composite, multicenter, phase 3 randomized trial. Lancet Oncol 2013; 14: 989–98CrossRefPubMedGoogle Scholar
  18. 18.
    Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a non-steroidal aromatase inhibitor. J Clin Oncol 2013; 31: 2128–35CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Fallowfield LJ, Kilburn LS, Langridge C, et al. Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomization. Br J Cancer 2012; 106: 1062–7CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366: 520–9CrossRefPubMedGoogle Scholar
  21. 21.
    Bliss JM, Kilburn LS, Coleman RE, et al. Disease-related outcomes with long-term follow-up: an updated analysis of the inter-group-exemestane study. J Clin Oncol 2012; 30: 709–17CrossRefPubMedGoogle Scholar
  22. 22.
    Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011; 364: 2381–91CrossRefPubMedGoogle Scholar
  23. 23.
    van de Velde CJ, Rea D, Seynaeve C, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): A randomized phase 3 trial. Lancet 2011; 377(9762): 321–31CrossRefPubMedGoogle Scholar
  24. 24.
    Guarneri V, Generali DG, Frassoldati A, et al. Double-blind, placebo-controlled, multicenter, randomized, phase IIb neo-adjuvant study ofletrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 2014; 32: 1050–7CrossRefPubMedGoogle Scholar
  25. 25.
    Goss PE, Ingle JN, Martino S, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol 2013; 24: 355–61CrossRefPubMedGoogle Scholar
  26. 26.
    Schwartzberg LS, Franco SX, Florance A, et al. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptorpositive metastatic breast cancer. Oncologist 2010; 15: 122–9CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Johnston S, Pippen J, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538–46CrossRefPubMedGoogle Scholar
  28. 28.
    Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neo-adjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptorpositive breast cancer. J Clin Oncol 2009; 27: 2630–7CrossRefPubMedGoogle Scholar
  29. 29.
    Kidwell KM, Harte SE, Hayes DF, et al. Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy. Cancer 2014; 120: 2403–11CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Xu B, Jiang Z, Shao Z, et al. Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: results of a multicentre, double-blind, randomized phase III trial. Cancer Chemother Pharmacol 2011; 67: 223–30CrossRefPubMedGoogle Scholar
  31. 31.
    Colleoni M, Giobbie-Hurder A, et al. Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study. J Clin Oncol 2011; 29: 1117–24CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 2009; 361: 766–76CrossRefGoogle Scholar
  33. 33.
    Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012; 30: 1919–25CrossRefPubMedGoogle Scholar
  34. 34.
    Wolff AC, Lazar AA, Bondarenko I, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013; 31: 195–202CrossRefPubMedGoogle Scholar
  35. 35.
    Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBISII): an international, double-blind, randomized placebocontrolled trial. Lancet 2014; 383(9922):1041–8CrossRefPubMedGoogle Scholar
  36. 36.
    Hadji P, Blettner M, Harbeck N, et al. The Patient’s Anastrozole Compliance to Therapy (PACT) Program: a randomized, in-practice study on the impact of a standardized information program on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer. Ann Oncol 2013; 24: 1505–12CrossRefPubMedGoogle Scholar
  37. 36a.
    Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27—a randomized controlled phase III trial. J Clin Oncol 2013; 31: 1398–404CrossRefPubMedPubMedCentralGoogle Scholar
  38. 37.
    Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009; 27: 4530–5CrossRefPubMedGoogle Scholar
  39. 38.
    Bertelli G, Hall E, Ireland E, et al. Long-term endometrial effects in postmenopausal women with early breast cancer participating in the intergroup exemestane study (IES)—a randomized controlled trial of exemestane versus continued tamoxifen after 2-3 years tamoxifen. Ann Oncol 2010; 21: 498–505CrossRefPubMedGoogle Scholar
  40. 39.
    Llombart-Cussac A, Ruiz A, Antón A, Barnadas A, Antolín S, Alés-Martínez JE, et al. Exemestane versus anastrozole as front-line endocrine therapy in postmenopausal patients with hormone receptor-positive, advanced breast cancer: final results from the Spanish Breast Cancer Group 2001-03 phase 2 randomized trial. Cancer 2012; 118: 241–7CrossRefPubMedGoogle Scholar
  41. 40.
    Fontein DB, Nortier JW, Liefers GJ, et al. High non-compliance in the use of letrozole after 2.5 years of extended adjuvant endocrine therapy. Results from the IDEAL randomized trial. Eur J Surg Oncol 2012; 38: 110–7CrossRefPubMedGoogle Scholar
  42. 41.
    Markopoulos C, Polychronis A, Dafni U, et al. Lipid changes in breast cancer patients on exemestane treatment: Final results of the TEAM Greek substudy. Annals of Oncology 2009; 20: 49–55CrossRefPubMedGoogle Scholar
  43. 42.
    Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma. Suggestion for a new method of treatment, with illustrative cases. Lancet 1896; 2: 104–7Google Scholar
  44. 43.
    Fontein DB, Houtsma D, Hille ET, et al. Relationship between specific adverse events and efficacy of exemestane therapy in early postmenopausal breast cancer patients. Annals of Oncology 2012; 23: 3091–7CrossRefPubMedGoogle Scholar
  45. 44.
    Schia von G, Smith IE. Status of adjuvant endocrine therapy for breast cancer. Breast Cancer Research 2014; 16: 206CrossRefGoogle Scholar
  46. 45.
    Buzdar A, Hortobagyi G. Update on Endocrine Therapy for Breast Cancer. Clinical Cancer Research 1998; 4: 527–34PubMedGoogle Scholar
  47. 46.
    Aydiner A. Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women. The Breast 2013; 22: 121–9CrossRefPubMedGoogle Scholar
  48. 47.
    Aapro M, van de Velde CJ, Markopoulos C, et al. Should all postmenopausal patients with hormone receptor-positive breast cancer receive initial therapy with aromatase inhibitors? The Breast 2013; 22: 488–94CrossRefPubMedGoogle Scholar
  49. 48.
    Demicheli R, Bonadonna G, Hrushesky WJ, et al. Menopausal status dependence of the timing of breast cancer recurrence after surgical removal of the primary tumour. Breast Cancer Res 2004; 6:R689–96CrossRefPubMedPubMedCentralGoogle Scholar
  50. 49.
    Mansell J, Monypenny IJ, Skene AI, et al. Patterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer. Breast Cancer Res Treat 2009; 117: 91–8CrossRefPubMedGoogle Scholar
  51. 50.
    Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): A randomised controlled trial. Lancet 2007; 369(9561): 559–70CrossRefPubMedGoogle Scholar
  52. 51.
    Early breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005; 365(9472): 1687–717CrossRefGoogle Scholar
  53. 52.
    BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 2009; 361: 766–76CrossRefGoogle Scholar
  54. 53.
    Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group, Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45–53CrossRefPubMedGoogle Scholar
  55. 54.
    Coates AS, Keshaviah A, Thürlimann B, et al. 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 2007; 25: 486–92CrossRefPubMedGoogle Scholar
  56. 55.
    Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365(9453): 60–2CrossRefPubMedGoogle Scholar
  57. 56.
    Baum M, Budzar AU, Cuzick J, et al. 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. Lancet 2002; 359(9324): 2131–9CrossRefPubMedGoogle Scholar
  58. 57.
    Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–57CrossRefGoogle Scholar
  59. 58.
    Jones SE, Seynaeve C, Hasenburg A, et al. Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive postmenopausal early breast cancer. Oral presentation at San Antonio Breast Cancer Symposium (SABCS), San Antonio, Texas, USA, 10-14 December 2008Google Scholar
  60. 59.
    Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081–92CrossRefPubMedGoogle Scholar
  61. 60.
    Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in post-menopausal women with early breast cancer: NCIC CTG MA.27—a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10; 31:1398–404CrossRefPubMedPubMedCentralGoogle Scholar
  62. 61.
    van de Velde CJ, Verma S, van Nes JG, Masterman C, et al. Switching from tamoxifen to aromatase inhibitors for adjuvant endocrine therapy in postmenopausal patients with early breast cancer. Cancer Treat Rev. 2010; 36: 54–62CrossRefPubMedGoogle Scholar
  63. 62.
    Kaufmann M, Jonat W, Hilfrich J, et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol 2007; 25: 2664–70CrossRefPubMedGoogle Scholar
  64. 63.
    Boccardo F, Guglielmini P, Bordonaro R, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: long term results of the Italian Tamoxifen Anastrozole trial. Eur J Cancer. 2013 May; 49:1546–54CrossRefPubMedGoogle Scholar
  65. 64.
    Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28: 509–18CrossRefPubMedGoogle Scholar

Copyright information

© Hellenic Surgical Society and Springer-Verlag Wien 2016

Authors and Affiliations

  • Dimitrios Mantas
    • 1
    Email author
  • J. D. Kostakis
    • 1
  • C. Markopoulos
    • 1
  1. 1.Breast Unit, 2nd Propedeutic Surgical Department, Athens Medical SchoolLaiko General HospitalAthensGreece

Personalised recommendations