Advertisement

The role of aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women

      Abstract

      For endocrine therapy of hormone-sensitive advanced breast cancer in postmenopausal women, the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are effective both as alternatives to tamoxifen in first-line treatment and following first-line tamoxifen failure. These three agents are currently being evaluated as adjuvant therapy of early breast cancer, again relative to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy); sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy); or following 5 years of tamoxifen (extended adjuvant therapy). Results of the first early adjuvant trial (Arimidex®, Tamoxifen Alone or in Combination [ATAC]) demonstrated that anastrozole was significantly more effective than tamoxifen in reducing the risk of disease recurrence. Two trials sequencing 2–3 years of an aromatase inhibitor after 2–3 years of tamoxifen have also reported results. A large trial (International Collaborative Cancer Group [ICCG] trial 96) found switching to exemestane to be significantly superior to continuing on tamoxifen in disease-free survival, and in a small study (Italian Tamoxifen Arimidex [ITA] trial), similarly sequencing anastrozole after tamoxifen significantly reduced the hazard of recurrence compared with remaining on tamoxifen. Extended adjuvant therapy with 5 years of letrozole versus placebo following 5 years of tamoxifen was evaluated in the MA.17 trial. Compared with placebo, letrozole resulted in a significant improvement in disease-free survival that was irrespective of whether patients had lymph node-positive or -negative tumours. Results of these four trials emphasise the important role of aromatase inhibitors in the adjuvant setting, yet the optimal approach still needs to be defined. A number of trials further evaluating the three adjuvant treatment strategies are ongoing.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Dowsett M.
        Rationale for the endocrine treatment of breast cancer.
        in: Dowsett M. Endocrine aspects of breast cancer. Parthenon, Camforth, England1992: 11-24
        • Clemons M.
        • Goss P.
        Estrogen and the risk of breast cancer.
        N Engl J Med. 2001; 344: 276-285
        • Miller W.R.
        Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer.
        Semin Oncol. 2003; 30: 3-11
      1. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998, 351, 1451–1467

        • Fisher B.
        • Costantino J.
        • Redmond C.
        • Poisson R.
        • Bowman D.
        • Couture J.
        • et al.
        A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen receptor-positive tumors.
        N Engl J Med. 1989; 320: 479-484
        • Santen R.J.
        • Harvey H.A.
        Use of aromatase inhibitors in breast carcinoma.
        Endocrine-Relat Cancer. 1999; : 75-92
        • Stein R.C.
        • Dowsett M.
        • Hedley A.
        • Gazet J.-.C.
        • Ford H.T.
        • Coombes R.C.
        The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer.
        Br J Cancer. 1990; 62: 679-683
        • Geisler J.
        • Haynes B.
        • Anker G.
        • Dowsett M.
        • Lønning P.E.
        Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study.
        J Clin Oncol. 2002; 20: 751-757
        • Dombernowsky P.
        • Smith I.
        • Falkson G.
        • et al.
        Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.
        J Clin Oncol. 1998; 16: 453-461
        • Gershanovich M.
        • Chaudri H.A.
        • Campos D.
        • et al.
        Letrozole, a new oral aromatase inhibitor: randomized trial comparing 2.5 mg daily, 0.5 mg daily, and aminoglutethimide in postmenopausal women with advanced breast cancer.
        Ann Oncol. 1998; 9: 639-645
        • Buzdar A.
        • Jonat W.
        • Howell A.
        • et al.
        Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials.
        Cancer. 1998; 83: 1142-1152
        • Kaufmann M.
        • Bajetta E.
        • Dirix L.Y.
        • et al.
        Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial.
        J Clin Oncol. 2000; 18: 1399-1411
        • Rose C.
        • Vtoraya O.
        • Pluzanska A.
        • et al.
        An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole.
        Eur J Cancer. 2003; 39: 2318-2327
        • Bonneterre J.
        • Buzdar A.
        • Nabholtz J.M.
        • Robertson J.F.R.
        • Thürlimann B.
        • von Euler M.
        • et al.
        Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma: results of two randomized trials designed for combined analysis.
        Cancer. 2001; 92: 2247-2258
        • Mouridsen H.
        • Gershanovich M.
        • Sun Y.
        • et al.
        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.
        J Clin Oncol. 2001; 19: 2596-2606
      2. Mouridsen H, Gershanovich M, Sun Y, R P-C, Boni C, Monnier A, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003, 21, 2101–2109

        • Paridaens R.
        • Dirix L.
        • Lohrisch C.
        • et al.
        Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer.
        Ann Oncol. 2003; 14: 1391-1398
        • Paridaens R.
        • Therasse P.
        • Dirix L.
        • Beex L.
        • Picvcart M.J.
        • Cameron D.
        • et al.
        First results of a randomized phase III trial comparing exemestane versus tamoxifen as first-line hormone therapy (HT) for postmenopausal women with metastatic breast cancer (MBC) – EORTC 10951 in collaboration with Exemestane Working Group and NCIC.
        Eur J Cancer Suppl. 2004; 2 ([abstract 241]): 126
        • Paridaens R.
        • Therasse P.
        • Dirix L.
        • Beex L.
        • Piccart M.
        • Cameron D.
        • et al.
        First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) – a randomized phase III trial of the EORTC Breast Group [abstract 515].
        Proc Am Soc Clin Oncol. 2004; 23: 6
        • Wong Z.-.W.
        • Ellis M.J.
        First-line endocrine treatment of breast cancer: aromatase inhibitor or antiestrogen?.
        Br J Cancer. 2004; 90: 20-25
        • Buzdar A.U.
        Anastrozole (ArimidexTM) – an aromatase inhibitor for the adjuvant setting?.
        Br J Cancer. 2001; 85: 6-10
        • Goss P.E.
        Emerging role of aromatase inhibitors in the adjuvant setting.
        Am J Clin Oncol (CCT). 2003; 26: S27-S33
        • Goss P.E.
        • Strasser K.
        Aromatase inhibitors in the treatment and prevention of breast cancer.
        J Clin Oncol. 2001; 19: 881-894
        • Fisher B.
        • Dignam J.
        • Bryant J.
        • Wolmark N.
        Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B 14 randomized trial.
        J Natl Cancer Inst. 2001; 93: 684-690
        • Goss P.E.
        Preliminary data from ongoing adjuvant aromatase inhibitor trials.
        Clin Cancer Res. 2001; 7: 4397s-4401s
        • Ingle J.N.
        Adjuvant endocrine therapy in postmenopausal breast cancer.
        Clin Cancer Res. 2003; 9: 480s-485s
        • Mauriac L.
        • Smith I.
        Aromatase inhibitors in early breast cancer treatment.
        Semin Oncol. 2003; 30: 46-57
      3. The ATAC (Arimidex tamoxifen alone or in combination) Trialists’ Group. 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, 2131–2139

      4. The ATAC (Arimidex tamoxifen alone or in combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, tamoxifen alone or in combination) trial efficacy and safety update analyses. Cancer 2003, 98, 1802–1810

        • Tobias J.S.
        Anastrozole maintains a beneficial efficacy and side effect profile: updated results from the ATAC (‘Arimidex’, Tamoxifen, alone or in combination) trial.
        Eur J Cancer Suppl. 2003; 1 ([abstract O-34]): 11
        • Dowsett M.
        Analysis of time to recurrence in the ATAC (arimidex, tamoxifen, alone or in combination) trial according to estrogen receptor and progesterone receptor status.
        Breast Cancer Res Treat. 2003; 82 ([abstract 4]): S7
        • Howell A.
        Effect of anastrozole on bone mineral density: 2-year results of the ’arimidex’ (anastrozole), tamoxifen, alone or in combination (ATAC) trial.
        Breast Cancer Res Treat. 2003; 82 ([abstract 129]): S27
      5. Thürlimann B, Mauriac L, Mouridsen H. Phase III randomized study of adjuvant letrozole versus tamoxifen in postmenopausal women with operable, hormone receptor-positive breast cancer. Protocol IBCSG-1-98. <www.cancer.gov/clinicaltrials>; 2004 [accessed 14.01.04]

      6. Rea D. Phase III randomized study of adjuvant exemestane versus adjuvant tamoxifen in postmenopausal women with early breast cancer. Protocol CRC-TU-TEAM. <www.cancer.gov/clinicaltrials>; 2004 [accessed 14.01.04]

        • Markopoulos C.
        • Polychronis A.
        • Farfarelos C.
        • et al.
        The effect of exemestane (Aromasin®) on the lipidemic profile of breast cancer patients: preliminary results of the TEAM trial Greek sub-study.
        Breast Cancer Res Treat. 2003; 82 ([abstract 440]): S105
        • Sawada S.
        • Sato K.
        Effect of anastrozole and tamoxifen on serum lipid levels in Japanese postmenopausal women with early breast cancer.
        Breast Cancer Res Treat. 2003; 82 ([abstract 143]): S31-S32
        • Coombes R.C.
        • Hall E.
        • Gibson L.J.
        • 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: 1081-1092
        • Goss P.E.
        • Qi S.
        • Josse R.G.
        • Pritzker K.P.H.
        • Mendes M.
        • Hu H.
        • et al.
        The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats.
        Bone. 2004; 34: 384-392
        • Lønning P.E.
        • Geisler J.
        • Krag L.E.
        • Ottestad L.
        • Bremnes Y.
        • Hagen A.I.
        • et al.
        Effect of exemestane on bone: a randomized placebo controlled study in postmenopausal women with early breast cancer at low risk.
        Proc Am Soc Clin Oncol. 2004; 23 ([abstract 518]): 6
        • Boccardo F.
        • Rubagotti A.
        • Amoroso D.
        • et al.
        Tamoxifen (TMX) followed by an aromatase inhibitor (AI) in early breast cancer. A pooled analysis of two consecutive trials.
        Eur J Cancer Suppl. 2003; 1 ([abstract O-37]): 12
        • Boccardo F.
        • Rubagotti A.
        • Amorosa D.
        • et al.
        Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment [abstract 3].
        Breast Cancer Res Treat. 2003; 82 (and oral presentation at Twenty-Sixth Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3, 2003): S6-S7
        • Goss P.E.
        • Ingle J.N.
        • Martino S.
        • Robert N.J.
        • Muss H.B.
        • Piccart M.J.
        • et al.
        A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.
        N Engl J Med. 2003; 349: 1793-1802
        • Whelan T.
        • Goss P.
        • Ingle J.
        • Pater J.
        • Shepherd L.
        • Palmer M.
        • et al.
        Assessment of quality of life (QOL) in MA.17, a randomized placebo-controlled trial of letrozole in postmenopausal women following five years of tamoxifen [abstract 517].
        Proc Am Soc Clin Oncol. 2004; 23: 6
      7. Goss PE. NCIC CTG MA.17-final analysis of updated data – a placebo-controlled trial of letrozole following tamoxifen as adjuvant therapy in postmenopausal women with early stage breast cancer. In: Oral presentation at the Fortieth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 7, 2004. <www.asco.org>; 2004 [accessed 11.06.04]

        • Mamounas E.P.
        Adjuvant exemestane therapy after 5 years of tamoxifen: rationale for the NSABP B-33 trial.
        Oncology (Huntingt). 2001; 15: 35-39
      8. Mamounas T. Phase III randomized study of exemestane in postmenopausal women with resected stage I, II, or IIIA breast cancer who have completed five years of tamoxifen. Protocol NSABP-B-33. <www.cancer.gov/clinicaltrials>; 2004 [accessed 14.01.04]

        • Smith I.E.
        • Dowsett M.
        Aromatase inhibitors in breast cancer.
        N Engl J Med. 2003; 348: 2431-2442
        • Winer E.P.
        • Hudis C.
        • Burstein H.J.
        • Bryant J.
        • Chlebowski R.T.
        • Ingle J.N.
        • et al.
        American Society of Clinical Oncology Technology Assessment Working Group update: use of aromatase inhibitors in the adjuvant setting.
        J Clin Oncol. 2003; 21: 2597-2599
        • Goldhirsch A.
        • Wood W.C.
        • Gelber R.D.
        • Coates A.S.
        • Thürlimann B.
        • Senn H.-.J.
        Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer.
        J Clin Oncol. 2003; 21: 3357-3365
      9. Goss PE. NCIC CTG MA.17-final analysis of updated data – a placebo-controlled trial of letrozole following tamoxifen as adjuvant therapy in postmenopausal women with early stage breast cancer. <http://www.ctg.queensu.ca/public/asco/ma17-asco-2004.pdf>; 2004 [accessed 24.09.04]