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Published on 1 November 2006

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AIs after tamoxifen for postmenopausal breast cancer


Mariangela Ciccarese

Emilio Bria
Department of Medical Oncology
Regina Elena National Cancer Institute

The meta-analysis carried out by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) demonstrated that annual breast cancer death rate was reduced by 31% after five years of adjuvant tamoxifen in women with oestrogen (ER)-positive early breast cancer.(1) Tamoxifen had been considered the standard first-line endocrine therapy for postmenopausal patients with metastatic breast carcinoma until the publication of a phase III trial using aromatase inhibitors (AIs). Some trials performed in the past years have assessed the superiority of AIs over tamoxifen as first hormonal treatment for patients with known hormone ­receptor-positive metastatic breast cancer. In addition, these results generated new questions about the best hormonal strategy in the adjuvant setting. AIs are compared with tamoxifen as “upfront” treatment (ie, just after surgery) for a planned five years,(2,3) or after five years (“extended switch”)(4) or two to three years (“early switch”) of tamoxifen. In order to quantify the benefits of AIs in event-free and overall survival after two to three years of tamoxifen, we performed a meta-analysis based on published data. The comprehensive analysis was conducted following four steps:

  • Definition of outcomes.
  • Definition of the criteria applied for the selection of eligible trials.
  • Definition of the search strategy.
  • Description of the used statistical method.(5,6)

We considered the sequence tamoxifen/AIs as experimental and the tamoxifen arm as standard comparator. Primary outcome for benefit analysis was event-free survival (EFS), defined as the time (expressed in months) between randomisation and appearance of relapse (local or distant, or both) or secondary breast cancer appearance or death not related to breast cancer. Secondary endpoints were:

  • Overall survival (OS), defined as the time expressed in months between randomisation and death (from any cause).
  • Survival excluding death due to disease progression.
  • Contralateral breast cancer risk.
  • Incidence of neoplasm other than breast cancer.
  • Toxicity.

We gathered all phase III prospective and randomised trials published as formal papers in peer-reviewed journals or presented at the American Society of Clinical Oncology (ASCO), European Cancer Conference (ECCO), European Society for Medical Oncology (ESMO) or San Antonio Breast Cancer Symposium (SABCS) until October 2005. The log of relative risk ratio (RR) was estimated for each considered endpoint, and 95% confidence intervals (CIs) were derived.(7) Absolute benefits for each outcome were calculated (ie, absolute benefit = exp {HR × log[control survival]} – control survival).(8) The number of patients needed to treat for one single beneficial patient was determined (NNT: 1/[(absolute benefit)/100]).

Five trials (n=8,794) were selected,(9–12) designed to assess whether AIs (anastrozole in three trials and aminoglutetimide and exemestane in another) for two to three years improved EFS after two to three years of tamoxifen. Although patients’ pretreatment ­characteristics were different, almost all results showed a positive, homogenous trend in favour of sequential tamoxifen/AIs. The risk of any event was reduced by 23% when administering AIs after tamoxifen, providing an absolute risk reduction of 3.8% (see Table 1). The most intriguing result was the increase in OS, which translated into an absolute benefit of 1.2%. Our analysis represents one of the early experiences of meta-analysis in adjuvant hormonal treatment for postmenopausal patients with AIs. The most important new result is the OS gain (absolute reduction of 1.2% at five years); this actually translates into more than 100 patients cured by such treatment.


Moreover, the early-switch approach decreases the incidence of contralateral breast cancer when using third-generation AIs (ie, anastrozole and exemestane). Significant toxicity outcomes are the important reduction (60% risk decrease) in endometrial carcinoma associated with AIs and the reduction of bone fractures (50% risk decrease) with tamoxifen. This latest result confirms findings from recent studies suggesting a protective effect on bone in postmenopausal patients linked to tamoxifen.(13)

“Early-switch” strategy in the adjuvant treatment of hormone receptor-positive breast cancer improves EFS and OS, with a reduction of endometrial carcinoma with AIs and a reduction of bone fractures with tamoxifen.


  1. 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 randomised trials.Lancet 2005;365:1687-717.
  2. The ATAC Trialists’ Group.Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’adjuvant treatment for breast cancer.Lancet 2005;365: 60-2.
  3. Thurlimann B, Keshaviah A,Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005:353:2747-57.
  4. Goss PE, Ingle JN, Martino S, 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;349:1793-802.
  5. Pignon JP, Hill C. Meta-analyses of randomized clinical trials in oncology. Lancet Oncol 2001;2:475-82.
  6. Bria E, Giannarelli D, Felici A, et al. Taxanes with anthracyclines as first line chemotherapy for metastatic breast cancer: pooled analysis of 2805 patients. Cancer 2005;10:672-9.
  7. Douglas-Case L, Kimmick G,Paskett ED, et al. Interpreting measures of treatment effect in cancer clinical trials. Oncologist 2002;7:181-7.
  8. Parmar MKB, Machin D. Survival analysis: a practical approach. Chichester: John Wiley; 1995.
  9. Boccardo F, Rubagotti A, Amoroso D, et al. Sequential tamoxifen and aminoglutetimide versus tamoxifen alone in the adjuvant treatment of ­postmenopausal breast cancer patients: results of an Italian Cooperative Study. J Clin Oncol 2001;19: 4209-15.
  10. Coombes RC, Hall E, Gibson LJ,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;350:1081-92.
  11. Boccardo F, Rubagotti A,Puntoni M, et al. Switching to anastrozole versus continued ­tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole (ITA) trial.J Clin Oncol 2005;23:1-10.
  12. Jakesz R, Jonat W, Gnant M, et al. 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 2005;366:455-62.
  13. Goss PE, Ingle JN, Martino S, 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;349:179-802.

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