Table 44: Aromatase inhibitors and disease-free survival in early breast cancer

Introduction: Aromatase inhibitors lower estrogen levels in the body by blocking aromatase, an enzyme that converts other hormones into estrogen. Aromatase inhibitors are used to treat hormone-receptor positive breast cancers, either as a first hormone therapy or after treatment with tamoxifen. Unlike tamoxifen, aromatase inhibitors are used to treat postmenopausal women only.

Large randomized controlled trials have found the aromatase inhibitors letrozole (Femara), anastrozole (Arimidex) and exemestane (Aromasin) improve disease-free survival compared to placebo or the use of tamoxifen alone. A pooled analysis of 8,794 women (from five studies) found the use of aromatase inhibitors also increased overall survival compared to the use of tamoxifen alone [1]. 

Timing of aromatase inhibitor use

Whether the use of aromatase inhibitors alone improves disease-free survival compared to sequential therapy (tamoxifen followed by an aromatase inhibitor or vice versa) is still under study.  

Side effects of aromatase inhibitors versus tamoxifen 

Aromatase inhibitors have some side effects. They can cause a modest decrease in bone mineral density and increase the risk of bone fractures [2-6]. The use of aromatase inhibitors may also lead to more heart problems than the use of tamoxifen [6].

However, compared to tamoxifen, aromatase inhibitors appear less likely to lead to endometrial cancer or blood clots in the large veins [6].

Learn about the strengths and weaknesses of different types of studies.

Study selection criteria: Randomized clinical trials of aromatase inhibitors with at least 350 participants (all postmenopausal women with early breast cancer) and meta-analyses.

* Statistically significant difference between the two groups.

† ARNO 95 results were similar when examined separately with 93.5% disease-free survival among women taking aromatase inhibitor versus 89.3% among those who continued on tamoxifen.

‡ Results estimated from fewer years of median follow-up.

§ When studied by race, results showed a survival benefit among Caucasian women, but not among minority women.

║In a subgroup analysis, women who switched to letrozole after a median of 3 years after finishing tamoxifen appeared to have improved disease-free survival. However, this subgroup analysis was not randomized. These women are included in the disease-free survival rates for those who took letrozole.

¶ Some women switched from placebo to exemestane after the first study results showed a benefit with exemestane. These women are included in the disease-free survival rates for those who took placebo.
 

References  

1. Bria E, Ciccarese M, Giannarelli D, et al. Early switch with aromatase inhibitors as adjuvant hormonal therapy for postmenopausal breast cancer: pooled-analysis of 8794 patients. Cancer Treat Rev. 32(5):325-32, 2006.

2. Perez EA, Josse RG, Pritchard KI, et al. 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(22):3629-35, 2006.

3. Cuzick J, Sestak I, Baum M, et al. for the ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 11(12):1135-41, 2010.

4. Lonning PE, Geisler J, Krag LE, et al. 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(22):5126-37, 2005.

5. Rabaglio M, Sun Z, Price KN, et al. for the BIG 1-98 Collaborative and International Breast Cancer Study Groups. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. 20(9):1489-98, 2009.

6. Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 103(17):1299-309, 2011.

7. Regan MM, Neven P, Giobbie-Hurder A, et al. for the members of the BIG 1-98 Collaborative Group and the International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncol. 12(12):1101-1108, 2011.

8. Coombes RC, Kilburn LS, Snowdon CF, et al. for the Intergroup Exemestane Study (IES). Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 369(9561):559-70, 2007.

9. Jakesz R, Jonat W, Gnant M, et al. on behalf of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) and the German Adjuvant Breast Cancer Group (GABG). 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(9484):455-62, 2005.

10. 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. 25(19):2664-70, 2007.

11. Aihara T, Takatsuka Y, Ohsumi S, et al. Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study. Breast Cancer Res Treat. 121(2):379-87, 2010.

12. Boccardo F, Rubagotti A, Guglielmini P, et al. 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:vii10-vii14, 2006.

13. Ingle JN, Tu D, Pater JL, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 19(5):877-82, 2008.

14. Moy B, Tu D, Pater JL, et al. Clinical outcomes of ethnic minority women in MA.17: a trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Ann Oncol. 17(11):1637-43, 2006.

15. Goss PE, Ingle JN, Pater JL, et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 26(12):1948-55, 2008.

16. Mamounas EP, Jeong JH, Wickerham DL, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol. 26(12):1965-71, 2008.

17. 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. 28(3):509-18, 2010.

Updated 01/13/12