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Originally published as JCO Early Release 10.1200/JCO.2009.22.2695 on March 30 2009 © 2009 American Society of Clinical Oncology.
Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer
University Division of Medical Oncology and Hematology, Institute for Cancer Research and Treatment, Torino, Italy To the Editor: We have read with interest the article by Seruga and Tannock,1 who critically analyzed the role of aromatase inhibitors as up-front drugs in the adjuvant treatment of postmenopausal hormone receptor–positive breast cancer. Although we basically agree with the line of reasoning of the two respected authors, we feel that some of their conclusions need to be taken with caution. The five most influential trials comparing 5 years of tamoxifen with aromatase inhibitors either up front or administered sequentially after tamoxifen (early switch) confirm that aromatase inhibitors can control cancer regrowth after surgery better than tamoxifen does.2–6 At the present time, however, this superiority has not yet translated into convincing survival benefits. A significant survival advantage is in fact confirmed only in clinical trials using the early switch strategy.7 According to the authors' introductory statements, this would call for adoption of aromatase inhibitors after 2 to 3 years of tamoxifen as a standard of care, an issue that does not emerge clearly from the article. Indeed, the 100-month follow-up analysis of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial comparing 5 years of anastrozole with 5 years of tamoxifen failed to show a survival advantage in favor of anastrozole.2,3 We strongly agree that the 1% excess in deaths without tumor progression observed in the anastrozole arm needs to be looked at carefully, although no precise patterns have emerged that can relate those deaths with treatment. However, a recent update of the Breast International Group (BIG) 1-98 study at 76 months of median follow-up did show a strong trend toward better overall survival in patients receiving letrozole as compared with tamoxifen (HR, 0.87; 95% CI, 0.75 to 1.02).8 This trend became significant when the analysis was censored for patients crossing over from tamoxifen to letrozole at the time of study unblinding. The authors claim that "the goals of therapy for any stage or type of cancer are to improve the duration and/or the quality of survival" and that "investigators supporting the use of aromatase inhibitors instead of tamoxifen must prove that such new treatment is more effective in one or both of these key end points." By applying the results of the updated analysis of the BIG 1-98 trial, the use of letrozole instead of tamoxifen could have spared deaths in nearly 40 out of 2,459 (1.6%) women treated with tamoxifen. With regard to quality of life, it is important to underline that avoiding a recurrence in nearly 3% of patients treated with aromatase inhibitors instead of tamoxifen means also to avoid the distressing situation of cancer relapse, which severely compromises quality of life.9 Published studies allow readers as well as health care providers to make calculations and draw conclusions on cancer-related events that actually happened during the study. When the study is published, one looks back and may conclude that the avoidance of a few local or distant relapses or deaths by using a more active drug could be just a marginal achievement, especially if treatment-related costs increase considerably. However, medical oncologists in their current clinical practice are faced with patients who are at risk for those events and whose wishes are to receive the treatment that reduce such risk the most, be it local relapse or the appearance of distant metastases.10 We therefore argue that, at least conceptually, the statement that "an initial delay to relapse for women receiving up-front anastrozole might be balanced by longer survival after relapse for those who receive tamoxifen" can be accepted. For example, for two thirds of patients, survival after relapse will translate into coping with metastatic disease, chronic treatments, and death as the result of progressive disease. The introduction of aromatase inhibitors in the setting of patients with operable breast cancer has determined an obvious focus on new class-specific adverse effects and concerns about the lack of long-term safety data. Effects like joint disorders are frequent and often related to premature treatment discontinuation.11,12 However, we would like to comment on two points. First, compliance with oral therapy is the real problem health care systems need to focus on, not just compliance with aromatase inhibitors or tamoxifen.13,14 Second, if serious adverse effects are of concern, the only way to avoid the risk is to avoid the exposure, unless there are effective preventive measures. The risk of tamoxifen-related thromboembolic events peaks early during treatment.15,16 The incidence of endometrial cancer doubles after just 1 year of treatment with tamoxifen.17 On the other hand, the risk of osteoporotic fractures increases sharply during the initial year of exposure to aromatase inhibitors, and then tends to remain to constant during treatment.18,19 Therefore switching drugs means, of course, shorter exposure to both drugs and lower overall occurrences of undesirable effects. However, for a woman who is to begin adjuvant therapy, it also means being exposed to the potential harms of both classes of drugs. There is no primary prevention measure of the most serious adverse events related to tamoxifen. Attempts at screening patients with transvaginal ultrasonography have resulted in an increase in invasive diagnostic procedures and complications.20,21 Furthermore, as the ATAC trialists reported, women taking tamoxifen were frequently submitted to unnecessary gynaecologic surgery.22 In contrast, the acceleration of the physiologic phenomenon of bone loss from the use of aromatase inhibitors can respond to primary prevention measures that range, according to severity, from lifestyle changes to pharmacologic treatment. We must remember that these measures are relevant in the general population of postmenopausal women, not just in cancer patients.23 In summary, the available studies point to the fact that tamoxifen is still a good endocrine therapy for the adjuvant treatment of postmenopausal hormone receptor–positive early breast cancer, but aromatase inhibitors are superior in terms of antitumor activity and are not necessarily more toxic. The size of the benefit may vary considerably according to the individual risk of relapse, and this may translate for some patients into a disproportionate use of the available resources compared with what can be achieved in terms of better outcome. It is therefore of the utmost importance to identify accurate predictors of efficacy that can guide treatment choices. In this respect, we agree that for specific subsets of postmenopausal patients, tamoxifen will still represent the adjuvant endocrine therapy of choice. However, while waiting for the promises of personalized medicine to become reality, we shall not agree that "up-front aromatase inhibitors can be recommended only in women who have contraindications to the use of tamoxifen." AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Seruga B, Tannock IF: Up-front use of aromatase inhibitors as adjuvant therapy for breast cancer: The emperor has no clothes. J Clin Oncol 27:840–842, 2009. 2. 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 9:45–53, 2008.[CrossRef][Medline] 3. Coates AS, Keshaviah A, Thurlimann 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 25:486–492, 2007. 4. 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 Trial. J Clin Oncol 23:5138–5147, 2005. 5. 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 369:559–570, 2007.[CrossRef][Medline] 6. 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 366:455–462, 2005.[CrossRef][Medline] 7. Jonat W, Gnant M, Boccardo F, et al: Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: A meta-analysis. Lancet Oncol 7:991–996, 2006.[CrossRef][Medline] 8. Mouridsen HT, Giobbie-Hurder A, Mauriac L, et al: BIG 1-98: a randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Cancer Res 69:66s; 2009 (suppl 2) abstr 13. 9. Northouse LL, Mood D, Kershaw T, et al: Quality of life of women with recurrent breast cancer and their family members. J Clin Oncol 20:4050–4064, 2002. 10. Ravdin PM, Siminoff IA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16:515–521, 1998.[Abstract] 11. Fontaine C, Meulemans A, Huizing M, et al: Tolerance of adjuvant letrozole outside of clinical trials. Breast 17:376–381, 2008.[CrossRef][Medline] 12. Crew KD, Greenlee H, Capodice J, et al: Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25:3877–3883, 2007. 13. Evans L, Spelman M: The problem of non-compliance with drug therapy. Drugs 25:63–76, 1983.[Medline] 14. Kruse W, Rampmaier J, Ullrich G, et al: Patterns of drug compliance with medications to be taken once and twice daily assessed by continuous electronic monitoring in primary care. Int J Clin Pharmacol Ther 32:452–457, 1994.[Medline] 15. Abramson N, Costantino JP, Garber JE, et al: Effect of factor V Leiden and prothrombin G20210–>A mutations on thromboembolic risk in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention trial. J Natl Cancer Inst 98:904–910, 2006. 16. Cuzick J, Wale C: A detailed analysis of the benefits of anastrozole over tamoxifen for venous thromboembolic events (VTEs) after 5 years treatment. Breast Cancer Res Treat 100:S24; 2006 (suppl 1) abstr 104. 17. Tamoxifen for early breast cancer. An overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451–1467, 1998.[CrossRef][Medline] 18. Buzdar A, Howell A, Cuzick J, et al: Comprehensive side-effect 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, 2006.[CrossRef][Medline] 19. Coleman RE, Banks LM, Girgis SI, et al: 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, 2007.[CrossRef][Medline] 20. Love CD, Muir BB, Scrimgeour JB, et al: Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 17:2050–2054, 1999. 21. Gerber B, Krause A, Muller H, et al: Effects of adjuvant tamoxifen on the endometrium in postmenopausal women with breast cancer: A prospective long-term study using transvaginal ultrasound. J Clin Oncol 18:3464–3470, 2000. 22. Duffy SR, Distler W, Howell A, et al: A lower incidence of gynecologic adverse events and interventions with anastrozole than with tamoxifen in the ATAC trial. Am J Obstet Gynecol 200:80–87, 2009.[Medline] 23. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause 13:340–367, 2006.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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