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Originally published as JCO Early Release 10.1200/JCO.2009.25.4326 on November 2 2009 © 2009 American Society of Clinical Oncology.
Reply to A. Sánchez-Muñoz et alUniversity Division of Medical Oncology and Hematology, Institute for Cancer Research and Treatment, Candiolo, Italy
Department Medical Oncology, National Cancer Research Institute, Genoa, Italy
University Division of Medical Oncology and Hematology, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy We thank Dr Sànchez-Muñoz and colleagues for their interest in our letter1 on aromatase inhibitors (AIs) in the adjuvant treatment of postmenopausal women with hormone receptor–positive breast cancer. Most of their concerns about AIs in this clinical setting were also expressed by Seruga and Tannock in their Comments and Controversies article,2 which was the subject of our previous submission. In fact, the large trials comparing AIs with tamoxifen do not provide, as of yet, convincing evidence of a survival benefit in favor of these compounds.3–8 Furthermore, AIs are accompanied by an increase in the rate of osteoporosis and osteoporotic fracture, myalgias and arthralgias, which is likely to impact negatively on patient tolerance and compliance with treatment. Based on these and other concerns, Dr Sànchez-Muñoz and colleagues propose that both tamoxifen and AIs, either alone or administered sequentially, are valuable therapeutic options in postmenopausal women with hormone receptor–positive early breast cancer. Treatment choices in the clinical practice should rely on factors other than differences in efficacy, where efficacy is the ability to prolong survival. Interestingly, patient preferences after adequate information on the options available are not explicitly considered among the factors influencing treatment selection. Compared with tamoxifen, AIs have been associated with consistent reductions in the rate of breast cancer–related events. Moreover, as presented in Table 1 of Dr Sànchez-Muñoz et al's letter, trends toward an improvement in overall survival favoring AIs are emerging. Should we omit this information when, in the clinical practice, we are advising a postmenopausal woman about the most appropriate endocrine treatment for her hormone receptor–positive disease? A recently presented meta-analysis showed an absolute 5-year gain in recurrence-free survival favoring AIs over tamoxifen of approximately 3% regardless of the strategy used ("upfront" or "early switch").9 Focusing on 9,015 patients enrolled in "early switch" trials, a 6-year gain in breast cancer–specific survival of 1.6% was observed in patients assigned to AIs.9 These data do confirm the superiority of AIs over tamoxifen, although we believe that the ongoing debate around the clinical relevance of these small improvements is fully justified. In contrast, we have also to consider that more than half of relapses and deaths in patients with hormone receptor–positive breast cancer occur beyond 5 years from surgery.10,11 As presented in Table 1 of Dr Sànchez-Muñoz et al's letter, follow-up of these trial ranges between 28 and 100 months, which could be considered a fragment of the natural history of this type of disease. Due to the "carryover effect" of endocrine therapy, recently confirmed in the Arimidex, Tamoxifen Alone, or in Combination trial for anastrozole with respect to recurrence-free survival,3 one should cautiously abstain from excluding that improvements or trends toward better outcomes will increase in magnitude or become significant with additional follow-up. Regarding toxicity, we insist on the fact that two most fearsome complications related to tamoxifen, thromboembolic events, and endometrial cancer, cannot be effectively prevented and their risk increases early during exposure. Conversely, osteoporosis and osteoporotic fractures can be managed with preventive or therapeutic measures. Furthermore, it is reasonable to assume that the relative increase in osteoporosis and osteoporotic fractures seen in the randomized trials comparing AIs with tamoxifen is partly magnified by the protective effects that tamoxifen has on bone health. Indeed, one double blind, randomized trial showed just a modestly enhanced bone loss from the femoral neck and no influence on lumbar bone loss in postmenopausal patients receiving exemestane compared with those assigned to placebo for 2 years.12 Interestingly, the mean annual rate of bone mineral density loss in the spine and in the femoral neck in patients receiving placebo was higher than expected. Therefore, we believe that osteoporosis should be looked at as a general health care problem affecting postmenopausal women and patients with breast cancer as well, rather than a specific complication of treatment with AIs. For all these reasons, although we respect Dr Sànchez-Muñoz et al's opinion, we would like to defend our statement that "... aromatase inhibitors are superior (to tamoxifen) and not necessarily more toxic." At the same time, in partial agreement with both Drs Seruga and Sànchez-Muñoz et al, we believe that tamoxifen can still have a role in the adjuvant treatment of these patients provided that, in the near future, we establish accurate predictors of efficacy that can help in decision making. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Montemurro F, Aglietta M, Del Mastro L: Aromatase inhibitors as adjuvant therapy for breast cancer. J Clin Oncol 27:2566–2567, 2009. 2. 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. 3. 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] 4. 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. 5. 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. 6. 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] 7. 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] 8. 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] 9. Ingle JN, Dowsett M, Cuzick J, et al: Aromatase inhibitors versus tamoxifen as adjuvant therapy for postmenopausal women with estrogen receptor positive breast cancer: Meta-analyses of randomized trials of monotherapyand switching strategies. Cancer Res 69:66s; 2009 (suppl 2) abstr 12. 10. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738–2746, 1996. 11. Kennecke HF, Olivotto IA, Speers C, et al: Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen. Ann Oncol 18:45–51, 2007. 12. 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 23:5126–5137, 2005.
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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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