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Originally published as JCO Early Release 10.1200/JCO.2008.19.5594 on January 12 2009 © 2009 American Society of Clinical Oncology.
Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No ClothesDivision of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada
In 2004, an American Society of Clinical Oncology (ASCO) technology assessment on adjuvant use of aromatase inhibitors (AIs) was updated to indicate that optimal adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer should include an AI, either as up-front therapy or as sequential therapy after tamoxifen.1 This recommendation was on the basis of improved disease-free survival (DFS) observed with AIs, given that no trial at that time had demonstrated improvement in overall survival. This recommendation and the publicity relating to trials such as the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have had substantial impact worldwide on the endocrine treatment of early breast cancer.2 On the basis of the recent published update of the ATAC trial with a median 8 or more years of follow-up, and the report at the San Antonio Breast Cancer Meeting in December 2007, advertisements proclaim that the long-term data demonstrate continuing effectiveness for anastrozole over tamoxifen through treatment completion and beyond (for example, see the advertisement in the March 10, 2008 issue of this journal; Vol 26, No. 8). The goals of therapy for any stage or type of cancer are to improve the duration and/or quality of survival. If we are to switch from an inexpensive and well-established treatment such as tamoxifen to a more expensive and newer alternative (an AI), then the onus of the companies and investigators supporting that switch must be to prove that the new treatment is more effective in one or both of those key end points. The ATAC study is a large and well-designed trial that compares up-front therapy using anastrozole with that using tamoxifen for 5 years in postmenopausal women with hormone-sensitive early breast cancer. Results of the trial continue to show a significant improvement in DFS in favor of anastrozole (hazard ratio [HR] = 0.85), but they do not show improved overall survival (HR = 1.0).4 A related study, Breast International Group 1-98 (BIG 1-98), which is comparing up-front letrozole therapy with up-front tamoxifen therapy for 5 years, also shows improved DFS in favor of letrozole (HR = 0.82), but differences in overall survival are not significant after a relatively short median follow-up of 51 months (HR = 0.91).5 There are several reasons why improvement in DFS may not translate into improved overall survival for women participating in trials of adjuvant therapy for breast cancer. First, the definition of DFS varies among trials evaluating AIs,6 but these studies included local recurrence and new primary breast cancer (including preinvasive disease in the ATAC but not the BIG 1-98 trial), which have a minimal effect on overall survival. Second, an initial delay to relapse for women receiving up-front anastrozole might be balanced by longer survival after relapse for those who receive tamoxifen. Third, an improvement in cancer-specific survival might be counterbalanced by an increase in deaths as a result of other causes; indeed, there is a trend for such an effect in the ATAC trial, given that the 8-year results show a nonsignificant reduction in deaths after recurrence for the anastrozole arm counterbalanced by an increase in deaths without recurrence. Time-trends in the three publications reporting outcomes from the ATAC trial at median follow-up of 33, 68, and 100 months4,7,8 show an increasing excess in noncancer deaths for women receiving anastrozole as compared with tamoxifen, whereas the deficit in deaths after cancer recurrence for women receiving anastrozole has remained constant in the last two reports (Table 1); this raises concerns about the long-term serious toxicity of anastrozole.
There is strong evidence that DFS is a good surrogate for overall survival in trials of adjuvant therapy for colorectal cancer,9 but support for surrogacy of DFS in adjuvant trials for breast cancer is less solid.10 In some trials, an early large improvement in DFS has translated into a smaller later improvement in overall survival; however, smaller differences in DFS at short follow-up, as observed in trials comparing different endocrine therapies, may not be associated with subsequent differences in overall survival. If overall survival is similar after adjuvant treatment with an AI or tamoxifen, up-front use of an AI might be preferred if it is better tolerated than tamoxifen and leads to better quality of life. Some would argue that quality of life will be better if there is a delay of recurrence of breast cancer, but that depends on the toxicity of treatment. The ATAC investigators have published specific analyses of quality of life and of adverse effects of treatment.11,12 They evaluated quality of life using the Functional Assessment of Cancer Treatment–Breast (FACT-B) and its endocrine subscale, and reported no overall differences between the arms of the study.11 The abstract of their article describing adverse effects indicates that treatment-related adverse effects occurred significantly less often with anastrozole than with tamoxifen, as did treatment-related serious adverse events and adverse events leading to withdrawal.12 However, these statements seem inconsistent with data provided in the article. For example, there were 340 fractures reported in patients receiving anastrozole (as compared with 237 for those receiving tamoxifen (P < .0001), yet the overall incidence of treatment-related serious adverse effects was reported as only 146 for anastrozole versus 277 for tamoxifen (P < .0001). Moreover, the only mention of arthralgias is a statement that few patients withdrew because of them (13 v six patients). This is not the experience of physicians managing patients outside of a clinical trial, where arthralgias and/or bone pain have been reported by 45% to 60% of patients, and despite use of anti-inflammatory medication, led to cessation of therapy in approximately 20% of women.13–15 In the ATAC trial (as opposed to BIG 1-98), there was no checklist of questions regarding toxicity, but there was instead a nonspecific request for physicians to report adverse events. By contrast, in the BIG 1-98 study there was such a checklist, and 20% and 13.5% of women reported arthralgias while receiving letrozole and tamoxifen, respectively (P < .01).5 As aptly stated by Coates et al16 in a comment on the most recent ATAC publication,4 "If you do not look, you do not find." Noncompliance with treatment may occur without withdrawal from a study, and there is evidence that adherence to endocrine therapy in women with breast cancer is quite poor. In a study of women receiving adjuvant treatment, nonadherence to tamoxifen (defined as taking the drug on fewer than 80% of days for which it was prescribed) increased from 17% in the first year to 50% in the fourth year,17 and in another study, nonadherence (defined as 180 consecutive days without taking tamoxifen) increased from 22% in the first year to 35% after 3.5 years.18 In a study of 12,000 women who initiated anastrozole, similar or even worse trends for adherence to the drug were observed;19 the annual rate of nonadherence (defined as taking anastrozole on fewer than 80% of days for which it was prescribed) increased from 22% to 31% in the first year to 32% to 50% in the third year in data sets from three health programs. Emerging data indicate that the occurrence of hot flashes in women receiving adjuvant tamoxifen may be correlated with a reduced risk of breast cancer,20,21 and a similar analysis from the ATAC trial suggested that women who had hot flashes had significantly lower recurrence rates (regardless of treatment).22 Nonadherence to the drugs might be an explanation for lack of hot flashes in some women, leading to a higher chance of recurrence. Although there is no evidence for superiority of AIs over tamoxifen when used as initial treatment, they remain useful drugs for the adjuvant therapy of breast cancer. They provide an alternative for women at high risk of toxicity from tamoxifen, such as those with a history of thromboembolic disease. Some trials have investigated switching to an AI after initial tamoxifen, and a meta-analysis of the trials suggests an advantage in overall survival from the time of switching compared with continued tamoxifen;23,24 this strategy allows shorter exposure to the specific toxicities of tamoxifen and AIs. The MA.17 trial demonstrated that extended treatment with letrozole beyond 5 years of tamoxifen decreased the rate of relapse,25 but it is not known if this strategy of prolonged treatment improves survival when compared with earlier switching. It has been suggested that evaluation of CYP2D6 genotype might be used to select patients who are poor metabolizers of tamoxifen and unlikely to respond to it.26 Whereas genetic polymorphism of CYP2D6 has been shown to influence the metabolism of tamoxifen,27,28 results from retrospective clinical studies evaluating the effect of these polymorphisms on outcome of breast cancer in women who receive adjuvant tamoxifen are conflicting.29 In summary, recent evidence from clinical trials does not support the routine initial use of up-front AIs as adjuvant therapy. Recommendations for their use have been made on the basis of improvement in DFS despite evidence that it is an imperfect surrogate for overall survival, including evidence from serial reports of the ATAC trial (Table 1) and with no evidence of better tolerance or quality of life. Furthermore, several studies suggesting cost-benefit of up-front anastrozole compared with tamoxifen30–32 based their conclusions on the expectation that DFS would translate into improved survival, and at 8 or more years of follow-up, that has not occurred. If AIs do not improve survival when compared with tamoxifen, their added cost per life-year gained is infinite, and they are cost-ineffective. Despite the lack of supportive evidence, it is surprising how dramatically patterns of clinical practice have changed to endorse the up-front use of AIs.2 Future results from the BIG 1-98 clinical trial may or may not demonstrate benefit in overall survival for the up-front use of letrozole in comparison to tamoxifen alone or to the switching strategy, but on the basis of current data, up-front use of an AI can be recommended only in women who have contraindications to the use of tamoxifen.
The author(s) indicated no potential conflicts of interest.
Conception and design: Bostjan Seruga, Ian Tannock Financial support: Ian Tannock Administrative support: Ian Tannock Collection and assembly of data: Bostjan Seruga, Ian Tannock Data analysis and interpretation: Bostjan Seruga, Ian Tannock Manuscript writing: Bostjan Seruga, Ian Tannock Final approval of manuscript: Bostjan Seruga, Ian Tannock
We thank Mark Clemons, MD, for his helpful comments about an earlier draft of this manuscript.
1. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:619–629, 2005. 2. Chlebowski RT: Clinical trial presentations, agency guidelines, and oncology practice: Findings from the arimidex, tamoxifen, alone or in combination trial. Clin Breast Cancer 8:343–346, 2008.[CrossRef][Medline] 4. 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] 5. 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. 6. Hudis CA, Barlow WE, Costantino JP, et al: Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The STEEP system. J Clin Oncol 25:2127–2132, 2007. 7. Baum M, Budzar AU, Cuzick J, et al: 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 359:2131–2139, 2002.[CrossRef][Medline] 8. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60–62, 2005.[CrossRef][Medline] 9. Sargent DJ, Patiyil S, Yothers G, et al: End points for colon cancer adjuvant trials: Observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 25:4569–4574, 2007. 10. Ng R, Pond GR, Tang PA, et al: Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006. Ann Oncol 19:481–486, 2008. 11. Cella D, Fallowfield L, Barker P, et al: Quality of life of postmenopausal women in the ATAC ("Arimidex", Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for early breast cancer. Breast Cancer Res Treat 100:273–284, 2006.[CrossRef][Medline] 12. 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] 13. 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. 14. Presant CA, Bosserman L, Young T, et al: Aromatase inhibitor-associated arthralgia and/or bone pain: Frequency and characterization in non-clinical trial patients. Clin Breast Cancer 7:775–778, 2007.[CrossRef][Medline] 15. Fontaine C, Meulemans A, Huizing M, et al: Tolerance of adjuvant letrozole outside of clinical trials. Breast 17:376–381, 2008.[CrossRef][Medline] 16. Coates A, Mouridsen H, Thurlimann B: Inappropriate ATAC on tamoxifen. Lancet Oncol 9:315–316, 2008.[CrossRef][Medline] 17. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602–606, 2003. 18. Barron TI, Connolly R, Bennett K, et al: Early discontinuation of tamoxifen: A lesson for oncologists. Cancer 109:832–839, 2007.[CrossRef][Medline] 19. Partridge AH, LaFountain A, Mayer E, et al: Adherence to initial adjuvant anastrozole therapy among women with early-stage breast cancer. J Clin Oncol 26:556–562, 2008. 20. Mortimer JE, Flatt SW, Parker BA, et al: Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat 108:421–426, 2008.[CrossRef][Medline] 21. Cuzick J, Sestak I, Cella D, Fallowfield L; on behalf of the ATAC Trialists' Group. Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: A retrospective analysis of the ATAC trial. Lancet Oncol 2008 10 29, [Epub ahead of print]. 22. Cuzik J: Hot flushes and the risk of recurrence: Retrospective, exploratory results from the ATAC trial. Breast Cancer Res Treat 106: 2007 (suppl l1) abstr 2069. 23. 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] 24. 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] 25. Goss PE: Extending the benefits of adjuvant therapy in early HR+ breast cancer. Breast Cancer Res Treat, 10.1007/s10549-008-0129-8, [epub ahead of print on September 11, 2008].[CrossRef] 26. Punglia RS, Burstein HJ, Winer EP, et al: Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: A modeling analysis. J Natl Cancer Inst 100:642–648, 2008. 27. Stearns V, Johnson MD, Rae JM, et al: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764, 2003. 28. Borges S, Desta Z, Li L, et al: Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61–74, 2006.[CrossRef][Medline] 29. Hayes DF, Stearns V, Rae J, et al: A model citizen? Is tamoxifen more effective than aromatase inhibitors if we pick the right patients? J Natl Cancer Inst 100:610–613, 2008. 30. Rocchi A, Verma S: Anastrozole is cost-effective vs tamoxifen as initial adjuvant therapy in early breast cancer: Canadian perspectives on the ATAC completed-treatment analysis. Support Care Cancer 14:917–927, 2006.[CrossRef][Medline] 31. Moeremans K, Annemans L: Cost-effectiveness of anastrozole compared to tamoxifen in hormone receptor-positive early breast cancer: Analysis based on the ATAC trial. Int J Gynecol Cancer 16:576–578, 2006 (suppl l2.[CrossRef][Medline] 32. Locker GY, Mansel R, Cella D, et al: Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: A US healthcare system perspective—The 5-year completed treatment analysis of the ATAC (‘Arimide’, Tamoxifen Alone or in Combination) trial. Breast Cancer Res Treat 106:229–238, 2007.[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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