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Journal of Clinical Oncology, Vol 23, No 33 (November 20), 2005: pp. 8544-8546 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.7416
Optimum Use of Aromatase Inhibitors in the Adjuvant Treatment of Early Breast CancerBreast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Cancer Research United Kingdom, Department of Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary College, London, United Kingdom To the Editor: We have read with interest the report of Punglia et al on optimizing adjuvant endocrine therapy for postmenopausal women with early-stage breast cancer.1 Although this article depicts an interesting hypothesis, it must be noted that this is generated as a result of statistical modelling based on assumptions drawn from multiple clinical trials with widely differing designs. Statistical modelling can be useful to estimate outcomes or effects, or to strengthen a hypothesis to encourage further clinical testing; however, the accuracy of the outcomes of such mathematical calculations is solely dependent on the assumptions that are put into the model. The Punglia et al model is dependent on the following basic assumptions, which we would like to discuss in more detail: The three respective hazard ratios (HRs) from three adjuvant trials of aromatase inhibitors (AIs) as initial therapy or as sequential therapy with cross-over from tamoxifen after 2 or 5 years. The underlying recurrence rates as reported in the Early Breast Cancer Trialists’ Cooperative Group (EBCTCG) overview.2 The HRs used in this model were based on a mixture of end points: disease-free survival (DFS; the ATAC,3 IES,4 BIG 1-98,5 and ITA6 trials) and time to recurrence (TTR; the MA 177 and ABCSG/ARNO8 trials). It is inappropriate to mix results based on different efficacy end points as these data are not interchangeable. Furthermore, any results will be biased toward outcomes based on TTR where the HRs were more favorable than those reported for DFS. It is also of note that more up-to-date data are now available for several of these trials.9-12 Incorporation of the most recent HR for TTR (0.74) from the hormone receptor-positive subgroup of the ATAC trial9 would increase the estimates for the proportion of patients recurrence-free at 10 years by 2% to 3%, with the proportion recurrence-free at 10 years increasing from 0.83 to 0.85 in node-negative patients and from 0.66 to 0.69 in node-positive patients. Conversely, inclusion of the HR for TTR (0.70) from the most recent results of the IES trial10 would slightly decrease the estimate of patients recurrence-free at 10 years. Had these HRs been incorporated into the Punglia et al model, the overall results would have been different, with the sequencing strategy no longer showing a lower risk of recurrence, and initial therapy with an AI appearing to be the superior strategy. As the EBCTCG overview uses TTR as the primary end point, the recurrence rates quoted for tamoxifen are only a relevant comparator to TTR end points for AIs. Recurrence is the most sensitive end point for evaluating efficacy in terms of breast cancer treatment as it includes distant and local recurrence as well as contralateral tumors and is preferable to DFS, which also includes non-breast-cancer-related deaths in patients who have not had a recurrence. This further reinforces the importance of using HRs from only TTR end points in these studies. Perhaps even more importantly, the Punglia et al model assumes a constant recurrence rate for each 5-year period, taking no account of the recognized peak in recurrences that occurs with tamoxifen treatment approximately 2 years after primary therapy.13 Therefore, the number of early recurrences occurring during tamoxifen treatment has been underestimated, particularly in node-positive patients. The impact of this assumption has not been critically discussed in this article, but is clearly shown in Figure 1. When the constant recurrence rates assumed in the Punglia et al model are overlaid on the curves for recurrence from the completed treatment analysis of the ATAC trial, the number of unaccounted recurrences becomes apparent (see shaded areas). This assumption contrasts with that in another recently reported model for postmenopausal women with hormone receptor-positive early breast cancer receiving AIs as adjuvant therapy.14 Here, Cuzick et al used the most recent results from the ATAC trial to model rates in the first 6 years, followed by the EBCTCG overview data for years 7 to 10 to give a more accurate reflection of the clinical situation.
In addition, in Table 2 of the Punglia et al article, and in the corresponding text referring to area under the curve (AUC), estimates of recurrence demonstrated a 1% improvement in recurrence for switching (2.5 years of tamoxifen followed by 5 years of an AI) versus an AI upfront. However, the cumulative 10-year AUC estimate for time free of recurrence was higher for an AI upfront (by 0.1 patient-month), confirming the effect of early recurrences. The Punglia et al article makes little comment on the modest nature of the improvement, or the AUC end point of patient-months, which reveals consistently better outcomes for patients receiving an AI upfront. This end point (termed time lost to recurrence in the Cuzick et al model) is an important one as it weighs time spent without a recurrence more favorably than time spent with a recurrence; we feel these data should have been discussed further in the Punglia et al article. Figure 1B of the Markov model treatment scenarios in the Punglia et al article is inaccurate with respect to its representation of the switch to an AI after 2.5 years as this does not reflect any of the switching trials conducted to date. The figure implies that this scenario is based on 2.5 years of tamoxifen followed by 5 years of an AI (ie, a total of approximately 7 years of treatment). However, the accompanying text shows that this particular scenario is based on the data from the IES trial, which is a standard switch trial of 2 to 3 years of tamoxifen followed by 2 to 3 years of an AI with a median follow-up of approximately 36 months. Although this is unlikely to affect the outcomes described in Table 2 and Figures 2 and 3, it will affect the carryover effect sensitivity analyses (Figure 4). This model assumes complete carryover (ie, the AI HR applies over 10 years), partial carryover (ie, AI equivalent to tamoxifen [HR = 1] post-treatment), or no carryover (ie, AI equivalent to placebo post-treatment). Given the assumption of a total of approximately 7 years treatment in the 2.5 year switch scenario, the sensitivity analyses will be biased compared with 5 years of continuous AI treatment. Furthermore, both the IES and ATAC trials now have median follow-up similar to their respective treatment period and we know that the Kaplan-Meier curves in the ATAC trial continue to diverge at 6 years (ie, 1 year after treatment completion). Thus, the assumption of no carryover seems invalid. It must also be emphasized that the patient populations from initial therapy and switching trials are different, with the latter likely to be biased, as noted by Punglia et al, towards a more endocrine-sensitive population. This highlights a limitation of the Punglia et al model and others, which by their nature need to assume that the patient populations included are similar for their results to be valid. Switching trials do not account for patients who do not complete 2 to 3 years of tamoxifen due to relapse or withdrawal and so are effectively based on a preselected population; therefore, the HRs versus tamoxifen are likely to be more favorable than in initial therapy adjuvant trials. Similarly, this and other models do not take account of the varying tolerability profiles of the compared treatments and the excess adverse events and withdrawals that may occur if tamoxifen is used for the first 2 years following primary therapy. The model also assumes that all AIs are similar based on pharmacologic and laboratory data, which is in contrast to the recommendations of the ASCO Technology Assessment that states "closely related agents with similar mechanisms of actions may have different toxicity profiles."15 In summary, all models are based on assumptions and as such, their results should be treated with caution and should not alone drive changes in clinical practice. True clinical outcomes can only be determined from large prospective randomized trials. Until mature results are available from trials directly comparing initial AI therapy with sequencing tamoxifen and an AI (eg, BIG 1-98), clinical decisions for women with hormone-sensitive early breast cancer should still be based on the best available efficacy data for each treatment scenario, bearing in mind the tolerability profile of each agent, and any patient preference for treatment. Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
REFERENCES
1. Punglia RS, Kuntz KM, Winer EP, et al: Optimizing adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer: A decision analysis. J Clin Oncol 23:5178-5187, 2005 2. 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 365:1687-1717, 2005[CrossRef][Medline] 3. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) Trialists Group: 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. Cancer 98:1802-1810, 2003[CrossRef][Medline]
4. 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 350:1081-1092, 2004 5. Thurlimann B, Kesaviah A, Mouridsen H, et al: BIG 1-98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. J Clin Oncol 23:6s, 2005 (suppl, abstr 511) 6. Boccardo F, Rubagotti A, Amoroso D, et al: Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat 82:S6-S7, 2003 (suppl 1)
7. 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 349:1793-1802, 2003 8. 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] 9. 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] 10. Coombes RC, Hall E, Snowdon CF, et al, on behalf of the Intergroup Exemestane Study (IES): The Intergroup Exemestane Study: A randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen–updated survival analysis. Breast Cancer Res Treat 88:S7, 2004 (suppl 1) 11. Thürlimann B: Letrozole vs tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. BIG 1-98: A prospective randomized double-blind phase III study. St. Gallen Breast Cancer Conference 2005, St. Gallen, Switzerland, January 26-29, 2005.
12. 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
13. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996 14. Cuzick J, Howell A: Optimal timing of the use of an aromatase inhibitor in the adjuvant treatment of postmenopausal hormone receptor–positive breast cancer. Proc Am Soc Clin Oncol 23:43s, 2005 (abstr 658)
15. 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 women with hormone receptor–positive breast cancer: Status Report 2002. J Clin Oncol 20:3317-3327, 2002
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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