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Originally published as JCO Early Release 10.1200/JCO.2005.02.964 on July 5 2005 © 2005 American Society of Clinical Oncology. Optimizing Adjuvant Endocrine Therapy in Postmenopausal Women With Early-Stage Breast Cancer: A Decision AnalysisFrom the Division of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham & Women's Hospital; Department of Radiation Oncology, Harvard Medical School; and Department of Health Policy and Management, Harvard School of Public Health, Boston, MA. Address reprint requests to Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: hburstein{at}partners.org
PURPOSE: The optimal adjuvant endocrine strategy for postmenopausal breast cancer is unknown. Options include the antiestrogen tamoxifen, estrogen deprivation with aromatase inhibitors, and sequential therapy with tamoxifen and then an aromatase inhibitor. METHODS: We developed Markov models to simulate 10-year disease-free survival among postmenopausal women with hormone receptor–positive breast cancer. The treatment strategies analyzed were 5 years of tamoxifen alone, 5 years of an aromatase inhibitor alone, and sequential treatment consisting of tamoxifen with cross over to an aromatase inhibitor at 2.5 or 5 years. Risk estimates were derived from reported randomized clinical trials. RESULTS: Sequential therapy with tamoxifen followed by cross over to an aromatase inhibitor at 2.5 years yielded a modest improvement in disease-free survival compared with planned aromatase inhibitor monotherapy. At 10 years, the cross-over strategy yielded absolute disease-free survival rates of 83.7% and 67.6% for node-negative and node-positive patients, respectively, compared with 82.6% and 65.5%, respectively, for aromatase inhibitor monotherapy, which is a 6% relative risk reduction. Sequential therapy improved disease-free survival estimates by year 6 after treatment initiation. Later cross over from tamoxifen to an aromatase inhibitor at 5 years did not further improve 10-year disease-free survival estimates. Sensitivity analyses suggest that sequential treatment strategies optimized 10-year disease-free and distant disease–free survival independent of the degree of the beneficial carryover effect after aromatase inhibitor therapy or the ratio of local to distant tumor recurrence. CONCLUSION: Modeling estimates suggest that sequential adjuvant therapy with tamoxifen followed by an aromatase inhibitor after 2.5 years yields improved outcomes compared with either drug alone or cross-over treatment after 5 years of tamoxifen.
Postmenopausal women with hormone receptor–expressing breast cancer (either estrogen receptor or progesterone receptor) constitute the largest group of patients diagnosed with early-stage breast cancer.1 Because adjuvant endocrine therapy is the most important systemic treatment for such women, improving both disease-free and overall survival, it is important to optimize such treatments. Historically, the selective estrogen receptor modulator tamoxifen has been the mainstay of adjuvant endocrine therapy.1,2 Five years of tamoxifen therapy has been established as the optimal duration of treatment based on long-term results from randomized clinical trials.3 Recently, aromatase inhibitors have been studied in the adjuvant setting either as alternatives to tamoxifen or as sequential therapy after tamoxifen among postmenopausal women. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial compared primary use of an aromatase inhibitor, anastrozole, with either tamoxifen alone or the combination of the two as adjuvant therapy for early-stage breast cancer. The ATAC study demonstrated modest improvements in disease-free survival with use of anastrozole as monotherapy.4,5 There was no benefit to combining the estrogen-deprivation effects of anastrozole with the antiestrogen effects of tamoxifen. The Breast International Group (BIG) 1-98 trial has recently reported on the use of the aromatase inhibitor letrozole compared with tamoxifen as primary therapy for early-stage breast cancer,6 showing results similar to those seen in the ATAC study. Different trials have reported that the extended use of tamoxifen followed by aromatase inhibitor therapy may be clinically advantageous. The MA-17 trial, led by the National Cancer Institute of Canada, was open to women who had completed 5 years of tamoxifen as primary adjuvant therapy for early-stage breast cancer and who were without clinical evidence of recurrence. These patients were randomly assigned to either extended adjuvant therapy with the aromatase inhibitor, letrozole, or placebo.7 After 2 to 3 years of follow-up, extended treatment with letrozole after 5 years of tamoxifen demonstrated a reduction in the risk of both locoregional and distant breast cancer recurrence compared with placebo. The Intergroup Exemestane Study (IES) also compared sequential treatment strategies. In contrast to the MA-17 study, patients in the IES trial had received 2 to 3 years of tamoxifen without evidence of tumor recurrence before random assignment to either ongoing tamoxifen treatment or to the aromatase inhibitor exemestane. Cross over from tamoxifen to exemestane yielded improved disease-free survival.8 In the related but much smaller Italian Tamoxifen Anastrozole (ITA) trial among women with lymph node–positive breast cancer who were free of recurrence after 2 to 3 years of tamoxifen treatment, patients were randomly assigned to either ongoing tamoxifen or cross over to anastrozole.9 Again, a reduction in recurrence rates was seen among patients crossing over from tamoxifen to the aromatase inhibitor. Finally, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8/Arimidex-Nolvadex (ARNO) 95 trial also examined sequential therapy, either switching patients from tamoxifen to anastrozole after 2 years or leaving patients on tamoxifen for a total of 5 years.10 Again, this study demonstrated that cross over from tamoxifen to the aromatase inhibitor improved disease-free survival. To date, none of the trials has suggested an overall survival advantage for adjuvant use of aromatase inhibitors. Nonetheless, these data have raised important questions about the optimal adjuvant strategy for hormone receptor–positive, early-stage breast cancer. These trials suggest that, in the short term, aromatase inhibitor monotherapy and sequential therapy with tamoxifen followed by an aromatase inhibitor are both superior to tamoxifen monotherapy. However, it is not known how primary treatment with an aromatase inhibitor might compare with sequential treatment with tamoxifen followed by treatment with an aromatase inhibitor or how long-term follow-up might affect outcomes. Prospective clinical trials are comparing initial therapy with tamoxifen or an aromatase inhibitor and planned cross-over strategies. For instance, the four-arm BIG 1-98 trial randomly assigned patients to either tamoxifen or an aromatase inhibitor alone for 5 years or to sequential therapy (tamoxifen followed by an aromatase inhibitor or an aromatase inhibitor followed by tamoxifen) at 2 years. However, this study was initiated before the results of the MA-17 study and, thus, does not consider extended therapy with aromatase inhibitors after 5 years of tamoxifen or longer durations of aromatase inhibitor treatment. There are no extant trials that will address all the questions about optimal sequencing and duration of adjuvant endocrine treatments. Clinicians and patients seeking the best adjuvant endocrine option for newly diagnosed postmenopausal early-stage breast cancer are currently confronted with a simple but unanswered question. Is it better to receive primary treatment with an aromatase inhibitor or sequential treatment with tamoxifen followed by an aromatase inhibitor after 2 to 3 or 5 years? Because of gaps in the design and reporting of clinical trials, there are no data facilitating this choice. Therefore, we used the methods of decision analysis, incorporating reported risk ratios from existing treatment studies, to inform clinical decision making in this setting.
Decision Model We developed Markov models11 to simulate the clinical history of hypothetical cohorts of postmenopausal women with hormone receptor–positive invasive breast cancer. The models simulated transitions among the following three health states: (1) well with no evidence of cancer recurrence, (2) having recurrent local or regional disease or being diagnosed with a new primary breast cancer (either ipsilateral or contralateral), or (3) having metastatic disease (Fig 1A). Women newly diagnosed with breast cancer start the simulations in the well state and, each month, face a probability of experiencing a recurrence. Separate models were developed for axillary lymph node–negative or –positive patients receiving each of the following treatment strategies: aromatase inhibitor alone for 5 years, tamoxifen alone for 5 years, or sequential therapy with tamoxifen for 2.5 or 5 years followed by an aromatase inhibitor for 5 years (Fig 1B). We used a time horizon of 10 years and calculated the following clinical outcomes: disease-free survival, distant disease–free survival, average time spent without disease, and average time spent without distant disease. We did not factor in comorbid conditions or death from non–breast cancer causes. No dead health state was included in this time-limited model. We performed one- and two-way sensitivity analyses to test the robustness of the results to variations in model parameters. The model was designed and analyzed using DATA 3.5 (TreeAge Software, Williamstown, MA).
Data and Assumptions Model estimates were derived from the Early Breast Cancer Trialists' Collaborative Group overview of tamoxifen data,3 an update of the ATAC study comparing upfront aromatase inhibitor and tamoxifen,5 the MA-17 trial, which compared an aromatase inhibitor versus placebo after 5 years of tamoxifen,7 and the IES trial, which compared an aromatase inhibitor versus tamoxifen after 2 to 3 years of tamoxifen8 (Table 1).
We compared four treatment strategies: tamoxifen or aromatase inhibitor monotherapy or sequential tamoxifen then aromatase inhibitor therapy with cross over at 2.5 or 5 years (Fig 1B). For the tamoxifen-alone strategy, we assumed that the risk of local or distant recurrence was constant for each 5-year interval after the initial diagnosis. We derived monthly probabilities of recurrence that were consistent with reported recurrence-free probabilities3 (Table 1, Fig 1). For the aromatase inhibitor monotherapy strategy, we applied an 18% reduction in the recurrence rate (ie, hazard ratio = 0.82) relative to tamoxifen alone based on the benefit among patients with hormone receptor–positive, early-stage breast cancer in the ATAC study.5 In this study, 6,241 patients were randomly assigned to the monotherapy arms, with a total of 885 breast cancer events at a median follow-up of 47 months. Hazard ratio reductions were assumed to be constant after aromatase inhibitor introduction. Reductions in recurrence rate associated with sequential therapy were derived directly from clinical trial results and varied with the timing of cross over from tamoxifen to aromatase inhibitor. For the sequential treatment strategy of 2.5 years of tamoxifen followed by an aromatase inhibitor, the associated recurrence rate was 33% lower than the recurrence rate of tamoxifen alone (hazard ratio = 0.67) after cross over to an aromatase inhibitor, as in the IES trial8 (Fig 1C, Table 1), and was applied only to the proportion of patients remaining in the no disease state at 2.5 years. The IES study randomly assigned 4,742 patients and had 449 first events after a median follow-up of 30.6 months. For the sequential strategy of 5 years of tamoxifen followed by an aromatase inhibitor, the recurrence rate associated with cross over to an aromatase inhibitor was 43% lower than the recurrence rate of tamoxifen alone (hazard ratio = 0.57), as in the MA-17 study7 (Fig1C, Table 1), and was used to adjust the recurrence rates among only the proportion of patients in the no disease state at 5 years. At a median follow-up of 2.4 years, the MA-17 trial, which enrolled 5,157 patients, had 207 nonfatal breast cancer events. Corresponding to the designs of these randomized trials, the reduction in recurrence at time of aromatase inhibitor initiation applied to only those women who had not yet had disease recurrence and remained in the no disease state. The proportion of all recurrences that are distant versus local, regional, or contralateral primary was set at 0.55 for node-negative patients and 0.70 for node-positive patients, consistent with the randomized studies,4-8 and was independent of treatment strategy. The monthly rate of developing distant disease after a diagnosis of a local or regional recurrence or a new primary breast cancer was 0.00186, which was consistent with a 20% chance of developing distant disease by 10 years after a local or regional recurrence.12 We did not analyze overall survival in the model. To date, there are no statistically significant overall survival differences in any reported studies for adjuvant use of aromatase inhibitors, and only modest numbers of patients in the randomized studies have died as a result of breast cancer. Clinical practice and guideline decisions on use of aromatase inhibitor therapy have all been made based on disease-free survival outcomes.
Sensitivity Analyses We also performed a two-way sensitivity analysis to study the effects of varying both the hazard ratio with primary aromatase inhibitor therapy at time 0 (ie, no cross over) on the x-axis and the hazard ratio associated with sequential therapy with tamoxifen followed by an aromatase inhibitor after 5 years on the y-axis. Because only two variables may be varied in a two-way sensitivity analysis, the hazard ratio associated with cross over to an aromatase inhibitor at 2.5 years was set as the average of the no cross-over and 5-year cross-over hazard ratios or the average of the (x, y) coordinates. The strategy that optimized 10-year disease-free survival for a particular point in the analysis was represented by a point of color (red for aromatase inhibitor upfront, green for cross over at 2.5 years, and blue for cross over at 5 years). The collection of points defines zones that describe the constraints for a particular treatment strategy to be optimal. For example, for the aromatase inhibitor upfront strategy to be optimal, the intersection of the vertical line from the x-axis describing an initial hazard ratio and the horizontal line from the y-axis describing the hazard ratio associated with cross over at 5 years must land within the red zone. We analyzed the impact of the proportion of recurrences that were local/regional or distant using a sensitivity analysis that varied the proportion from 0 to 1 and was designed to select the strategy that optimized 10-year distant disease–free survival. We also performed a one-way sensitivity analysis to explore the impact of varying the rate of developing distant metastasis after locoregional recurrence on 10-year distant disease–free survival among the different treatment scenarios.
Planned sequential therapy with tamoxifen with cross over to an aromatase inhibitor improved 10-year disease-free and distant disease–free survival compared with 5 years of therapy with either tamoxifen or an aromatase inhibitor alone (Table 2, Figs 2A and 2B). Similar trends were noted for node-positive and node-negative patients. Sequential therapy with tamoxifen followed by an aromatase inhibitor at 2.5 years (green line) reduced estimated 10-year recurrence rates by approximately 6%, increasing disease-free survival from 82.6% to 83.7% among node-negative patients and from 65.5% to 67.6% among node-positive patients, compared with aromatase inhibitor monotherapy (red line). The improvement was noted by year 6 of treatment. Sequential therapy with cross over at year 5 (blue line) was not superior to cross over at year 2.5 for 10-year disease outcomes.
Quantitative estimates of disease-free survival and patient-months without disease are listed in Table 2. Absolute risk of recurrence at 10 years was lower with the cross-over strategy at 2.5 years compared with other treatment scenarios, achieving a 1% to 2% absolute improvement in recurrence risk. However, the cumulative 10-year area under the curve estimate of patient-months free of recurrence favored upfront aromatase inhibitor strategy by 0.1 patient-month as a result of the lower likelihood of early recurrence. Estimates for distant disease–free survival were similar to findings observed with disease-free survival (Table 2). The benefit of sequential therapy with 2 to 3 years of tamoxifen followed by cross over to an aromatase inhibitor among postmenopausal women with node-positive breast cancer was greater in the ITA trial than in the IES trial, from which our baseline estimates were derived (hazard ratio = 0.36, compared with a hazard ratio = 0.67 in IES trial).9 Using this more favorable clinical estimate, the sequential therapy strategy with tamoxifen followed by cross over to an aromatase inhibitor at 2.5 years seemed even more advantageous, reducing the relative risk of recurrence by 30% compared with aromatase inhibitor monotherapy (Fig 2C, Table 2). Because the outcomes depend on both the hazard ratio for initial treatment with an aromatase inhibitor versus tamoxifen and on the cross-over benefit derived from switching from tamoxifen to aromatase inhibitor therapy, we performed a two-way sensitivity analysis on these two variables. Figure 3 identifies strategy zones that optimize 10-year disease-free outcome for the hazard ratio associated with an initial aromatase inhibitor versus tamoxifen (range, 0.6 to 1.0; x-axis) and the hazard ratio (range, 0.2 to 0.8; y-axis) seen with sequential therapy with tamoxifen followed by cross over to an aromatase inhibitor after 5 years among node-negative and node-positive patients.
The figures serve as a vehicle for characterizing circumstances in which monotherapy with an aromatase inhibitor would yield superior outcomes compared with cross-over therapy and, conversely, in which sequential strategies would yield improved 10-year outcomes. As anticipated, the best strategy for optimizing 10-year disease-free survival depends on the relative magnitude of these two hazard ratios. If the difference between initial therapy with tamoxifen or aromatase inhibitor becomes larger (ie, initial hazard ratio decreases), then, by necessity, the hazard ratio for sequential treatment must be more profound to justify cross-over therapy. Figure 3 allows for easy estimation of the best treatment scenario should new data emerge. For example, if there is a hazard ratio of initial therapy of 0.82, then hazard ratios of 0.68 for cross over at 5 years would be needed to warrant consideration of cross-over therapy. Conversely, if smaller differences between initial therapy with tamoxifen and an aromatase inhibitor are reported in forthcoming studies, then less marked differences in sequential treatment would still warrant consideration of a cross-over treatment plan. After our initial modeling efforts, new reports of adjuvant aromatase inhibitor trials did emerge, including a primary comparison of letrozole with tamoxifen (BIG 1-98)6 and a study of sequential tamoxifen followed by anastrozole versus tamoxifen alone (ABCSG8/ARNO95).10 We have used these two-way sensitivity analyses to explore whether the new data would affect our conclusions. The BIG 1-98 trial yielded a hazard ratio of 0.81 in favor of the aromatase inhibitor. As can be seen in Figure 3, a shift along the x-axis or no cross-over hazard ratio from 0.82, as in ATAC trial, to 0.81, as in BIG 1-98 trial, has no effect on optimal treatment outcomes. The results of the ABCSG/ARNO trial demonstrated a hazard ratio of 0.60 in favor of cross over from tamoxifen to an aromatase inhibitor at 2 years. Because this benefit exceeds the modeling estimate of 0.67 derived from the IES trial, it entirely reinforces the findings from our initial modeling studies. These results assume that there is a carryover effect of aromatase inhibitor therapy beyond 5 years of treatment. To date, the follow-up time reported in adjuvant trials of aromatase inhibitor therapy is not adequate for demonstrating whether there is, in fact, a carryover effect of aromatase inhibitor therapy as has been shown for use of 5 years of adjuvant tamoxifen.3 We conducted a sensitivity analysis to explore this assumption, varying the potential benefit in the following three ways: (1) full carryover, where the reduction in risk with aromatase inhibitors continues beyond 5 years of aromatase inhibitor therapy; (2) equivalent carryover to the effect historically seen with tamoxifen; and (3) no carryover effect, with the risk of recurrence after completing aromatase inhibitor therapy reverting back to the risk of patients free of recurrence through 5 years who never received adjuvant endocrine therapy. As shown in Figure 4, strategies of sequential tamoxifen with cross over to an aromatase inhibitor are preferred, regardless of assumptions about the benefits of aromatase inhibitor carryover effect. As the aromatase inhibitor carryover effect diminishes, the advantages of sequential treatment with tamoxifen followed by aromatase inhibitor cross over become more pronounced relative to primary use of aromatase inhibitor therapy.
We also explored whether differences in rates of local recurrence versus distant recurrence or assumptions about the likelihood of developing metastatic disease after local recurrence would affect the observed outcomes. Neither varying the ratio of distant to local recurrences nor changing assumptions about the rate of developing distant metastasis after locoregional recurrence alter the observed effects of cross-over treatment versus monotherapy for distant disease–free survival (data not shown).
Tamoxifen has been the standard adjuvant endocrine treatment for postmenopausal women diagnosed with hormone receptor–positive breast cancer. Recent clinical trials have demonstrated advantages for incorporating aromatase inhibitors into adjuvant therapy, reducing risks of both distant metastasis and local recurrence. It is not known whether the optimal strategy for using aromatase inhibitors would be upfront treatment or sequential therapy after tamoxifen. There are many ongoing or recently closed trials examining various treatment options for postmenopausal women with early-stage, hormone receptor–positive breast cancer. However, none of these trials compare all possible treatment strategies. Because of this gap in the design of prospective studies and current clinical treatment options and because data are not yet available from related prospective clinical trials, we used Markov modeling and available clinical data to estimate the optimal treatment strategy to inform current decision making. The models suggest that, given the currently available data, postmenopausal women with hormone receptor–positive breast cancer would maximize their expected 10-year disease-free and distant disease–free survival with sequential therapy consisting of an initial 2.5 years of tamoxifen and a subsequent 5 years of aromatase inhibitor therapy. Sensitivity analyses suggest that sequential treatment strategies yield optimal results regardless of assumptions about the carryover effects of aromatase inhibitors, the rate of distant metastasis after local recurrence, or the ratio of local to distant recurrences. We acknowledge that the differences between the various treatment options are small, which is consistent with the generally favorable prognosis for this group of patients and the modest improvements seen in the trials of aromatase inhibitor therapy. We used the best estimates for hazard ratio reductions provided by the trials but provided the two-way sensitivity analysis in Figure 3 to study how much variation in the hazard ratios from those reported is required before other strategies become optimal. Within the ranges studied in the two-way sensitivity analysis, there is no area where tamoxifen alone is the optimal treatment strategy as long as the hazard ratio with use of an aromatase inhibitor is less than 1. After our initial modeling efforts, two additional studies (the BIG 1-98 trial and the ABCSG8/ARNO95 trial) reported their results.6,10 These newer data entirely support the major findings of our modeling. The BIG 1-98 data comparing the aromatase inhibitor letrozole with tamoxifen showed a nearly identical hazard ratio (hazard ratio = 0.81) as the ATAC trial, which had a similar schema and outcome (hazard ratio = 0.82). The cross-over improvement resulting from sequential switching of treatment at 2 years in the ABCSG/ARNO trial was slightly more favorable than the improvement seen in the IES trial (hazard ratio, 0.60 v 0.67, respectively). We did not incorporate this data point into our models. However, this finding would support and magnify the potential gains seen with cross-over treatment at 2 to 3 years compared with either primary treatment with an aromatase inhibitor or extended therapy after 5 years of tamoxifen. We made several assumptions that may or may not be borne out by long-term results of prospective clinical trials. We assumed that all commercially available aromatase inhibitors yield similar benefits, which seems reasonable based on available laboratory and pharmacologic data. We used hazard ratios that were available from reported trials; ongoing studies will provide further estimates that can be used, as in Figure 3, to determine the best treatment plans. Furthermore, because limited information is available from the adjuvant trials, we did not take into account biologic subsets of breast cancers, such as estrogen receptor–positive and progesterone receptor–negative tumors or human epidermal growth factor receptor 2–positive tumors, in which some treatments may have selective advantage. We also did not take into account clinical factors such as side effect profiles of the different classes of drugs, individual patient preferences or contraindications to therapy, and costs of the different treatment agents. We also did not take into account the treatment scenario of an aromatase inhibitor followed by tamoxifen because no quantitative estimates of outcomes for such a strategy are available. An interesting finding is that the best long-term clinical outcome may not emerge until after 5 years of initial therapy. This suggests that results generated in short-term follow-up, which are the only type reported to date for use of aromatase inhibitors in the adjuvant setting, may not accurately reflect late consequences of treatment. This longer term perspective is critical in early-stage breast cancer, when patients tend to have a favorable prognosis but remain at jeopardy for recurrence through long periods of follow-up.13 Our analysis is only applicable to women with greater than a 10-year life expectancy who are likely to see this longer term benefit because we did not model death as a result of competing causes. Meanwhile, our analyses imply that many patients with postmenopausal, hormone receptor–positive, early-stage breast cancer may benefit from a planned sequential endocrine therapy that is built around primary tamoxifen treatment and cross over to secondary therapy with an aromatase inhibitor after 2 to 3 years. This strategy seems the best because of the relatively small upfront differences between tamoxifen and aromatase inhibitors (18% risk reduction) versus the relatively large gains made with sequential treatment (33% to 64% risk reduction). It is not known why initial tamoxifen treatment followed by an aromatase inhibitor might achieve superior clinical results. The mechanisms of tamoxifen resistance in breast cancer remain only poorly characterized.14 Some laboratory models suggest that, over time, the partial estrogen-agonist effects of tamoxifen contribute to tamoxifen-stimulated breast cancer growth.15 Under these circumstances, the tamoxifen withdrawal and estrogen-deprivation effects that accompany cross over from tamoxifen to an aromatase inhibitor could be particularly effective. However, not all laboratory models suggest that cross-over therapy is beneficial. In one system designed to maximize the impact of aromatase enzyme expression by breast tumor cells, early and continued aromatase inhibitor therapy yielded superior tumor control compared with tamoxifen or cross-over strategies.16 Finally, it is important to note that the patient populations in the primary and cross-over trials were not the same; some patients were naive to endocrine therapy, whereas others were disease free after some period of adjuvant endocrine therapy. As in our model, patients in the IES, ITA, and MA-17 trials were required to be without tumor recurrence at the time of cross-over treatment. A possible explanation for the lower hazard ratios seen with cross-over treatment may be the selection of tumors that are more sensitive to endocrine manipulation. If this is the case, it might imply that different strategies are appropriate for patients with tumors that have differing sensitivity to antiestrogen therapy. Tumors with more exquisite sensitivity to antiestrogen treatment might do better with cross-over treatment than tumors with more intrinsic resistance to endocrine therapy. This possibility awaits further clarification from retrospective analyses of these large phase III studies. Pending definitive results from large, prospective clinical trials with long-term follow-up, the best endocrine strategy for postmenopausal, estrogen receptor–positive breast cancer is unknown. However, our models suggest that use of both antiestrogen (ie, tamoxifen) and estrogen-deprivation (ie, aromatase inhibitors) strategies in sequential fashion may be superior to either strategy alone for long-term prevention of breast cancer recurrence. Clinicians and patients may find these data valuable as they discuss drug choices, associated side effects, and duration of therapy for optimal endocrine treatment of early-stage breast cancer in postmenopausal women.
Althoguh all authors have completed the disclosure declaration, the following author or their immediate family members have 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 description 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) $10,000-99,999 (C)
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 30:5-15, 2001
2. Goldhirsh A, Wood WC, Gelber RD, et al: Meeting highlights: Updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357-3365, 2003 3. 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 randomized trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 4. 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 randomized trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 5. 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-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline] 6. Thurlimann B, Keshaviah A, Mouridsen H, et al: BIG 1-98: Randomized, double-blind phase III study to evaluate letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Proc Am Soc Clin Oncol 23:6S, 2005 (suppl; abstr 511)
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. 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 9. 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, 2003 (suppl 1; abstr 3) 10. Jakesz R, Kaufmann M, Gnant M, et al: Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years of adjuvant tamoxifen: Combined results from 3,123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial. Breast Cancer Res Treat 88:S7, 2004 (suppl 1; abstr 2) 11. Sonnenberg FA, Beck JR: Markov models in medical decision making: A practical guide. Med Decis Making 13:322-338, 1993 12. Abner AL, Recht A, Eberlein T, et al: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11:44-48, 1993[Abstract]
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. Schiff R, Massarweh S, Shou J, et al: Breast cancer endocrine resistance: How growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 9:447S-454S, 2003 (suppl) 15. Yue W, Santen RJ: Aromatase inhibitors: Rationale for use following antiestrogen therapy. Semin Oncol 23:21-27, 1995 (suppl 9)
16. Long BJ, Jelovac D, Handratta V, et al: Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. J Natl Cancer Inst 96:456-465, 2004 Submitted October 29, 2004; accepted May 26, 2005.
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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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ABSTRACT
INTRODUCTION
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