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Originally published as JCO Early Release 10.1200/JCO.2007.14.7744 on March 10 2008 © 2008 American Society of Clinical Oncology.
Optimizing Endocrine Therapy for Estrogen Receptor–Positive Breast Cancer: Treating the Right Patients for the Right Length of TimeDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Patients with estrogen receptor (ER) –positive tumors are at continued risk of relapse for many years after initial breast cancer diagnosis. Among women treated with tamoxifen for 5 years, more than half of all recurrences occur between 6 to 15 years after diagnosis.1 Although tamoxifen (and probably the aromatase inhibitors [AIs]) lower the risk of recurrence for several years after they are stopped, late recurrences and deaths remain a major clinical challenge. If we want to reduce morbidity and mortality from ER-positive breast cancer, we must focus on strategies to confront this challenge. The use of a first-line AI for 5 years has been shown to improve disease-free survival (DFS) in patients with early-stage, ER-positive disease, compared with tamoxifen. However, no difference in overall survival has emerged.2,3 With 100-month median follow-up, there is no difference in overall survival between women randomly assigned to either 5 years of tamoxifen or anastrozole.4 Trials comparing a 5-year course of tamoxifen with a 2- to 3-year course of tamoxifen followed by either exemestane or anastrozole for a total of 5 years of adjuvant treatment have demonstrated improvements in DFS and improvements in overall survival of borderline statistical significance.5-7 Thus, although the incorporation of an AI at some time during the first 5 years represents an advance over the use of tamoxifen alone, it is unlikely that a 5-year course of treatment, no matter which of the available agents is used, will have a substantial impact on either survival or late recurrence. The addition of adjuvant chemotherapy to endocrine treatment does not reduce the risk of late recurrence, and there is increasing doubt about the importance of chemotherapy in subsets of patients with ER-positive disease.1,8 In this issue of the Journal of Clinical Oncology, three reports9-11 directly address the impact of extended hormonal therapy in postmenopausal women with ER- and/or progesterone receptor–positive tumors. Collectively, these analyses indicate that extending the duration of endocrine treatment beyond 5 years reduces the risk of late events, with limited adverse effects on quality of life (QOL). The MA.17 investigators previously reported results from the primary analysis of that trial, which randomly assigned 5,187 women who had completed 5 years of tamoxifen therapy to either letrozole or placebo for an additional 5 years. The use of letrozole was associated with a significant improvement in DFS and, among the node-positive subset, a survival benefit.12 A strength of the study was the inclusion of a large cohort of older patients, with approximately one fourth of patients older than 70 years on study entry. Muss et al9 now report that the benefits, as well as the risks, associated with letrozole were similar across all age groups. In older patients, toxicities were similar to rates associated with placebo; though there was an initial decrement in QOL with letrozole, this difference disappeared by 36 months. In 2003, after MA.17 was unblinded, approximately two thirds of patients who had originally been assigned to the placebo arm chose to switch to letrozole. Goss et al10 now report that both DFS and distant DFS were superior in the group of women who chose to switch to letrozole, even though letrozole was not started until a median of 2.8 years from the completion of tamoxifen, or approximately 8 years from initial diagnosis. Furthermore, this improvement in DFS and distant DFS was seen despite the fact that the group of women who chose not to take letrozole were, by all measures, at lower risk of disease recurrence than those who chose letrozole. Of course, it is unknown if the same result would be observed if the prior treatment had been an AI rather than tamoxifen. In 2008, with a growing number of women now completing a 5-year course of primary AI treatment, this question is becoming more relevant than ever. An unavoidable consequence of the unblinding of MA.17 was the early termination of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33, a trial that initially randomly assigned women who had completed a 5-year course of tamoxifen to a 2-year course of exemestane or placebo. At the time of study closure, 1,598 of a planned 3,000 patients were enrolled, and women enrolled onto both arms were offered exemestane for 5 years. Seventy-two percent of women on the exemestane arm and 44% of those on the placebo arm accepted the offer. As reported by Mamounas et al,11 after a median follow-up of 30 months, an intent-to-treat analysis demonstrated a nonstatistically significant improvement in DFS for the group of women initially assigned to receive exemestane. The study has major limitations given the unblinding, uneven crossover, and relatively short follow-up. Nevertheless, the findings are consistent with the primary results from the MA.17 trial: the use of an AI after a 5-year course of tamoxifen reduces the risk of disease recurrence. What are the implications of these three related studies, and how do they inform clinical practice in 2008? Clearly, the studies confirm the ongoing risk of late recurrence in women with ER-positive breast cancer. Women initially randomly assigned to placebo in either MA.17 or B-33 had a 2% to 3% annual risk of a breast cancer recurrence or new primary. Similarly, among patients initially randomly assigned to the placebo arm of MA.17, and who chose not to cross over, nearly 5% of patients experienced a DFS event at a median follow-up of less than 3 years. A closer examination of the post-unblinding patients in MA.17 who chose not take letrozole reveals that nearly half of the DFS events were ipsilateral recurrences (many of which, in this patient population, would be expected to be true second primaries) or contralateral cancers. Similarly, on the placebo arm of B-33, local recurrences and contralateral primaries were as common as either distant or regional recurrences. Although the prevention of second breast primaries is a laudable goal, these second primaries, unlike distant or regional recurrences, are unlikely to lead to death. Both tamoxifen and raloxifene prevent invasive breast cancers in women at elevated risk of developing the disease, but the majority of women choose not to take medications for a small absolute reduction in the risk of developing a new breast cancer.13-15 Women with a history of breast cancer may be more likely to opt for a treatment that will reduce the risk of a second primary. The actual definition of DFS varied between studies, such that lobular carcinoma in situ was counted as an event in MA.17, but not in B-33, and conversely, second nonbreast primary cancers and death from any cause were included as DFS events in B-33 but not in MA.17. These differences have led to a proposal from Hudis et al16 to standardize the definition of end points in future trials. We must be precise in our reporting of outcomes, and we need to be clear about the specific benefits of a proposed treatment when we are making recommendations to patients. Many women, however, are at risk for distant recurrence—the event that we most urgently want to prevent. On an annual basis, approximately 1% to 2% of women on the placebo arm of MA.17 developed a distant recurrence during follow-up. Can we identify which patients are at greatest risk of a distant recurrence so that these women can be targeted for extended endocrine therapy, while perhaps sparing those women whose risk may be extremely low? It is widely appreciated that ER-positive breast cancer is heterogeneous, and includes distinct subtypes of disease that have been characterized by both clinical, pathologic, and genomic characteristics.17,18 To date, almost all studies examining predictors of recurrence have focused either on any recurrence, or on early recurrence. For example, lack of progesterone receptor expression, HER2 overexpression, high histologic/nuclear grade, and lymph node involvement all predict for a higher risk of recurrence within the first 5 years of diagnosis.19 If we are to avoid treating all women for ever-longer periods of time, a fresh focus on predictors of late recurrence will be needed. One might imagine, for example, molecular assays, akin to the 21-gene recurrence score or the Dutch 70-gene signature, that might be calibrated to predict the risk of late recurrence.18,20 Some of the prognostic factors, such as HER2 positivity, that predict for early recurrence may also predict for a lower risk of late recurrence if a patient has survived disease free for 5 years. Other factors, such as node positivity, increase the risk of both early and late recurrence.1,12 Furthermore, novel techniques could and should be explored to detect minimal residual disease at the 5-year time point. The presence of bone marrow micrometastases at the time of initial diagnosis does not correlate with recurrence during years 5 to 10,21 but cytokeratin positive cells can be detected in the bone marrow even out to 4 years after diagnosis, and possibly beyond.22 Whether the presence of these cells correlates with late recurrences is not known at this time. Other less-invasive techniques, including serum DNA integrity or proteomic profiles, could also be explored. The need for predictors of late recurrence is underscored by the toxicities that accompany therapy with the AIs. The QOL data from the MA.17 trial are reassuring, but they must be interpreted cautiously. Of the approximately 480 women older than age 70 years who completed the baseline QOL survey in MA.17, just fewer than half completed the 24-month survey. It is unknown whether the patients who did not complete the survey were systematically different from those who completed the survey, and it is possible that larger changes in QOL could have been missed. In addition, although most patients tolerate AIs well, there is increasing recognition of a subset of patients who experience life-altering arthralgias or other adverse effects, leading to difficult discussions weighing QOL against recurrence risk.23 Finally, in an era of increasing use of AIs within the first 5 years after diagnosis, how do we incorporate the results of MA.17 and NSABP B-33 into clinical practice? For high-risk postmenopausal patients, most clinicians are uncomfortable with 5 years of tamoxifen before changing to an AI. Yet, there are neither safety nor efficacy data at this time supporting a course of more than 5 years of AI therapy. The inconsistent results from studies of more than 5 years of tamoxifen therapy caution us not to assume that extending AI therapy will lead to benefits that outweigh the potential risks.24-27 For this reason, both NSABP B-42 and MA.17R, which randomly assign women who have had 5 years of an AI to an additional 5 years or placebo, are critical studies. Another approach, which may be gaining traction in the breast cancer community, is to refine the predictors of tamoxifen benefit to identify the group of patients who can be treated with 2 to 5 years of tamoxifen before receiving an AI. Recent data suggest an opportunity to move beyond pharmacologic measures. In the Women's Intervention Nutrition Study, a low-fat diet was associated with an improvement in relapse-free survival.28 Unfortunately, follow-up was suspended after a median of 60 months because of funding limitations. In addition, one question that has been raised is whether the observed effect was as a result of the change in diet versus weight loss. The Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) will evaluate prospectively the impact of weight loss on DFS in women with early-stage breast cancer. In the Nurses’ Health Study, physical activity was associated with improvements in overall survival; of interest, the effect seemed strongest in women with ER-positive tumors.29 Ligibel et al30 have demonstrated the feasibility of an exercise intervention in breast cancer survivors, and have also shown that exercise can lower insulin levels in these women. An ongoing Cancer and Leukemia Group B–supported pilot study is evaluating the feasibility of a telephone-based exercise intervention in patients after adjuvant chemotherapy for breast or colorectal cancer, and may eventually lead to a phase III study to determine whether increasing physical activity reduces the risk of recurrence. Such an approach could be considered in women who are at risk of late recurrence, and might well be associated with other health benefits. The results of MA.17 and NSABP B-33, taken in context with the other adjuvant endocrine trials reported in the last 5 to 7 years, strongly argue for a paradigm shift in the clinical research focus and management of patients with ER-positive breast cancer. We do not have the luxury of only focusing on treatments and outcomes during the first 5 years after diagnosis. We need to identify predictors of late recurrence and treatment approaches that will change the low, but unrelenting, risk of recurrence seen in patients with ER-positive breast cancer. This research must expand to include premenopausal as well as postmenopausal women. Perhaps most importantly, we need to recognize the heterogeneity of both breast cancer and patients with breast cancer, to develop individualized treatment strategies that lead to the greatest benefit while minimizing risk. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Nancy U. Lin, Eric P. Winer Final approval of manuscript: Nancy U. Lin, Eric P. Winer REFERENCES 1. EBCTCG: 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] 2. 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] 3. Thürlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 4. Arimidex, Tamoxifen Alone or in Combination (ATAC) Trialists’ Group: 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. 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. 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 8. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726-3734, 2006 9. Muss HB, Tu D, Ingle JN, et al: Efficacy, toxicity and quality of life in older women with early stage breast cancer treated with letrozole or placebo after five years of tamoxifen: NCIC CTG Intergroup trial MA.17. J Clin Oncol 26:1956-1964, 2008 10. Goss PE, Ingle JN, Pater JL, et al: Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer completing 5 years of tamoxifen. J Clin Oncol 26:1948-1955, 2008 11. Mamounas EP, Jeong J-H, Wickerham DL, et al: Benefit from exemestane as extended adjuvant therapy following five years of adjuvant tamoxifen: Intent-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 Trial. J Clin Oncol 26:1965-1971, 2008 12. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005 13. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998 14. Vogel VG, Costantino JP, Wickerham DL, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727-2741, 2006 15. Melnikow J, Paterniti D, Azari R, et al: Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction. Cancer 103:1996-2005, 2005[CrossRef][Medline] 16. 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 17. Sørlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 18. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 19. Mauriac L, Keshaviah A, Debled M, et al: Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. Ann Oncol 18:859-867, 2007 20. van de Vijver MJ, He YD, van’t Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002 21. Braun S, Vogl FD, Naume B, et al: A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793-802, 2005 22. Slade MJ, Singh A, Smith BM, et al: Persistence of bone marrow micrometastases in patients receiving adjuvant therapy for breast cancer: Results at 4 years. Int J Cancer 114:94-100, 2005[CrossRef][Medline] 23. 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 24. Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: A randomized study updated to 15 years. J Natl Cancer Inst 93:456-462, 2001 25. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684-690, 2001 26. Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer: Eastern Cooperative Oncology Group. J Natl Cancer Inst 88:1828-1833, 1996 27. Peto R, Davies C, Collaboration oBotA: ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): International randomized trial of 10 versus 5 years of adjuvant tamoxifen among 11,500 women—Preliminary results. San Antonio Breast Cancer Symposium, December 14-16, 2007, San Antonio, TX (abstr 48) 28. Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women's Intervention Nutrition Study. J Natl Cancer Inst 98:1767-1776, 2006 29. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:2479-2486, 2005 30. Ligibel J, Campbell N, Partridge A, et al: Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26:907-912, 2008 Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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