Commentary (Ligibel/Winer): Adjuvant Hormonal Therapy in Early Breast Cancer

In their article entitled "Adjuvant Hormonal Therapy in Early Breast Cancer," Kumar and Leonard summarize much of the available data from trials of hormonal therapy in preand postmenopausal women. They conclude that the use of aromatase inhibitors has led to an improvement in disease-free survival in postmenopausal patients with early-stage breast cancer, but that the optimal timing of aromatase inhibitor therapy and the long-term side effects of the drugs remain uncertain. The authors also highlight the benefits associated with tamoxifen in premenopausal women and discuss the unresolved role of ovarian ablation in this population. Large Trials in Postmenopausal Women
In the postmenopausal setting, the efficacy of the aromatase inhibitors has been evaluated in five major trials. Two of these trials, the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial[1] and the Breast International Group (BIG) 1-98 trial,[2] have compared aromatase inhibitors to tamoxifen as initial hormonal therapy in the adjuvant setting. Three other trials have looked at crossover strate-gies. The Intergroup Exemestane Study (IES)[3] and the Austrian Breast & Colorectal Cancer Study Group (ABCSG) Trial 8/German ARNO 95 trial[4] evaluated a crossover to an aromatase inhibitor compared to continued tamoxifen in women who had completed 2 to 3 years of tamoxifen therapy. The National Cancer Institute of Canada MA.17 trial looked at the use of an aromatase inhibitor compared to placebo after 5 years of tamoxifen.[5] The primary end point in each of these adjuvant investigations was disease- free or event-free survival, although the definition of this end point differed somewhat across trials. Each study demonstrated a decrease in breast cancer events in women who were treated with an aromatase inhibitor. In the ATAC trial, the absolute improvement in disease-free survival among women with hormone-receptor-positive tumors was 3.3% at 6 years of follow-up.[6] A similar risk reduction was demonstrated in the BIG 1-98 trial, which reported an absolute improvement in diseasefree survival of 2% in the letrozole (Femara) arm at 25.8 months median follow-up.[2] The crossover trials also demonstrated significantly lower rates of breast cancer events in patients treated with an aromatase inhibitor after tamoxifen compared to tamoxifen alone. In the IES trial, there was a 4.7% difference in event rates between the two groups at 30.6 months median follow-up,[3] and in the ABCSG/ ARNO trial, the 3-year event-free survival was 95.8% in the crossover group vs 92.7% in the group treated with 5 years of tamoxifen.[4] Of note, none of these trials have yet demonstrated a survival advantage for either upfront or sequential aromatase inhibitor therapy. In the MA.17 trial, women randomized to letrozole had a 43% reduction in the risk of an event, which translated into an absolute improvement in diseasefree survival of 6% at 4 years. An unplanned subgroup analysis at 33 months median follow-up also demonstrated a borderline significant (P = .04) survival advantage in lymphnode- positive patients treated with letrozole compared to those treated with placebo,[7] suggesting that extended adjuvant hormonal therapy may improve survival, particularly in higher-risk patients. As the authors suggest, results from these five large trials provide robust evidence that most postmenopausal women with hormone-receptor-positive breast cancer should receive an aromatase inhibitor at some point during their course of treatment. However, the optimal timing and duration of aromatase inhibitor therapy remains uncertain. Preliminary evidence has shown that certain subgroups of patients, such as those with estrogenreceptor (ER)-positive/progesteronereceptor (PR)-negative tumors and those with HER2-overexpressing tumors, might preferentially benefit from treatment with an aromatase inhibitor, suggesting that one treatment approach might not be best for all patients.[4,8,9] Additionally, since the median follow- up of these adjuvant trials is relatively short, it is difficult to predict the long-term toxicity of the aromatase inhibitors. Although the available data suggest that these agents are well tolerated with a low incidence of discontinuation due to adverse events, there was a numeric increase in non- breast cancer deaths in both the ATAC and BIG 1-98 trials.[1,2] While these differences are not statistically significant, they bear watching. Further study will be needed to determine the ultimate efficacy and safety of the aromatase inhibitors before it is possible to determine a "best" strategy for hormonal therapy in postmenopausal women. Ovarian Suppression in Premenopausal Women
In premenopausal women, the authors focus on the unresolved questions surrounding the use of ovarian suppression. Multiple European studies have demonstrated the equivalence of CMF (cyclophosphamide, methotrexate, fluorouracil)-type chemotherapy and ovarian suppression administered with or without tamoxifen.[ 10-12] Unfortunately, most of the trials failed to administer tamoxifen to women who were randomized to chemotherapy, preventing comparisons between ovarian suppression plus tamoxifen and chemotherapy plus tamoxifen. Studies have not demonstrated a definite benefit for ovarian ablation/ suppression in addition to chemotherapy.[ 13] However, the statistical power to detect a difference is limited in many trials since the majority of women develop temporary or permanent amenorrhea as a consequence of chemotherapy. In a subset analysis of the ECOG/Intergroup trial, there was the suggestion that ovarian suppression might add to the benefits of chemotherapy with or without tamoxifen in women under age 40, but conclusive trials looking at the use of ovarian suppression in women who retain ovarian function after chemotherapy are lacking.[14] While ovarian suppression is unquestionably an effective treatment for premenopausal women with hormonereceptor- positive disease, many questions remain unanswered: (1) To what extent does ovarian suppression add to the benefits that are seen with tamoxifen alone? (2) Does ovarian suppression further lower the risk of recurrence in women who remain premenopausal after chemotherapy and are planning to receive tamoxifen? (3) How long should ovarian suppression be continued once initiated? and (4) Do the benefits associated with ovarian suppression vary according to biologic subtype (eg, HER2-positive vs -negative) and patient age? On a selective basis, some oncologists are substituting ovarian suppression for chemotherapy in premenopausal women with receptor-positive disease, particularly those with a relatively low risk of disease recurrence. This approach is consistent with the recent St. Gallen guidelines.[15] In order to explore the benefits of ovarian ablation when given with modern treatment regimens, several clinical trials are being conducted in theUnited States and Europe. The Suppression of Ovarian Function Trial (SOFT) is assessing ovarian ablation in addition to tamoxifen in premenopausal women with early-stage breast cancer. Women enrolled in this trial may have received chemotherapy but must continue to menstruate afterward or have an estradiol level in the premenopausal range. The Tamoxifen and Exemestane Trial (TEXT), the first large study to evaluate the use of an aromatase inhibitor in premenopausal women, looks at the relative benefits of ovarian ablation plus either exemestane (Aromasin) or tamoxifen. Finally, the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial looks at the additional benefit of chemotherapy in premenopausal women treated with ovarian ablation plus tamoxifen. The results of these trials should help define the role of both ovarian suppression and chemotherapy in premenopausal women with hormoneresponsive breast cancer. Conclusions
The past few years have seen many new treatment options for women with hormone-responsive breast cancer, and hormonal therapy recommendations will continue to evolve over the next 5 to 10 years. The use of prolonged therapy with aromatase inhibitors and/or other agents will undergo further evaluation, and combinations of endocrine agents with novel inhibitors of other pathways are also under evaluation. The results of many ongoing clinical trials will be necessary before it is possible to define optimal treatment strategies for either pre- or postmenopausal women. In the interim, we agree with Drs. Kumar and Leonard that physicians need to weigh the risks and benefits of the various treatment options and design a treatment plan for each patient.

Disclosures:

Dr. Winer serves on advisory boards for Astra Zeneca and Pfizer.

References:

1. Baum M, Buzdar 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.
2. Thurlmann B: Letrozole as adjuvant therapy for women with hormone receptor positive breast cancer (abstract 1). Breast Cancer Res Treat 88(1S):57, 2004.
7. Goss P, Ingle JN, Martino S, et al: Updated analysis of the NCIC CTG MA.17 randomized placebo controlled trial of letrozole after five years of tamoxifen in postmenopausal women with early stage breast cancer in American Society of Clinical Oncology Annual Meeting (abstract 847). Proc Am Soc Clin Oncol 23:87, 2004.
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11. Castiglione-Gertsch M, O’Neill A, Price KN, et al: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node negative breast cancer: A randomized trial. J Natl Cancer Inst 95:1833-1846, 2003.
12. Schmid P, Untch M, Wallwiener D, et al: Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Anticancer Res 22:2325-2532, 2002.
13. Early Breast Cancer Trialists Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomized trials. Lancet 348:1189-1196, 1996.
14. Davidson N, O’Neill AM, Vukov AM, et al: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol Aug 15, 2005 [Epub ahead of print].
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