Adjuvant Hormonal Therapy in Early Breast Cancer

For many years, tamoxifen has been the gold standard adjuvant hormonal therapy with the greatest impact in early breast cancer for both pre- and postmenopausal women. Tamoxifen-based adjuvant endocrine therapy and chemotherapy have together contributed substantially to the reduction in breast cancer mortality that has occurred in recent years. Over the past few years, the role of aromatase inhibitors has grown in prominence and they are now on the threshold of supplanting tamoxifen as the new gold standard adjuvant therapy for postmenopausal women with estrogen-receptor–positive disease. With extended use of oral antihormones such as tamoxifen, the role of ovarian suppression on the other hand has become less clear in the adjuvant setting. This article reviews the most important data regarding the various adjuvant hormonal treatments in the management of early breast cancer and will also give a brief overview of the role of these agents in the neoadjuvant setting.

In its earliest stages, breast cancer is most often treated first with surgery, but an increasing number of women then also receive adjuvant therapy-which often takes the form of hormonal therapy-to prevent recurrence and improve survival. While tamoxifen was long the agent of choice in this setting, a variety of other hormonal options continue to be explored. Adjuvant Hormonal Therapy in Postmenopausal WomenTamoxifen
The most widely prescribed anticancer drug in the world, tamoxifen, blocks the estrogenic stimulation of breast cancer cells by inhibiting both the dimerization and translocation of the estrogen receptor (ER).[1] It has been studied in randomized controlled trials since the 1970s, and along with chemotherapy, has accounted for the reduction in breast cancer mortality seen in recent years.[2] Among the earliest of such studies was the Nolvadex Adjuvant Trial Organization (NATO) trial, which demonstrated the efficacy of tamoxifen in reducing relapse rates and death.[3] The trial of the Scottish Group was the first to report the benefit of adjuvant tamoxifen given up front for 5 years compared to the same drug given at relapse, showing the superiority of early treatment in terms of both disease- free and overall survival.[4] Starting in 1985, the Oxford Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has published regular systematic reviews of tamoxifen research, most recently in 2000. The 1998 overview, which included more than 30,000 ER-positive women, showed a 47% proportional reduction in recurrence and a 27% improvement in mortality rates over a 10-year follow-up period. Although the absolute benefit was greater for nodepositive patients, the proportional reduction in recurrence rates was similar for both node-negative and nodepositive patients. This benefit was seen irrespective of age, menopausal status, daily tamoxifen dose, and whether chemotherapy was given or not. A similar gain occurred in a small subset of ER-poor but progesteronereceptor- positive patients, but the number was too small to draw definite conclusions.[5] The optimal duration of therapy with tamoxifen is also uncertain, although a minimum of 5 years is recommended. Trials examining the optimal duration of tamoxifen therapy (the adjuvant Tamoxifen Treatment offer more [aTTom] and Ajuvant Tamoxifen Longer Against Shorter [ATLAS] trials) are ongoing. Aromatase Inhibitors
The aromatase inhibitors act by inhibiting the aromatase enzyme, which in postmenopausal women is primarily located in the skeletal muscle and fat, and is responsible for peripheral aromatization of androgens to estrogens.[ 6] These agents are divided into the steroidal inhibitors, ie, formestane and exemestane (Aromasin), which are irreversible (suicide) inhibitors, and the nonsteroidal inhibitors, ie, anastrozole (Arimidex) and letrozole (Femara), which reversibly bind to the aromatase enzyme at a site distant to the hormone-binding site. Data from patients with advanced disease have indicated that these thirdgeneration aromatase inhibitors are more potent than tamoxifen in their anticancer activity.[7] More recently, Ellis et al showed in a randomized phase III primary therapy study that letrozole produced a significantly greater response and breast-conservation rate than tamoxifen and that this effect was greatest in ER-positive and HER1- and HER2-positive tumors.[8] These findings were corroborated by another European multicenter study.[9]

• ATAC-The first and largest trial evaluating aromatase inhibitors in the adjuvant setting was a head-to-head comparison between aromatase inhibitors and tamoxifen-the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which randomized 9,366 postoperative postmenopausal women to either tamoxifen or anastrozole or to a combination of the two. The first results, published in 2002, showed the superior efficacy of anastrozole compared to tamoxifen in terms of both disease-free survival and the incidence of contralateral breast cancers.[10] Since then, there have been two more updates-the latest by Howell et al showing that after a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival and time to recurrence, and significantly reduced distant metastasis.[11] In addition, anastrozole produced fewer side effects such as gynecologic and vascular symptoms, but tamoxifen was superior in terms of musculoskeletal events and fractures.
• Other Key Trials-Since the ATAC study, other important trials of adjuvant aromatase inhibitor therapy in postmenopausal postoperative women have been conducted. As the efficacy of this class of drugs became clearer, they began to be assessed in the large cohort of women worldwide who were already undergoing tamoxifen therapy. The Intergroup Exemestane study was a large randomized trial involving 4,742 patients randomized to either switching to exemestane after 2 to 3 years of tamoxifen or continuing with tamoxifen to 5 years. At 3 years follow-up, the exemestane group was found to be associated with a significantly improved disease-free survival (hazard ratio [HR] = 0.68; 95% confidence interval [CI] = 0.56-0.82; P < .0001) but no differences in overall survival. Fewer toxic effects were seen with exemestane.[12] The National Cancer Institute of Canada (NCIC) MA.17 study, on the other hand, assessed the role of letrozole after 5 years of tamoxifen in a randomized double-blind placebocontrolled trial. A total of 5,187 patients were randomized to either letrozole or placebo after 5 years of tamoxifen, the primary end point being disease-free survival. The 4-year disease-free survival was estimated to be 93% and 87%, respectively (P ≤ .001). This translated to a 4.7% difference in absolute terms for disease- free survival.[13] This study has been criticized for its early termination, because with a longer follow-up period until distant disease-free rates or overall survival were measured, this information could have been correlated with late-onset adverse events such as osteoporotic fractures.[14] In light of the above data, the American Society of Clinical Oncology (ASCO) technologic assessment update in November 2004 concluded that aromatase inhibitors should be included in the adjuvant management of postmenopausal women with breast cancer, but that the timing of their use in any given patient is not established.[15] Very recently, the first results of a trial comparing letrozole with tamoxifen immediately after surgery were presented at the triennial symposium held in St. Gallen, Switzerland. Briefly, the results are similar to the early results of the ATAC trial, with the primary end point-disease-free survival- showing a significant benefit for the aromatase inhibitors at a level similar to that of anastrozole in the ATAC trial.[16] In the United Kingdom, guidelines for adjuvant hormonal therapy in early breast cancer need to be developed. Factors such as risk and possibly biologic markers such as HER2 (which has been associated with a tendency to enhanced resistance to tamoxifen) may be worth considering, if selection is to be employed in allocating aromatase inhibitors in preference to or in sequence with tamoxifen.

Adjuvant Hormonal Therapy in Premenopausal WomenTamoxifen
In premenopausal women, tamoxifen remains the adjuvant hormonal therapy of choice-a fact borne out by the EBCTCG overview data. In contrast to earlier reviews by the EBCTCG and others, the benefit of tamoxifen is not limited to women between ages 50 and 69 (as well as over 70); the 1998 overview also showed a significant benefit in women under age 50-once again, irrespective of nodal status, although there is greater benefit in node-positive patients. The 1998 overview draws no conclusions about continuing tamoxifen beyond 5 years, but it showed that 5 years of tamoxifen is superior to lesser durations in terms of improved recurrence rates, reduced contralateral breast cancer incidence, and significantly improved overall survival. The precise duration of optimal treatment is as yet an unresolved issue. The Scottish Cancer Trials Breast Group conducted a study of tamoxifen continuation beyond 5 years, showing no statistically significant benefit and, moreover, a nonsignificant trend toward increased endometrial carcinoma.[17] Similarly, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial reported a worse disease-free survival in women using tamoxifen for 10 years rather than 5 years.[18] However, an Eastern Cooperative Oncology Group (ECOG) study did show a significant improvement in time to relapse with extended tamoxifen use.[19] The ATLAS and aTTom trials are two large studies aimed at conclusively answering these questions, but the fact that neither of these trials has been interrupted suggests that there may not be significant differences between the two arms. Ovarian Suppression/Ablation
Ovarian ablation was the original systemic treatment studied for advanced breast cancer more than 100 years ago. Early studies indicated a response rate of approximately 30% for unselected women with metastatic breast cancer and a greater than 80% response rate for women with ER-positive breast cancer.[20,21] The 2000 EBCTCG overview regarding ovarian suppression analyzed data on 4,900 node-positive and -negative women, with or without chemotherapy, and concluded that ovarian suppression did have a significant positive impact on overall survival (56.7% vs 46.3%) but only in patients who did not receive chemotherapy. There was no impact on survival in patients who received chemotherapy.[22] However, the only trial to examine the impact of ovarian suppression in women treated with tamoxifen for 5 years failed to show any additional protection with ovarian suppression. This UK trial of over 2,000 women has not been fully reported, but abstracts were presented at the 2004 ASCO meeting.[23] Several trials have shown the equivalence of ovarian ablation and chemotherapy in hormone-responsive tumors. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial randomized 1,640 node-positive early breast cancer patients to either goserelin (Zoladex) or six cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy. At a median follow-up of 6 years, there was no difference in disease-free survival between groups (HR = 1.01; 95% CI = 0.84-1.20) for ER-positive patients, but for ER-negative patients, goserelin was inferior to chemotherapy (HR = 1.76; 95% CI = 1.27-2.44). Amenorrhea occurred in a greater proportion of goserelin patients than in women who received CMF chemotherapy.[ 24] The criticism about these and other trials[25,26] has been that in most trials, the comparison has been with non-anthracycline-containing regimens, which are now known to be inferior to anthracycline-containing regimens. Many of these trials were underpowered, seldom included tamoxifen in the treatment arms, and were not always restricted to ER-positive patients. Trials of ovarian suppression in addition to chemotherapy in hormoneresponsive breast cancer have not shown a survival benefit from the addition of ovarian suppression, although some studies (Intergroup [INT] 0101 trial, International Breast Cancer Study Group [IBCSG] VIII trial) show a trend favoring the addition of luteinizing hormone-releasing hormone (LHRH) analogs for diseasefree survival. The INT 0101 trial randomized more than 1,000 patients with ER-positive, node-positive disease to CAF (cyclophosphamide, doxorubicin [Adriamycin], fluorouracil) or CAFZ (CAF with goserelin) or CAFZT (CAF with goserelin and tamoxifen) and concluded that there was no difference in overall survival, but the addition of tamoxifen did improve disease-free survival. In a subgroup analysis of the youngest patients (< 40 years), there was a trend favoring the addition of goserelin.[27,28] The Zoladex in Premenopausal Patients (ZIPP) trial was a 2*2 factorial study that randomized 2,648 premenopausal women to 2 years of tamoxifen, goserelin, the combination, or no hormonal manipulation. At a median follow-up of 4 years, a significant 25% increase in disease-free survival was seen for women receiving goserelin. This improvement was seen only in ER-positive women and extended to women who had received chemotherapy and tamoxifen. There was no improvement in overall survival across the different arms.[29] Overall, these data suggest that the maximum survival benefit is seen in patients with ER-positive disease who do not develop chemotherapy-related amenorrhea, but prospective evaluation of LHRH in combination with chemotherapy is warranted. The predictive value of chemotherapyinduced amenorrhea has been alluded to by del Mastro et al, who analyzed 10 studies and concluded that druginduced amenorrhea is associated with a 44% reduction in the rate of relapse.[30] Consensus Recommendations
In light of the data discussed above, two recent consensus meetings have published their recommendations on adjuvant endocrine therapy for premenopausal women. In 2000, the National Institutes of Health (NIH) concluded that adjuvant chemotherapy should be offered to the majority of premenopausal women with early breast cancer, and that tamoxifen should be given to ER-positive patients for 5 years. The panel did not recommend the use of ovarian suppression in patients who were receiving both chemotherapy and tamoxifen for 5 years, but its use could be considered instead of tamoxifen in selected patients. In contrast, the St. Gallen panel in 2003 highlighted the primacy of endocrine therapy in the management of premenopausal women and recommended the combination of tamoxifen for 5 years as an acceptable alternative to chemotherapy in ERpositive women. Conclusions Despite the emergence of the thirdgeneration aromatase inhibitors as perhaps the new gold standard adjuvant therapy for postmenopausal women, the absolute benefit, when compared to existing standard treatments, is modest at best. The long-term toxicity of these agents (specifically in relation to osteoporosis) is not known, and we await several more years of follow-up of patients in the trials mentioned above. In light of observations in the recent letrozole trial (Breast International Group I-98), careful monitoring of cardiovascular events will also be important in determining the relative risks of these agents for middle-aged and elderly women, in whom preexisting risk factors for cardiovascular disease are prevalent. The optimal sequencing of aromatase inhibitors in postmenopausal women is also not known and is a field for further prospective evaluation. With the evolving disciplines of proteomics and genomics, it is hoped that in the future, it may become possible to tailor adjuvant hormonal therapy to an individual. Until such time, the clinician will be expected to make informed decisions for individual patients on the sequencing of these treatments from currently available data and from an assessment of the risks and benefits involved.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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