ABSTRACT: Endocrine therapy is a critical part of adjuvant therapy in women with hormone receptor–positive breast cancer, and has been shown to reduce the risk of recurrence and death from breast cancer. For decades, 5 years of tamoxifen(Drug information on tamoxifen) has been the standard treatment. For premenopausal women, it remains so, and we await the results of ongoing trials to define the role of ovarian suppression or ablation with endocrine therapy. If a woman becomes postmenopausal during treatment, consideration should be given to extended adjuvant therapy with an aromatase inhibitor (AI) for another 5 years. In postmenopausal women, trials have shown that AIs are more beneficial than tamoxifen in preventing disease recurrence. They have been compared as upfront treatment for 5 years, as sequential therapy after 2 to 3 years of tamoxifen, and as extended treatment for 5 years after 5 years of tamoxifen. Among the questions still being studied are the optimal duration of extended adjuvant therapy with AIs, how one AI performs compared to another, and whether there is a benefit to intermittent extended adjuvant treatment.
Introduction
Ball-and-stick model of the aromatase inhibitor exemestane(Drug information on exemestane) (Aromasin) molecule C20H24O2. Source: MindZiper, Wikimedia CommonsAdjuvant endocrine therapy is a standard treatment for hormone receptor (HR)-positive, early-stage breast cancer. Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for several decades in this setting. The benefits of adjuvant tamoxifen were shown in the first Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis[1] and have been confirmed in subsequent meta-analyses. Recently, aromatase inhibitors (AIs) have become the standard of care for postmenopausal women. In this article, we review the current guidelines for adjuvant endocrine therapy in both premenopausal and postmenopausal women, and we discuss the clinical trials that were used to develop these guidelines.
Guidelines for Premenopausal Women
The 2010 American Society of Clinical Oncology (ASCO) guidelines recommend tamoxifen for premenopausal women, since AIs are contraindicated in women with residual ovarian function.[2] These guidelines state that, currently, the benefit of ovarian suppression in this population is not known, and that the results of the Suppression of Ovarian Function (SOFT) trial are awaited to further define its role. The National Comprehensive Cancer Network (NCCN) guidelines recommend tamoxifen for 5 years (category 1 evidence) with or without ovarian suppression or ablation (category 2B evidence) if a woman is premenopausal at diagnosis.[3] At the end of the 5 years, if the patient is postmenopausal, another 5 years of treatment with an AI should be considered. The St. Gallen Expert Panel (2011) recommended tamoxifen alone, but stated that ovarian suppression plus tamoxifen was an acceptable alternative for premenopausal women.[4] For patients with a contraindication to tamoxifen, the St. Gallen Panel recommended ovarian function suppression plus an AI. The most recently published meta-analysis from the EBCTCG confirmed the benefits of tamoxifen in women younger than 45 years for reducing the risk of recurrence (hazard ratio [HR], 0.63; 2 P = .001) and breast cancer mortality (HR, 0.71; 2 P = .00002).[5]
Guidelines for Postmenopausal Women
The 2010 ASCO guidelines recommend that postmenopausal women with HR-positive breast cancer consider the use of an AI during adjuvant treatment, either as primary (initial) therapy, as sequential therapy (after 2 to 3 years of tamoxifen), or in the extended adjuvant setting (after 5 years of tamoxifen).[2] These guidelines state that the “optimal timing and duration of endocrine treatment remain unresolved,” although they recommend 5 years of an AI in the primary and extended adjuvant settings, and 5 years total endocrine therapy in the sequential setting. In absolute terms, the reduction in the risk of recurrence from AI-based therapy compared with tamoxifen is modest, less than 5%, through multiple years of follow-up, and the overall survival (OS) is equivalent in the primary and extended adjuvant trials. In two of the six sequential trials, there was a significant improvement in OS, although the absolute difference was small. Available data have not yet defined the optimal time for switching from tamoxifen to an AI. The guidelines recommend switching after 2 to 3 years of tamoxifen instead of after 5 years, although they do state that switching at 5 years is also supported by the available data.
The benefits of AI therapy appear to be a “class effect,” and if a patient is intolerant of one AI, she can switch to another. Randomized trials have not identified specific markers that predict maximum benefit from a certain adjuvant hormonal therapy—either tamoxifen or AI monotherapy, or sequential therapy. The NCCN guidelines are in agreement with American Society of Clinical Oncology (ASCO) recommendations.[3] If a woman is postmenopausal at diagnosis, options include an AI for 5 years, tamoxifen for 2 to 3 years followed by an AI to complete 5 years or for a total of 5 years of AI therapy, or an AI for 2 to 3 years followed by tamoxifen to complete 5 years. Yet another option is tamoxifen for 4.5 to 6 years, followed by an AI for 5 years (category 1 evidence). If a patient has a contraindication to an AI, cannot tolerate AIs, or refuses to take an AI, tamoxifen for 5 years should be considered. Members of the St. Gallen Expert Panel (2011) were evenly divided on the question of whether all postmenopausal patients should receive an AI; however, more were supportive of an AI for node-positive patients.[4] The Panel felt that 5 years was a sufficient duration and opposed further prolongation of therapy, even if the patients were node-positive or in the younger postmenopausal range (< 55 years).
Tamoxifen
Tamoxifen has been the gold standard for breast cancer hormonal therapy for over 30 years. The most recent EBCTCG meta-analysis included updated data from 20 trials (N = 21,457) of adjuvant tamoxifen for approximately 5 years vs no adjuvant tamoxifen.[5] For patients with estrogen receptor (ER)-positive disease (n = 10,645), tamoxifen reduced the rate of recurrence by 39% (relative risk [RR], 0.61; 2 P < .00001). Specifically, tamoxifen halved the risk of recurrence during years 0 through 4 (RR, 0.53) and reduced it by a third during years 5 through 9 (RR, 0.68; both, 2 P < .00001). After year 10, recurrence rates were similar (RR, 0.97) in the two groups, indicating no loss of the gains during years 0 through 9. The benefits of tamoxifen were independent of progesterone(Drug information on progesterone) receptor (PR) status/level, age, nodal status, tumor grade, tumor diameter, or the use of chemotherapy. Tamoxifen showed a substantial benefit even in patients with low levels of ER positivity. Tamoxifen reduced breast cancer mortality by about a third (RR, 0.70; P < .00001) throughout the first 15 years. Tamoxifen also reduced the risks of local recurrence (RR, 0.54; 2P < .00001), contralateral breast cancer (RR, 0.62; 2 P < .00001), and distant recurrence (RR, 0.63; 2P < .00001).
The established duration of tamoxifen therapy is 5 years. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial, 2,892 women with ER-positive, node-negative breast cancer were randomly assigned to receive either tamoxifen or placebo for 5 years.[6] Long-term follow-up results of this trial show that women benefited from 5 years of tamoxifen through 15 years, in both relapse-free survival (RFS) (HR, 0.58; 95% confidence interval [CI], 0.50–0.67; P < .0001) and OS (HR, 0.80; 95% CI, 0.71–0.91; P = .0008). This benefit was seen irrespective of age, menopausal status, and ER concentration.
Tamoxifen for 5 years has been shown to have a greater benefit than tamoxifen treatment for 1 to 2 years.[7] Continuation of tamoxifen for more than 5 years has not been shown to be more beneficial. In the NSABP B-14 trial, 1172 women who remained disease-free after 5 years of tamoxifen were randomly assigned to receive either placebo or an additional 5 years of tamoxifen.[8] With a follow-up of 7 years after randomization, there was a slight advantage noted in disease-free survival (DFS) (82% vs 78%; P = .03), RFS (94% vs 92%; P = .13), and OS (94% vs 91%; P = .07) for the women who discontinued tamoxifen. The Scottish trial also showed no advantage to tamoxifen continuation beyond 5 years, with a nonsignificant trend toward a worse outcome for longer use (HR, 1.27; 95% CI, 0.87–1.85).[9] In contrast, different results were seen in two more recent trials, the Adjuvant Tamoxifen Long Against Short (ATLAS) trial[10] and the Adjuvant Tamoxifen—to Offer More? (aTTom) study,[11] which have been presented but not yet published. The ATLAS trial randomly assigned 11,500 women (59% ER-positive, 41% ER-untested) who were disease-free after 5 years of tamoxifen to either continue tamoxifen for another 5 years or stop. With a 5-year follow-up, the longer duration was associated with a 12% relative risk reduction in breast cancer recurrence (HR, 0.88; P = .05). The aTTom trial randomly assigned 6934 women (39% ER-positive, 61% ER-untested) at the completion of 4 or more years of tamoxifen therapy to either 5 additional years of tamoxifen or cessation of tamoxifen therapy. With a median follow-up of 4.2 years, there was a slight, nonsignificant advantage for the 10-year arm (RR, 0.94; 95% CI, 0.81–1.09; P = .4). Thus, the optimal duration of therapy is not known, but it is at least 5 years.
Ovarian Suppression/Ovarian Ablation
Ovarian suppression (OvS)/ovarian ablation (OA) can be used in the adjuvant treatment of premenopausal breast cancer. OA can be accomplished via surgery (oophorectomy) or radiation; OvS is achieved via medications (luteinizing hormone–releasing hormone [LHRH] agonists). The EBCTCG meta-analysis included nearly 8000 women younger than 50 years of age with ER-positive or ER-unknown disease.[12] For women who received OvS/OA, there was a significant decrease in both the 15-year probability of breast cancer recurrence (2 P < .00001) and mortality (2P = .004) compared with those who received no ovarian treatment. Ovarian treatment had a smaller effect in the trials in which both groups received chemotherapy. There was no indication that the effects of OA differed from those of OvS.
A meta-analysis was performed of 11,906 premenopausal women (9022 HR-positive) from 16 clinical trials involving LHRH agonists, with a median follow-up of 6.8 years. When LHRH agonists were used alone and compared to no systemic therapy, there was no significant decrease in the risk of breast cancer recurrence, although the sample size was small (n = 338).[13] In 407 patients, OvS plus tamoxifen did significantly reduce recurrence and death after recurrence compared to no treatment, but the effects may have been due to tamoxifen. In 1013 patients, the addition of LHRH agonists to tamoxifen did not significantly decrease the risk of recurrence (HR, 0.85; P = .20) or death after recurrence (HR, 0.84; P = .33). In 3754 patients, the addition of LHRH agonists to tamoxifen, chemotherapy, or both reduced recurrence (HR, 0.88; P = .02) and death after recurrence (HR, 0.85; P = .08). When LHRH agonists were compared to chemotherapy (n = 3184), there were similar reductions in recurrence and death after recurrence. In addition, the comparison of LHRH agonists plus tamoxifen to chemotherapy without tamoxifen showed no significant differences (n = 1577). There was a benefit from LHRH agonists after chemotherapy in women younger than 40 years, in whom chemotherapy was less likely to cause permanent amenorrhea. In this meta-analysis, importantly, there were no trials that compared an LHRH agonist to chemotherapy with tamoxifen in both arms.
Data from studies combining OvS/OA with tamoxifen are still emerging, and results are unclear. Individual trials have failed to show any benefit for the addition of OvS/OA to tamoxifen compared to each therapy individually.[14-16]
Cancer Care Ontario (CCO) published guidelines on adjuvant ovarian ablation in the treatment of premenopausal women with early-stage invasive breast cancer, which were reviewed and endorsed by ASCO.[17] These guidelines state that OvS/OA is not recommended as an addition to systemic therapy with chemotherapy, tamoxifen, or the combination of tamoxifen and chemotherapy. They also stipulate that OvS/OA alone is not recommended as an alternative to any other form of systemic therapy and should be considered only for women who will not receive systemic treatment (eg, those patients who cannot tolerate or who refuse systemic therapy). When OvS with LHRH agonists is being considered, monthly injection is suggested. The ASCO ad hoc ovarian ablation guideline review panel suggested that treatment every 3 months might also be efficacious, based on emerging data. ASCO panel members also put forward two additional points. First, in patients who do embark on OvS using LHRH agonists, complete ovarian suppression is not always achieved. OvS cannot be confirmed by cessation of menses alone, and estradiol(Drug information on estradiol) assays are likely to be of variable quality. Second, many studies addressing the role of OA in premenopausal women with breast cancer included women with HR-negative disease or unknown HR status, and there is no evidence of OA benefit in these patients.
