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Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer
The Breast 24 (2015) S120eS125
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Original article
Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer Aju Mathew 1, Nancy E. Davidson* Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute and UPMC CancerCenter, University of Pittsburgh, 5150 Centre Avenue, Suite 500, Pittsburgh, PA 15232, USA
a b s t r a c t Keywords: Breast cancer Adjuvant therapy Endocrine Premenopausal
Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5e10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS þ tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS þ AI compared with OFS þ tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone. © 2015 Elsevier Ltd. All rights reserved.
Introduction The past two decades have witnessed tremendous advances in the treatment of breast cancer with significant strides made in improving outcomes in women with early breast cancer [1]. Adjuvant endocrine treatment in hormone responsive breast cancer has significantly contributed to this positive trend [2]. Three major adjuvant endocrine treatment options exist - tamoxifen, aromatase inhibitors (AI) and ovarian function suppression (OFS) either by ovarian ablation (surgical bilateral oophorectomy or ovarian irradiation) or using medications such as Gonadotropin-Releasing
Hormone (GnRH) agonists (also known as Luteinizing HormoneReleasing Hormone [LHRH] agonists). Various meta-analyses of randomized clinical trials have helped define the use of these three approaches either alone or in combination or in sequence in the adjuvant setting [3e5]. However, recent publications of trials investigating extended endocrine therapy and refining our knowledge about the role of OFS have illuminated this field further [6e11]. This article aims to review the recent updates in the field of adjuvant endocrine treatment of breast cancer in premenopausal women, especially with regards to the type and duration of treatment. Data about extended adjuvant endocrine treatment
* Corresponding author. Tel.: þ1 412 623 3205. E-mail address: [email protected] (N.E. Davidson). 1 Division of Medical Oncology, Department of Medicine, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA. http://dx.doi.org/10.1016/j.breast.2015.07.027 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
Tamoxifen The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) individual patient data meta-analysis continues to show a
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significant reduction of breast cancer deaths in patients with hormone receptor-positive breast cancer who received five years of tamoxifen, including women who were likely premenopausal by virtue of age at time of diagnosis, even after 15 years from study entry [3]. This comprehensive meta-analysis proved several principles of tamoxifen therapy. First, tamoxifen was found to be useful in decreasing breast cancer death and recurrence in hormone responsive breast cancer, even in weakly hormone receptor-positive tumors; but it did not improve breast cancer outcomes in hormone receptor-negative disease. Second, the benefit of at least 5 years of tamoxifen carries over for at least 10 more years (carry-over effect). Third, an improvement in breast cancer mortality was seen across all age groups, irrespective of menopausal status; although the risk of uterine cancer was higher in older women (Relative Risk [RR] of 2.96 in ages 55e69, 1.75 in ages 45e54 and 1.04 in women less than 45 years old). Finally, it also confirmed that longer tamoxifen use (5 years) was more efficacious than shorter duration (1e2 years). Based on small trials 5 years of adjuvant tamoxifen use has been the prevailing standard of care for more than a decade, though it was hypothesized that extended tamoxifen treatment could result in further improvement in outcomes. The joint analysis of E4181 and 5181 trials supported a longer time to relapse with a strategy of indefinite tamoxifen use compared to only 5 years in the subgroup of hormone receptor-positive disease (p ¼ 0.014), whereas the National Surgical Adjuvant Breast and Bowel Project (NSABP) B14 and the Scottish Adjuvant Tamoxifen trial found no beneficial effect with extended tamoxifen use [12e14]. More recently, two large randomized trials with a similar study design - Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial and the adjuvant TamoxifeneTo offer more (aTTom) trial - provide further guidance to answer the important question of extended tamoxifen use in hormone responsive breast cancer [6,7]. Although the ATLAS trial randomized 12,894 women with early breast cancer, the primary analysis was restricted to patients with hormone receptor-positive disease (n ¼ 6846) [6]. The study found a 2.8% absolute breast cancer mortality reduction for patients on extended tamoxifen use versus tamoxifen for 5 years after 10 years from randomization or 15 years from diagnosis of early-stage breast cancer (12.2% vs. 15.0%). The relative risk reduction was most notable after the end of the 10-year tamoxifen use (breast cancer mortality recurrence rate ratio in years 10e14 ¼ 0.71 [95% confidence interval (CI) 0.58e0.88]). Both the recurrence rate ratio and breast cancer mortality rate ratio were non-significant between the two cohorts in the years 5e9. Similar effects were seen across all subgroups of clinical importance, such as age, nodal status, tumor size, and menopausal status at study entry although only about 11% of women were premenopausal. The UK counterpart of the ATLAS trial e aTTom e randomized 6953 women who completed 5 years of adjuvant tamoxifen treatment to 5 more years of tamoxifen or none. Sadly estrogen receptor [ER] status was untested in many of these women [7]. The results of the aTTom trial were quite similar to the ATLAS. Patients on extended tamoxifen had significant reduction in breast cancer recurrence, breast cancer mortality and death during 10e14 years. The full publication of the aTTom trial is eagerly awaited. Taken together, ATLAS and aTTom trials provided strong evidence favoring extended tamoxifen for total treatment duration of 10 years rather than 5 years for selected patients [3,6,7]. The benefit appears to be enjoyed by premenopausal women though the numbers of such women in these studies are small. Aromatase inhibitors Aromatase inhibitors (AI) are a mainstay for management of breast cancer in postmenopausal women but are contraindicated as
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monotherapy for premenopausal patients. One proven strategy for extended adjuvant endocrine therapy in postmenopausal women involves completion of 5 years of tamoxifen followed by 5 years of adjuvant letrozole based on the results of the MA17 trial [15]. The MA17 trial found a 6% absolute improvement in 4-year diseasesurvival rate (87% vs. 93%) favoring letrozole compared with placebo. Importantly the same benefit was seen for women who were premenopausal at the time of tamoxifen initiation but became postmenopausal during tamoxifen administration [16]. Similar results were observed with the use of exemestane, a steroidal aromatase inhibitor (NSABP B33 trial) [17]. The results of the MA17 and NSABP B33 trials provide an alternative approach for extended adjuvant therapy for patients who are pre- or perimenopausal at the start of adjuvant tamoxifen treatment and then become postmenopausal while on treatment. This strategy might mitigate risk for endometrial cancer when compared with the use of 10 years of tamoxifen, making it an attractive strategy so long as it is clear that the patient has truly become menopausal before AI is started. Adverse effects of extended endocrine treatment The benefit of extended tamoxifen treatment comes with relatively low cost and toxicity, especially for premenopausal women. The ATLAS trial showed increased relative risk for incidence of pulmonary embolism (RR 1.87, 95% CI 1.13e3.07) and endometrial cancer (RR 1.74, 95% CI 1.30e2.34). No difference in risk for stroke was noted [6], and extended tamoxifen use was found to have a protective effect on the risk for ischemic heart disease. Unfortunately, the ATLAS trial does not report on quality of life outcomes such as sexual dysfunction or menopausal symptoms. The major concern with extended tamoxifen was the report of a 0.2% absolute mortality increase due to endometrial cancer (0.4% vs. 0.2%) in this study in which about 90% of study participants were postmenopausal at study entry. Similarly, the aTTom trial also reported an increase in mortality with an absolute risk of 0.5% (1.1% vs. 0.6%; p ¼ 0.02) [7]. It seems likely that the elevated risk of endometrial cancer is largely a function of the predominance of postmenopausal women in these trials, and this could support a strategy to switch from tamoxifen to an AI if the patient becomes postmenopausal. This approach is not devoid of side effects however. The MA17 trial reports increased incidence of hot flashes, arthritis, arthralgia and myalgia and slightly higher incidence of osteoporosis in patients on extended letrozole compared to placebo (5.8% vs. 4.5%; p ¼ 0.07), although there was no difference in fracture rates [15]. The NSABP B33 trial noted a higher incidence of grade 3 or 4 arthralgia (1.0% in exemestane group vs. 0.5% in placebo) and fatigue [17]. No difference in fracture rates was seen. Overall, the strategy of extended tamoxifen use appears to be safe in premenopausal women. The efficacy and safety data from the extended aromatase inhibitor trials also support a switch strategy from tamoxifen to an AI upon attaining menopause, for up to 5 years (total 10 years of endocrine treatment). American Society of Clinical Oncology guideline After reviewing the above mentioned trials, the American Society of Clinical Oncology (ASCO) Clinical Practice Guideline committee on adjuvant endocrine therapy for women with hormone responsive breast cancer recommended tamoxifen for 10 years, or tamoxifen for 5 years followed by either an aromatase inhibitor for 5 years (if patient is postmenopausal at the end of year 5) or tamoxifen for 5 more years (if patient is pre- or postmenopausal at the end of year 5) [18]. In aggregate then, the ASCO guideline endorsed extended adjuvant endocrine treatment for 10 years in
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premenopausal women with hormone responsive breast cancer. The most remarkable effect of the ATLAS and aTTom study was the carry-over effect of the benefits of adjuvant therapy to a period of at least 5 years from treatment discontinuation. Molecular tests to predict benefit for extended endocrine treatment Identifying patients who may benefit most from this carry-over effect, for instance, patients who are at the highest risk for late distant recurrences, may help predict benefit for extended endocrine treatment. While traditional prognostic factors such as age, tumor size, grade and nodal status could be used to identify patients who may benefit most from extended endocrine therapy, it has a limited role in identifying patients at the highest risk of late distant recurrences [18]. OncotypeDx recurrence score, a genomic profile test used in predicting benefit for adjuvant chemotherapy in early-stage breast cancer, initially failed to identify patients who may get late distant recurrences but recent unpublished data suggest that it might be valuable [19,20]. Zhang et al., used an algorithmic gene expression-based signature to predict early (0e5 years) and late (>5 years) risk of distant recurrences (Breast Cancer Index, BCI) [20,21]. In a retrospective analysis of tumor tissues of hormone responsive, node negative, early-stage breast cancer patients treated with tamoxifen, they showed that individuals with low BCI at the end of 5 years have a remarkably low rate of late distant recurrence (<5% for years 5e10). Another biomarker driven approach was recently published by Sestak et al. using the PAM50-based risk of recurrence (ROR) score in a retrospective analysis of two large clinical trials (ABCSG8 and ATAC) [22]. Similar to the BCI, the authors found that the risk of distant recurrences during years 5e10 in patients categorized as having low ROR score was remarkably lower than those in the intermediate or high risk group. The study also noted that a gene expression-based score would add clinically meaningful information on risk for late distant recurrences (during 5e10 years) to traditional prognostic factors based on age, grade, tumor size and nodal status. Presumably, patients with low BCI or low PAM50 ROR score could be spared extended endocrine treatment. While these studies provide a proof-of-principle for a molecular tool to predict late distant recurrences, such a biomarker driven approach may not be able to identify patients who may or may not absolutely require extended endocrine treatment. The use of such a biomarker approach in the setting of 10 years of endocrine therapy with its carry-over effect being significant during years 10e14, may necessitate an analysis of distant recurrence rate after year 10, and not just during 5e10 years after breast cancer diagnosis. Ovarian function suppression Ovarian function suppression (OFS) was one of the first adjuvant treatment modalities used in premenopausal breast cancer. There are two major approaches to suppress ovarian estrogen production: ovarian ablation by surgical oophorectomy or ovarian radiation, and OFS using GnRH agonists [23]. Prior studies noted some reduction in breast cancer recurrences in patients receiving some form of OFS in addition to tamoxifen, especially in younger women with hormone responsive breast cancer [24,25]. A large individual patient data meta-analysis of 16 trials conducted in premenopausal women with hormone responsive disease found reduction in recurrences when GnRH agonists were used in combination with chemotherapy or tamoxifen or both [4]. No statistically significant beneficial effect for GnRH agonist used as the only adjuvant systemic treatment was noted though statistical power was limited. The results of several of the included trials were confounded by
adjuvant chemotherapy use, which in itself causes OFS and may therefore indirectly act as an endocrine therapy. With these positive signals, four recently reported or updated randomized trials were initiated to investigate the efficacy and tolerability of OFS in combination with tamoxifen or aromatase inhibitors [8e11]. All four trials ensured that patients had endocrine-responsive early breast cancer and were premenopausal at the time of randomization, although some patients may have previously received adjuvant chemotherapy. OFS plus tamoxifen The Suppression of Ovarian Function Trial (SOFT) randomized 3066 premenopausal women with early-stage breast cancer to receive 5 years of tamoxifen, tamoxifen plus OFS or exemestane plus OFS; OFS was achieved with monthly doses of triptorelin, surgical oophorectomy or ovarian radiation [9]. Chemotherapy was permitted based on patient and physician choice but such patients had to demonstrate retention or return of ovarian function as documented by a premenopausal estradiol level. Randomization was stratified by prior receipt of adjuvant chemotherapy or not. Initially framed as a three arm trial, a subsequent revision of the analysis plan led to the decision to compare tamoxifen versus tamoxifen plus OFS. Thus the SOFT trial aimed to investigate differences in 5-year disease-free survival (DFS) (time from randomization to occurrence of local regional or distant breast cancer recurrence or contralateral breast cancer, death without recurrence or a non-breast second cancer) between tamoxifen plus OFS and tamoxifen. After a median follow-up of 67 months, there was no difference between the two groups in DFS rate (86.6% in tamoxifen plus OS group vs. 84.7% in tamoxifen group; p ¼ 0.10). The multivariable adjusted analysis suggested a 22% reduction in risk for DFS rate for patients on tamoxifen plus OFS (Hazard ratio [HR] 0.78; p ¼ 0.03). Of note, patients who did not receive adjuvant chemotherapy (comprising 46.7% of study population) had excellent outcome with DFS of greater than 90% in both groups. Nonetheless, the SOFT trial found that patients who received chemotherapy and remained premenopausal had a 3.6% improvement in DFS rate (80.7% in tamoxifen plus OFS group vs. 77.1% in tamoxifen group) [9]. The investigators assessed freedom from breast cancer as a secondary endpoint, defined as time from randomization to occurrence of locoregional or distant recurrence of breast cancer or contralateral breast cancer. More than 95% of patients who did not receive adjuvant chemotherapy remained free from breast cancer after 5 years. Among the cohort of patients who received adjuvant chemotherapy, the 5-year freedom from breast cancer rates are 82.5% for tamoxifen plus OFS and 78.0% in the tamoxifen-only group (HR 0.78; 95% CI, 0.60e1.02). In a prespecified analysis of women younger than 35 years (11.5% of total study participants), the rates of freedom from breast cancer were 78.9% (tamoxifen plus OFS) and 67.7% (tamoxifen alone). Of note, 94% of women in this age group received adjuvant chemotherapy. In summary, the SOFT found no overall benefit for adding ovarian suppression to tamoxifen in all premenopausal women, although it showed a beneficial effect on a subgroup analysis of women <35 years and patients who received chemotherapy. The Eastern Cooperative Oncology Group (ECOG) (E-3193, INT0142) trial also evaluated the role of tamoxifen plus OFS (using goserelin, surgical oophorectomy or ovarian irradiation) versus tamoxifen alone for 5 years in premenopausal women with nodenegative hormone responsive breast cancer [8]. The trial was prematurely closed due to slow accrual and hence its conclusions on efficacy are underpowered. With nearly 10 years of follow-up, the E-3193 trial showed no difference in overall survival or DFS between the two groups. However it did meet its endpoints for
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patient-reported quality of life and symptoms. Since none of the patients in this trial received adjuvant chemotherapy and because it collected toxicity and patient-reported outcomes at regular intervals during the study period, its findings that OFS diminishes quality of life relative to tamoxifen for the first 2e3 years and then differences are diminished by year 5 are important results. OFS plus aromatase inhibitors Although AI are contraindicated in premenopausal women, use of OFS either through GnRH agonists or ovarian ablation procedures permits their administration in pre- or perimenopausal patients. Extrapolating from the results of the AI versus tamoxifen trials in postmenopausal women, it was hypothesized that AI in combination with OFS may reduce breast cancer recurrences in women with premenopausal breast cancer compared with tamoxifen plus OFS or tamoxifen alone [5]. The Tamoxifen and Exemestane Trial (TEXT) in premenopausal women with hormone responsive breast cancer aimed to compare OFS plus tamoxifen versus OFS plus exemestane; participants were permitted to receive adjuvant chemotherapy at physician and patient discretion and 60% of patients did so. OFS was begun concomitant with chemotherapy if chemotherapy was used. As noted earlier the SOFT trial also had arms comparing tamoxifen plus OFS and exemestane plus OFS in addition to an arm of patients on only tamoxifen, and the primary analysis was confined to tamoxifen plus OFS versus tamoxifen alone [10]. Since SOFT and TEXT were very similar in design, the investigators decided to conduct a joint analysis of both trials to investigate the efficacy of exemestane plus OFS versus tamoxifen plus OFS [10]. After a median follow-up of 68 months, the SOFT/TEXT combined analysis found 3.8% absolute reduction in 5-year disease-free survival (DFS) rates in patients receiving exemestane plus OFS versus tamoxifen plus OFS (91.1% vs. 87.3%; HR 0.72, 95% CI, 0.60e0.85; p < 0.001) [10]. The 5-year breast cancer free rates also favored the exemestane group (92.8% vs. 88.8%). Exemestane plus OFS was found to be more efficacious in all the pre-specified subgroups stratified by chemotherapy use, nodal status and also in each of the trials separately. No difference in survival was seen at this analysis. An important finding of the SOFT/TEXT analysis was the 5-year breast cancer free rate of 97% with either therapy in patients who did not receive chemotherapy. The Austrian Breast and Colorectal Cancer Study Group (ABCSG) investigated the efficacy of anastrozole plus OFS or tamoxifen plus OFS in premenopausal women with hormone responsive breast cancer [11]. OFS was achieved by using goserelin. The ABCSG-12 trial also aimed to investigate an adjuvant role for bisphosphonates, in a factorial study design. The recently published final analysis following a median follow-up of 94 months showed no difference in DFS but noted a higher risk of death for patients treated with anastrozole plus goserelin (HR 1.63, 95% CI, 1.05e1.45; p ¼ 0.03), although the reason for this effect is unclear. Previous work from this study suggested that high body mass index may reduce efficacy of AI plus OFS but not tamoxifen plus OFS. Adverse effects of ovarian suppression The side effect profile of OFS with tamoxifen or exemestane is well described in these trials. The E-3193 trial collected data on health-related quality of life, menopausal symptoms and sexual functions at regular intervals until 5 years [8]. Since the trial participants did not receive chemotherapy, the toxicity and tolerability data will more accurately reflect the effects of endocrine treatment. It was observed that patients on tamoxifen plus OFS had significant deterioration of menopausal symptoms, sexual function and health-related quality of life compared with
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tamoxifen monotherapy at the end of 3 years. There was no significant difference in toxicity between the two groups at year 5. In the SOFT trial, there were more hot flushes, sexual dysfunction, vaginal dryness and metabolic syndrome in patients on combined tamoxifen plus OFS than tamoxifen alone. There was greater incidence of osteoporosis in the combination arm of SOFT (5.8% vs. 3.5%) [9]. The combined SOFT/TEXT analysis found a higher incidence of osteoporosis in the exemestane plus OFS cohort compared with tamoxifen plus OFS group (13.2% vs. 6.4%) [10]. The two groups had distinct side effect profiles e more fractures (6.8% vs. 5.2%), sexual dysfunction (vaginal dryness, dyspareunia and decreased libido) and musculoskeletal symptoms (88.7% vs. 76.0%) were noted in the OFS plus exemestane group and increased incidence of hot flushes (93.3% vs. 91.7%), thromboembolic events (2.2% vs. 1.0%) and urinary incontinence (17.8% vs. 13.1%) were seen in patients receiving tamoxifen plus OFS. Considerations about use of OFS-based strategies After the American Society of Clinical Oncology endorsed the Cancer Care Ontario guideline against the routine use of adjuvant OFS in premenopausal women with early-stage hormone-responsive breast cancer either alone, or in combination with chemotherapy or endocrine therapy, four major clinical studies have been published or updated (ABCSG-12, E-3193, SOFT/TEXT and SOFT) [26]. The SOFT results showed that adding OFS to tamoxifen does not improve DFS or reduce breast cancer recurrences in all patients with hormone responsive tumors as compared to using 5 years of tamoxifen alone [9]. However, the SOFT trial investigators found a beneficial effect in women who remained premenopausal after adjuvant chemotherapy use and in women younger than 35 years of age. The SOFT/TEXT joint analysis confirmed a significant beneficial effect for exemestane plus OFS versus tamoxifen plus OFS in all premenopausal women with hormone responsive breast cancer, although the absolute risk reduction was more pronounced in the cohort of patients who received adjuvant chemotherapy [10]. The analysis, however, observed a non-significant 14% increase in risk for death (p ¼ 0.37) in the group receiving exemestane plus OFS although further follow-up is needed, especially given the adverse effects of goserelin plus anastrozole seen in the ABCSG-12 study (63% increased risk for death with anastrozole use; p ¼ 0.03) [11]. Further follow-up and more mature data are clearly needed. Importantly, the SOFT trial shows that a large proportion of premenopausal women with low-risk tumors do extremely well with just 5-years of tamoxifen [9]. In aggregate the SOFT, SOFT/ TEXT, ABCSG-12 and the E-3193 trials show that the strategy of tamoxifen plus OFS is a reasonable approach in women with higher risk for tumor recurrence, although this should be balanced against the slightly higher risk for side effects [8e11]. Finally, short term results from SOFT and TEXT show the best breast cancer recurrence outcomes with AI plus OFS though further follow-up is vital since the side effect profile may also be greater and data about survival are immature. Of course, none of these trials take into account newer data on extended tamoxifen as a strategy. The issue of adherence to treatment has to be brought into the process of decision making. A large retrospective study has found that more than 50% patients are non-adherent to adjuvant endocrine treatment with tamoxifen or AI [27]. Patients who were nonadherent to optimal endocrine treatment had an increased risk for mortality after 10 years of follow-up [28]. While it appears that OFS-based strategies are effective, if the side effects of adding OFS cause significant distress for the patient, there will be a greater likelihood for non-compliance. At a minimum, in such situations
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premenopausal patients should be counselled to at least continue tamoxifen. Several questions regarding OFS remain unanswered. In the absence of comparative data, it is assumed that suppression of ovarian function with GnRH agonist therapy is equivalent to ovarian ablation using either surgical bilateral oophorectomy or ovarian irradiation [23]. The optimal duration of OFS is also uncertain. The large randomized trials used 3 years (ABCSG-12) or 5 years (TEXT, SOFT, E-3193) although some earlier trials included in the meta-analyses used shorter durations. At present it appears that 3e5 years duration is rational. The timing of initiation of OFS, especially in patients destined for adjuvant chemotherapy, is also unclear. The TEXT trial used OFS concomitantly with adjuvant chemotherapy whereas the SOFT participants were initiated on OFS up to 8 months from completion of chemotherapy [10]. The DFS in the chemotherapy cohort of patients on tamoxifen plus OFS was 84.6% in the TEXT and 80.6% in the SOFT [10]. Thus both sequential and concurrent approaches seem to be supported. Of note, the participants in the chemotherapy cohort in TEXT were older and had higher proportion of node-positivity and larger tumor size, and the SOFT participants included more patients with HER2-positive status, although inter-trial comparison is fraught with difficulty. The investigators of SOFT and TEXT plan to conduct an analysis of a possible predictive role for HER2-status in determining the type of adjuvant endocrine treatment. Another major concern for use of AI in combination with OFS in premenopausal women is the possibility of suboptimal suppression of ovarian estrogen production. The SOFT-EST, a prospective substudy of SOFT, observed that nearly 20% of patients on AI had suboptimal suppression of estrogen production during the study period [29]. The interaction of body mass index with AI use in premenopausal women is also an area of concern. The ABCSG-12 investigators noted a higher risk for death and disease recurrence in overweight premenopausal women receiving anastrozole plus OFS compared to women with normal body mass index [30]. Such a differential effect was not seen in women receiving tamoxifen plus OFS. Incomplete OFS or greater aromatase activity could result in suboptimal estrogen suppression and result in a greater risk for breast cancer recurrence in overweight or obese patients receiving OFS plus AI. It is also unclear if OFS will provide a carry-over effect as was seen with the use of extended tamoxifen treatment [6,7]. Clearly, our trials of adjuvant endocrine treatment require longer follow-up for a more complete understanding of benefits and risks of treatment, and the 5-year follow-up in the current analyses of SOFT and TEXT trials may be considered preliminary [9,10]. Conclusion The recent publication of several much awaited adjuvant endocrine treatment trials introduces more evidence-based choices for premenopausal women with hormone responsive early-stage breast cancer. The options are tamoxifen for 5 years (EBCTCG meta-analysis), switch strategy using tamoxifen for 5 years followed by an AI for 5 years in women who become postmenopausal while on adjuvant treatment (MA17, NSABP B-33), extended tamoxifen for 10 years (ATLAS, aTTom), and the addition of OFS to tamoxifen or an AI (SOFT, TEXT, ABCSG-12, E-3193). Women with low risk of recurrence could be offered tamoxifen for 5e10 years or the switch strategy if they become truly postmenopausal during adjuvant tamoxifen. Patients with a higher risk for recurrence could be offered tamoxifen plus OFS or AI plus OFS for 3e5 years. There is no information to support longer duration of OFS-based strategies. A potential advantage with use of AI plus OS could be jeopardized by suboptimal estrogen suppression.
Given the long natural history of hormone responsive breast cancer, longer follow-up of trials will be critical to ascertain benefit and document unexpected late toxicities, if any. A pressing need is the identification of markers that can identify patients who need extended adjuvant endocrine therapy as well as markers that might allow selection of those that would benefit from the addition of OFS. Studying post-progression molecular changes in patients who were on the extended tamoxifen or combination OFS strategies will be crucial in understanding potential mechanisms of resistance. Finally, most trials have used medical, surgical, and radiotherapeutic approaches to OFS interchangeably, but the equivalence of these therapies in the adjuvant setting especially in combination therapy is not certain and may require further assessment through follow-up of completed trials. What has become clear is that adjuvant endocrine therapy is a vital part of the treatment plan for most premenopausal women with hormone responsive breast cancer and a subset of these women with low risk tumors can be safely treated with simple endocrine therapy like tamoxifen alone. Conflict of interest statement The authors have no conflicts of interest. References [1] Siegel R, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65: 5e29. [2] Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353:1784e92. [3] Davies C, Godwin J, Gray R, Cutter D, Darby S, McGale P, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378: 771e84. [4] Cuzick J, Ambroisine L, Davidson N, Jakesz R, Kaufmann M, Regan M, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007;369:1711e23. [5] Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28:509e18. [6] Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805e16. [7] Gray RG, Rea DW, Handley K, Marshall A, Pritchard MG, Perry P, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31. Suppl; Abstr 5. [8] Tevaarwerk AJ, Wang M, Zhao F, Fetting JH, Cella D, Wagner LI, et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2014;32:3948e58. [9] Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Lang, E. Ciruelos, M. Bellet, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;372:436e46. ng I, et al. Adju[10] Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, La vant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371:107e18. [11] Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group trial 12. Ann Oncol 2014;26:313e20. [12] 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 1996;88:1828e33. [13] Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 2001;93:456e62. [14] Fisher B, Dignam J, Bryant J, Wolmark N. 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 2001;93:684e90.
A. Mathew, N.E. Davidson / The Breast 24 (2015) S120eS125 [15] Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, 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 2003;349: 1793e802. [16] Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Livingston RB, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol 2013;24:355e61. [17] Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the national surgical adjuvant breast and bowel project B-33 trial. J Clin Oncol 2008;26:1965e71. [18] Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 2014;32:2255e69. [19] Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817e26. [20] Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 2013;14:1067e76. [21] Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, et al. Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clin Cancer Res 2013;19:4196e205. [22] Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, et al. Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian Breast and Colorectal Cancer Study Group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol 2014;33:916e22.
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[23] Puhalla S, Brufsky A, Davidson N. Adjuvant endocrine therapy for premenopausal women with breast cancer. Breast 2009;18(Suppl. 3):S122e30. [24] Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Romeo D, Sismondi P, et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian breast cancer adjuvant study group 02 randomized trial. J Clin Oncol 2000;18: 2718e27. [25] The Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst 2007;99:516e25. [26] Griggs JJ, Somerfield MR, Anderson H, Henry NL, Hudis CA, Khatcheressian JL, et al. American Society of Clinical Oncology endorsement of the cancer care Ontario practice guideline on adjuvant ovarian ablation in the treatment of premenopausal women with early-stage invasive breast cancer. J Clin Oncol 2011;29:3939e42. [27] Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 2010;28:4120e8. [28] Hershman DL, Shao T, Kushi LH, Buono D, Tsai WY, Fehrenbacher L, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 2011;126:529e37. [29] Bellet M, Gray K, Francis P, et al. Estrogen levels in premenopausal (prem) patients (pts) with hormone-receptor positive (HRþ) early breast cancer (BC) receiving adjuvant triptorelin (Trip) plus exemestane (E) or tamoxifen (T) in the SOFT trial: SOFT-EST substudy. J Clin Oncol 2014;32. 5s, 2014 (suppl; abstr 585). [30] Pfeiler G, Konigsberg R, Fesl C, Mlineritsch B, Stoeger H, Singer CF, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol 2011;29:2653e9.
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Original article
Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer Aju Mathew 1, Nancy E. Davidson* Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute and UPMC CancerCenter, University of Pittsburgh, 5150 Centre Avenue, Suite 500, Pittsburgh, PA 15232, USA
a b s t r a c t Keywords: Breast cancer Adjuvant therapy Endocrine Premenopausal
Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5e10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS þ tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS þ AI compared with OFS þ tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone. © 2015 Elsevier Ltd. All rights reserved.
Introduction The past two decades have witnessed tremendous advances in the treatment of breast cancer with significant strides made in improving outcomes in women with early breast cancer [1]. Adjuvant endocrine treatment in hormone responsive breast cancer has significantly contributed to this positive trend [2]. Three major adjuvant endocrine treatment options exist - tamoxifen, aromatase inhibitors (AI) and ovarian function suppression (OFS) either by ovarian ablation (surgical bilateral oophorectomy or ovarian irradiation) or using medications such as Gonadotropin-Releasing
Hormone (GnRH) agonists (also known as Luteinizing HormoneReleasing Hormone [LHRH] agonists). Various meta-analyses of randomized clinical trials have helped define the use of these three approaches either alone or in combination or in sequence in the adjuvant setting [3e5]. However, recent publications of trials investigating extended endocrine therapy and refining our knowledge about the role of OFS have illuminated this field further [6e11]. This article aims to review the recent updates in the field of adjuvant endocrine treatment of breast cancer in premenopausal women, especially with regards to the type and duration of treatment. Data about extended adjuvant endocrine treatment
* Corresponding author. Tel.: þ1 412 623 3205. E-mail address: [email protected] (N.E. Davidson). 1 Division of Medical Oncology, Department of Medicine, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA. http://dx.doi.org/10.1016/j.breast.2015.07.027 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
Tamoxifen The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) individual patient data meta-analysis continues to show a
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significant reduction of breast cancer deaths in patients with hormone receptor-positive breast cancer who received five years of tamoxifen, including women who were likely premenopausal by virtue of age at time of diagnosis, even after 15 years from study entry [3]. This comprehensive meta-analysis proved several principles of tamoxifen therapy. First, tamoxifen was found to be useful in decreasing breast cancer death and recurrence in hormone responsive breast cancer, even in weakly hormone receptor-positive tumors; but it did not improve breast cancer outcomes in hormone receptor-negative disease. Second, the benefit of at least 5 years of tamoxifen carries over for at least 10 more years (carry-over effect). Third, an improvement in breast cancer mortality was seen across all age groups, irrespective of menopausal status; although the risk of uterine cancer was higher in older women (Relative Risk [RR] of 2.96 in ages 55e69, 1.75 in ages 45e54 and 1.04 in women less than 45 years old). Finally, it also confirmed that longer tamoxifen use (5 years) was more efficacious than shorter duration (1e2 years). Based on small trials 5 years of adjuvant tamoxifen use has been the prevailing standard of care for more than a decade, though it was hypothesized that extended tamoxifen treatment could result in further improvement in outcomes. The joint analysis of E4181 and 5181 trials supported a longer time to relapse with a strategy of indefinite tamoxifen use compared to only 5 years in the subgroup of hormone receptor-positive disease (p ¼ 0.014), whereas the National Surgical Adjuvant Breast and Bowel Project (NSABP) B14 and the Scottish Adjuvant Tamoxifen trial found no beneficial effect with extended tamoxifen use [12e14]. More recently, two large randomized trials with a similar study design - Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial and the adjuvant TamoxifeneTo offer more (aTTom) trial - provide further guidance to answer the important question of extended tamoxifen use in hormone responsive breast cancer [6,7]. Although the ATLAS trial randomized 12,894 women with early breast cancer, the primary analysis was restricted to patients with hormone receptor-positive disease (n ¼ 6846) [6]. The study found a 2.8% absolute breast cancer mortality reduction for patients on extended tamoxifen use versus tamoxifen for 5 years after 10 years from randomization or 15 years from diagnosis of early-stage breast cancer (12.2% vs. 15.0%). The relative risk reduction was most notable after the end of the 10-year tamoxifen use (breast cancer mortality recurrence rate ratio in years 10e14 ¼ 0.71 [95% confidence interval (CI) 0.58e0.88]). Both the recurrence rate ratio and breast cancer mortality rate ratio were non-significant between the two cohorts in the years 5e9. Similar effects were seen across all subgroups of clinical importance, such as age, nodal status, tumor size, and menopausal status at study entry although only about 11% of women were premenopausal. The UK counterpart of the ATLAS trial e aTTom e randomized 6953 women who completed 5 years of adjuvant tamoxifen treatment to 5 more years of tamoxifen or none. Sadly estrogen receptor [ER] status was untested in many of these women [7]. The results of the aTTom trial were quite similar to the ATLAS. Patients on extended tamoxifen had significant reduction in breast cancer recurrence, breast cancer mortality and death during 10e14 years. The full publication of the aTTom trial is eagerly awaited. Taken together, ATLAS and aTTom trials provided strong evidence favoring extended tamoxifen for total treatment duration of 10 years rather than 5 years for selected patients [3,6,7]. The benefit appears to be enjoyed by premenopausal women though the numbers of such women in these studies are small. Aromatase inhibitors Aromatase inhibitors (AI) are a mainstay for management of breast cancer in postmenopausal women but are contraindicated as
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monotherapy for premenopausal patients. One proven strategy for extended adjuvant endocrine therapy in postmenopausal women involves completion of 5 years of tamoxifen followed by 5 years of adjuvant letrozole based on the results of the MA17 trial [15]. The MA17 trial found a 6% absolute improvement in 4-year diseasesurvival rate (87% vs. 93%) favoring letrozole compared with placebo. Importantly the same benefit was seen for women who were premenopausal at the time of tamoxifen initiation but became postmenopausal during tamoxifen administration [16]. Similar results were observed with the use of exemestane, a steroidal aromatase inhibitor (NSABP B33 trial) [17]. The results of the MA17 and NSABP B33 trials provide an alternative approach for extended adjuvant therapy for patients who are pre- or perimenopausal at the start of adjuvant tamoxifen treatment and then become postmenopausal while on treatment. This strategy might mitigate risk for endometrial cancer when compared with the use of 10 years of tamoxifen, making it an attractive strategy so long as it is clear that the patient has truly become menopausal before AI is started. Adverse effects of extended endocrine treatment The benefit of extended tamoxifen treatment comes with relatively low cost and toxicity, especially for premenopausal women. The ATLAS trial showed increased relative risk for incidence of pulmonary embolism (RR 1.87, 95% CI 1.13e3.07) and endometrial cancer (RR 1.74, 95% CI 1.30e2.34). No difference in risk for stroke was noted [6], and extended tamoxifen use was found to have a protective effect on the risk for ischemic heart disease. Unfortunately, the ATLAS trial does not report on quality of life outcomes such as sexual dysfunction or menopausal symptoms. The major concern with extended tamoxifen was the report of a 0.2% absolute mortality increase due to endometrial cancer (0.4% vs. 0.2%) in this study in which about 90% of study participants were postmenopausal at study entry. Similarly, the aTTom trial also reported an increase in mortality with an absolute risk of 0.5% (1.1% vs. 0.6%; p ¼ 0.02) [7]. It seems likely that the elevated risk of endometrial cancer is largely a function of the predominance of postmenopausal women in these trials, and this could support a strategy to switch from tamoxifen to an AI if the patient becomes postmenopausal. This approach is not devoid of side effects however. The MA17 trial reports increased incidence of hot flashes, arthritis, arthralgia and myalgia and slightly higher incidence of osteoporosis in patients on extended letrozole compared to placebo (5.8% vs. 4.5%; p ¼ 0.07), although there was no difference in fracture rates [15]. The NSABP B33 trial noted a higher incidence of grade 3 or 4 arthralgia (1.0% in exemestane group vs. 0.5% in placebo) and fatigue [17]. No difference in fracture rates was seen. Overall, the strategy of extended tamoxifen use appears to be safe in premenopausal women. The efficacy and safety data from the extended aromatase inhibitor trials also support a switch strategy from tamoxifen to an AI upon attaining menopause, for up to 5 years (total 10 years of endocrine treatment). American Society of Clinical Oncology guideline After reviewing the above mentioned trials, the American Society of Clinical Oncology (ASCO) Clinical Practice Guideline committee on adjuvant endocrine therapy for women with hormone responsive breast cancer recommended tamoxifen for 10 years, or tamoxifen for 5 years followed by either an aromatase inhibitor for 5 years (if patient is postmenopausal at the end of year 5) or tamoxifen for 5 more years (if patient is pre- or postmenopausal at the end of year 5) [18]. In aggregate then, the ASCO guideline endorsed extended adjuvant endocrine treatment for 10 years in
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premenopausal women with hormone responsive breast cancer. The most remarkable effect of the ATLAS and aTTom study was the carry-over effect of the benefits of adjuvant therapy to a period of at least 5 years from treatment discontinuation. Molecular tests to predict benefit for extended endocrine treatment Identifying patients who may benefit most from this carry-over effect, for instance, patients who are at the highest risk for late distant recurrences, may help predict benefit for extended endocrine treatment. While traditional prognostic factors such as age, tumor size, grade and nodal status could be used to identify patients who may benefit most from extended endocrine therapy, it has a limited role in identifying patients at the highest risk of late distant recurrences [18]. OncotypeDx recurrence score, a genomic profile test used in predicting benefit for adjuvant chemotherapy in early-stage breast cancer, initially failed to identify patients who may get late distant recurrences but recent unpublished data suggest that it might be valuable [19,20]. Zhang et al., used an algorithmic gene expression-based signature to predict early (0e5 years) and late (>5 years) risk of distant recurrences (Breast Cancer Index, BCI) [20,21]. In a retrospective analysis of tumor tissues of hormone responsive, node negative, early-stage breast cancer patients treated with tamoxifen, they showed that individuals with low BCI at the end of 5 years have a remarkably low rate of late distant recurrence (<5% for years 5e10). Another biomarker driven approach was recently published by Sestak et al. using the PAM50-based risk of recurrence (ROR) score in a retrospective analysis of two large clinical trials (ABCSG8 and ATAC) [22]. Similar to the BCI, the authors found that the risk of distant recurrences during years 5e10 in patients categorized as having low ROR score was remarkably lower than those in the intermediate or high risk group. The study also noted that a gene expression-based score would add clinically meaningful information on risk for late distant recurrences (during 5e10 years) to traditional prognostic factors based on age, grade, tumor size and nodal status. Presumably, patients with low BCI or low PAM50 ROR score could be spared extended endocrine treatment. While these studies provide a proof-of-principle for a molecular tool to predict late distant recurrences, such a biomarker driven approach may not be able to identify patients who may or may not absolutely require extended endocrine treatment. The use of such a biomarker approach in the setting of 10 years of endocrine therapy with its carry-over effect being significant during years 10e14, may necessitate an analysis of distant recurrence rate after year 10, and not just during 5e10 years after breast cancer diagnosis. Ovarian function suppression Ovarian function suppression (OFS) was one of the first adjuvant treatment modalities used in premenopausal breast cancer. There are two major approaches to suppress ovarian estrogen production: ovarian ablation by surgical oophorectomy or ovarian radiation, and OFS using GnRH agonists [23]. Prior studies noted some reduction in breast cancer recurrences in patients receiving some form of OFS in addition to tamoxifen, especially in younger women with hormone responsive breast cancer [24,25]. A large individual patient data meta-analysis of 16 trials conducted in premenopausal women with hormone responsive disease found reduction in recurrences when GnRH agonists were used in combination with chemotherapy or tamoxifen or both [4]. No statistically significant beneficial effect for GnRH agonist used as the only adjuvant systemic treatment was noted though statistical power was limited. The results of several of the included trials were confounded by
adjuvant chemotherapy use, which in itself causes OFS and may therefore indirectly act as an endocrine therapy. With these positive signals, four recently reported or updated randomized trials were initiated to investigate the efficacy and tolerability of OFS in combination with tamoxifen or aromatase inhibitors [8e11]. All four trials ensured that patients had endocrine-responsive early breast cancer and were premenopausal at the time of randomization, although some patients may have previously received adjuvant chemotherapy. OFS plus tamoxifen The Suppression of Ovarian Function Trial (SOFT) randomized 3066 premenopausal women with early-stage breast cancer to receive 5 years of tamoxifen, tamoxifen plus OFS or exemestane plus OFS; OFS was achieved with monthly doses of triptorelin, surgical oophorectomy or ovarian radiation [9]. Chemotherapy was permitted based on patient and physician choice but such patients had to demonstrate retention or return of ovarian function as documented by a premenopausal estradiol level. Randomization was stratified by prior receipt of adjuvant chemotherapy or not. Initially framed as a three arm trial, a subsequent revision of the analysis plan led to the decision to compare tamoxifen versus tamoxifen plus OFS. Thus the SOFT trial aimed to investigate differences in 5-year disease-free survival (DFS) (time from randomization to occurrence of local regional or distant breast cancer recurrence or contralateral breast cancer, death without recurrence or a non-breast second cancer) between tamoxifen plus OFS and tamoxifen. After a median follow-up of 67 months, there was no difference between the two groups in DFS rate (86.6% in tamoxifen plus OS group vs. 84.7% in tamoxifen group; p ¼ 0.10). The multivariable adjusted analysis suggested a 22% reduction in risk for DFS rate for patients on tamoxifen plus OFS (Hazard ratio [HR] 0.78; p ¼ 0.03). Of note, patients who did not receive adjuvant chemotherapy (comprising 46.7% of study population) had excellent outcome with DFS of greater than 90% in both groups. Nonetheless, the SOFT trial found that patients who received chemotherapy and remained premenopausal had a 3.6% improvement in DFS rate (80.7% in tamoxifen plus OFS group vs. 77.1% in tamoxifen group) [9]. The investigators assessed freedom from breast cancer as a secondary endpoint, defined as time from randomization to occurrence of locoregional or distant recurrence of breast cancer or contralateral breast cancer. More than 95% of patients who did not receive adjuvant chemotherapy remained free from breast cancer after 5 years. Among the cohort of patients who received adjuvant chemotherapy, the 5-year freedom from breast cancer rates are 82.5% for tamoxifen plus OFS and 78.0% in the tamoxifen-only group (HR 0.78; 95% CI, 0.60e1.02). In a prespecified analysis of women younger than 35 years (11.5% of total study participants), the rates of freedom from breast cancer were 78.9% (tamoxifen plus OFS) and 67.7% (tamoxifen alone). Of note, 94% of women in this age group received adjuvant chemotherapy. In summary, the SOFT found no overall benefit for adding ovarian suppression to tamoxifen in all premenopausal women, although it showed a beneficial effect on a subgroup analysis of women <35 years and patients who received chemotherapy. The Eastern Cooperative Oncology Group (ECOG) (E-3193, INT0142) trial also evaluated the role of tamoxifen plus OFS (using goserelin, surgical oophorectomy or ovarian irradiation) versus tamoxifen alone for 5 years in premenopausal women with nodenegative hormone responsive breast cancer [8]. The trial was prematurely closed due to slow accrual and hence its conclusions on efficacy are underpowered. With nearly 10 years of follow-up, the E-3193 trial showed no difference in overall survival or DFS between the two groups. However it did meet its endpoints for
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patient-reported quality of life and symptoms. Since none of the patients in this trial received adjuvant chemotherapy and because it collected toxicity and patient-reported outcomes at regular intervals during the study period, its findings that OFS diminishes quality of life relative to tamoxifen for the first 2e3 years and then differences are diminished by year 5 are important results. OFS plus aromatase inhibitors Although AI are contraindicated in premenopausal women, use of OFS either through GnRH agonists or ovarian ablation procedures permits their administration in pre- or perimenopausal patients. Extrapolating from the results of the AI versus tamoxifen trials in postmenopausal women, it was hypothesized that AI in combination with OFS may reduce breast cancer recurrences in women with premenopausal breast cancer compared with tamoxifen plus OFS or tamoxifen alone [5]. The Tamoxifen and Exemestane Trial (TEXT) in premenopausal women with hormone responsive breast cancer aimed to compare OFS plus tamoxifen versus OFS plus exemestane; participants were permitted to receive adjuvant chemotherapy at physician and patient discretion and 60% of patients did so. OFS was begun concomitant with chemotherapy if chemotherapy was used. As noted earlier the SOFT trial also had arms comparing tamoxifen plus OFS and exemestane plus OFS in addition to an arm of patients on only tamoxifen, and the primary analysis was confined to tamoxifen plus OFS versus tamoxifen alone [10]. Since SOFT and TEXT were very similar in design, the investigators decided to conduct a joint analysis of both trials to investigate the efficacy of exemestane plus OFS versus tamoxifen plus OFS [10]. After a median follow-up of 68 months, the SOFT/TEXT combined analysis found 3.8% absolute reduction in 5-year disease-free survival (DFS) rates in patients receiving exemestane plus OFS versus tamoxifen plus OFS (91.1% vs. 87.3%; HR 0.72, 95% CI, 0.60e0.85; p < 0.001) [10]. The 5-year breast cancer free rates also favored the exemestane group (92.8% vs. 88.8%). Exemestane plus OFS was found to be more efficacious in all the pre-specified subgroups stratified by chemotherapy use, nodal status and also in each of the trials separately. No difference in survival was seen at this analysis. An important finding of the SOFT/TEXT analysis was the 5-year breast cancer free rate of 97% with either therapy in patients who did not receive chemotherapy. The Austrian Breast and Colorectal Cancer Study Group (ABCSG) investigated the efficacy of anastrozole plus OFS or tamoxifen plus OFS in premenopausal women with hormone responsive breast cancer [11]. OFS was achieved by using goserelin. The ABCSG-12 trial also aimed to investigate an adjuvant role for bisphosphonates, in a factorial study design. The recently published final analysis following a median follow-up of 94 months showed no difference in DFS but noted a higher risk of death for patients treated with anastrozole plus goserelin (HR 1.63, 95% CI, 1.05e1.45; p ¼ 0.03), although the reason for this effect is unclear. Previous work from this study suggested that high body mass index may reduce efficacy of AI plus OFS but not tamoxifen plus OFS. Adverse effects of ovarian suppression The side effect profile of OFS with tamoxifen or exemestane is well described in these trials. The E-3193 trial collected data on health-related quality of life, menopausal symptoms and sexual functions at regular intervals until 5 years [8]. Since the trial participants did not receive chemotherapy, the toxicity and tolerability data will more accurately reflect the effects of endocrine treatment. It was observed that patients on tamoxifen plus OFS had significant deterioration of menopausal symptoms, sexual function and health-related quality of life compared with
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tamoxifen monotherapy at the end of 3 years. There was no significant difference in toxicity between the two groups at year 5. In the SOFT trial, there were more hot flushes, sexual dysfunction, vaginal dryness and metabolic syndrome in patients on combined tamoxifen plus OFS than tamoxifen alone. There was greater incidence of osteoporosis in the combination arm of SOFT (5.8% vs. 3.5%) [9]. The combined SOFT/TEXT analysis found a higher incidence of osteoporosis in the exemestane plus OFS cohort compared with tamoxifen plus OFS group (13.2% vs. 6.4%) [10]. The two groups had distinct side effect profiles e more fractures (6.8% vs. 5.2%), sexual dysfunction (vaginal dryness, dyspareunia and decreased libido) and musculoskeletal symptoms (88.7% vs. 76.0%) were noted in the OFS plus exemestane group and increased incidence of hot flushes (93.3% vs. 91.7%), thromboembolic events (2.2% vs. 1.0%) and urinary incontinence (17.8% vs. 13.1%) were seen in patients receiving tamoxifen plus OFS. Considerations about use of OFS-based strategies After the American Society of Clinical Oncology endorsed the Cancer Care Ontario guideline against the routine use of adjuvant OFS in premenopausal women with early-stage hormone-responsive breast cancer either alone, or in combination with chemotherapy or endocrine therapy, four major clinical studies have been published or updated (ABCSG-12, E-3193, SOFT/TEXT and SOFT) [26]. The SOFT results showed that adding OFS to tamoxifen does not improve DFS or reduce breast cancer recurrences in all patients with hormone responsive tumors as compared to using 5 years of tamoxifen alone [9]. However, the SOFT trial investigators found a beneficial effect in women who remained premenopausal after adjuvant chemotherapy use and in women younger than 35 years of age. The SOFT/TEXT joint analysis confirmed a significant beneficial effect for exemestane plus OFS versus tamoxifen plus OFS in all premenopausal women with hormone responsive breast cancer, although the absolute risk reduction was more pronounced in the cohort of patients who received adjuvant chemotherapy [10]. The analysis, however, observed a non-significant 14% increase in risk for death (p ¼ 0.37) in the group receiving exemestane plus OFS although further follow-up is needed, especially given the adverse effects of goserelin plus anastrozole seen in the ABCSG-12 study (63% increased risk for death with anastrozole use; p ¼ 0.03) [11]. Further follow-up and more mature data are clearly needed. Importantly, the SOFT trial shows that a large proportion of premenopausal women with low-risk tumors do extremely well with just 5-years of tamoxifen [9]. In aggregate the SOFT, SOFT/ TEXT, ABCSG-12 and the E-3193 trials show that the strategy of tamoxifen plus OFS is a reasonable approach in women with higher risk for tumor recurrence, although this should be balanced against the slightly higher risk for side effects [8e11]. Finally, short term results from SOFT and TEXT show the best breast cancer recurrence outcomes with AI plus OFS though further follow-up is vital since the side effect profile may also be greater and data about survival are immature. Of course, none of these trials take into account newer data on extended tamoxifen as a strategy. The issue of adherence to treatment has to be brought into the process of decision making. A large retrospective study has found that more than 50% patients are non-adherent to adjuvant endocrine treatment with tamoxifen or AI [27]. Patients who were nonadherent to optimal endocrine treatment had an increased risk for mortality after 10 years of follow-up [28]. While it appears that OFS-based strategies are effective, if the side effects of adding OFS cause significant distress for the patient, there will be a greater likelihood for non-compliance. At a minimum, in such situations
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premenopausal patients should be counselled to at least continue tamoxifen. Several questions regarding OFS remain unanswered. In the absence of comparative data, it is assumed that suppression of ovarian function with GnRH agonist therapy is equivalent to ovarian ablation using either surgical bilateral oophorectomy or ovarian irradiation [23]. The optimal duration of OFS is also uncertain. The large randomized trials used 3 years (ABCSG-12) or 5 years (TEXT, SOFT, E-3193) although some earlier trials included in the meta-analyses used shorter durations. At present it appears that 3e5 years duration is rational. The timing of initiation of OFS, especially in patients destined for adjuvant chemotherapy, is also unclear. The TEXT trial used OFS concomitantly with adjuvant chemotherapy whereas the SOFT participants were initiated on OFS up to 8 months from completion of chemotherapy [10]. The DFS in the chemotherapy cohort of patients on tamoxifen plus OFS was 84.6% in the TEXT and 80.6% in the SOFT [10]. Thus both sequential and concurrent approaches seem to be supported. Of note, the participants in the chemotherapy cohort in TEXT were older and had higher proportion of node-positivity and larger tumor size, and the SOFT participants included more patients with HER2-positive status, although inter-trial comparison is fraught with difficulty. The investigators of SOFT and TEXT plan to conduct an analysis of a possible predictive role for HER2-status in determining the type of adjuvant endocrine treatment. Another major concern for use of AI in combination with OFS in premenopausal women is the possibility of suboptimal suppression of ovarian estrogen production. The SOFT-EST, a prospective substudy of SOFT, observed that nearly 20% of patients on AI had suboptimal suppression of estrogen production during the study period [29]. The interaction of body mass index with AI use in premenopausal women is also an area of concern. The ABCSG-12 investigators noted a higher risk for death and disease recurrence in overweight premenopausal women receiving anastrozole plus OFS compared to women with normal body mass index [30]. Such a differential effect was not seen in women receiving tamoxifen plus OFS. Incomplete OFS or greater aromatase activity could result in suboptimal estrogen suppression and result in a greater risk for breast cancer recurrence in overweight or obese patients receiving OFS plus AI. It is also unclear if OFS will provide a carry-over effect as was seen with the use of extended tamoxifen treatment [6,7]. Clearly, our trials of adjuvant endocrine treatment require longer follow-up for a more complete understanding of benefits and risks of treatment, and the 5-year follow-up in the current analyses of SOFT and TEXT trials may be considered preliminary [9,10]. Conclusion The recent publication of several much awaited adjuvant endocrine treatment trials introduces more evidence-based choices for premenopausal women with hormone responsive early-stage breast cancer. The options are tamoxifen for 5 years (EBCTCG meta-analysis), switch strategy using tamoxifen for 5 years followed by an AI for 5 years in women who become postmenopausal while on adjuvant treatment (MA17, NSABP B-33), extended tamoxifen for 10 years (ATLAS, aTTom), and the addition of OFS to tamoxifen or an AI (SOFT, TEXT, ABCSG-12, E-3193). Women with low risk of recurrence could be offered tamoxifen for 5e10 years or the switch strategy if they become truly postmenopausal during adjuvant tamoxifen. Patients with a higher risk for recurrence could be offered tamoxifen plus OFS or AI plus OFS for 3e5 years. There is no information to support longer duration of OFS-based strategies. A potential advantage with use of AI plus OS could be jeopardized by suboptimal estrogen suppression.
Given the long natural history of hormone responsive breast cancer, longer follow-up of trials will be critical to ascertain benefit and document unexpected late toxicities, if any. A pressing need is the identification of markers that can identify patients who need extended adjuvant endocrine therapy as well as markers that might allow selection of those that would benefit from the addition of OFS. Studying post-progression molecular changes in patients who were on the extended tamoxifen or combination OFS strategies will be crucial in understanding potential mechanisms of resistance. Finally, most trials have used medical, surgical, and radiotherapeutic approaches to OFS interchangeably, but the equivalence of these therapies in the adjuvant setting especially in combination therapy is not certain and may require further assessment through follow-up of completed trials. What has become clear is that adjuvant endocrine therapy is a vital part of the treatment plan for most premenopausal women with hormone responsive breast cancer and a subset of these women with low risk tumors can be safely treated with simple endocrine therapy like tamoxifen alone. Conflict of interest statement The authors have no conflicts of interest. References [1] Siegel R, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65: 5e29. [2] Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353:1784e92. [3] Davies C, Godwin J, Gray R, Cutter D, Darby S, McGale P, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378: 771e84. [4] Cuzick J, Ambroisine L, Davidson N, Jakesz R, Kaufmann M, Regan M, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007;369:1711e23. [5] Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28:509e18. [6] Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805e16. [7] Gray RG, Rea DW, Handley K, Marshall A, Pritchard MG, Perry P, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31. Suppl; Abstr 5. [8] Tevaarwerk AJ, Wang M, Zhao F, Fetting JH, Cella D, Wagner LI, et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2014;32:3948e58. [9] Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Lang, E. Ciruelos, M. Bellet, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;372:436e46. ng I, et al. Adju[10] Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, La vant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371:107e18. [11] Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group trial 12. Ann Oncol 2014;26:313e20. [12] 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 1996;88:1828e33. [13] Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 2001;93:456e62. [14] Fisher B, Dignam J, Bryant J, Wolmark N. 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 2001;93:684e90.
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