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Impact of ovarian function suppression in premenopausal women with estrogen receptor-positive early breast cancer

Lambertini, Matteoa; Viglietti, Giuliab; de Azambuja, Evandroa

doi: 10.1097/CCO.0000000000000491
BREAST CANCER: Edited by Giuseppe Curigliano

Purpose of review This manuscript aims at providing an updated overview on the role of adding ovarian function suppression to tamoxifen or an aromatase inhibitor as adjuvant endocrine therapy in premenopausal women with estrogen receptor-positive early breast cancer.

Recent findings Until recently, tamoxifen alone was the only recommended adjuvant treatment option for premenopausal women with estrogen receptor-positive disease. However, recent important evidence has contributed to significantly modify the endocrine treatment landscape in this setting.

Summary With the only exception of patients with low-risk clinical-pathological features characterized by excellent survival outcomes with tamoxifen alone, the use of ovarian function suppression is to be considered standard of care for most of premenopausal women with estrogen receptor-positive disease. Regarding the choice of its best partner as endocrine agent, the available data suggest that the higher the risk of disease recurrence the larger benefit can be observed with a more profound estrogen deprivation that can be obtained with ovarian function suppression and an aromatase inhibitor as compared to ovarian function suppression and tamoxifen. Despite the significant improvement in our understanding on the role of ovarian function suppression in this setting, several unanswered questions remain and further research efforts are needed in the field.

aDepartment of Medicine

bBreast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium

Correspondence to Matteo Lambertini, MD, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Boulevard de Waterloo 121, 1000 Brussels, Belgium. Tel: +32 2 541 3099; e-mail: matteo.lambertini85@gmail.com

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INTRODUCTION

Despite the increased risk of developing estrogen receptor-negative tumors as compared with older patients, luminal-like disease remain the most commonly diagnosed form of breast cancer also in young women [1]. Young age at diagnosis appears to retain an independent poor prognostic value only in women with luminal-like tumors [2]. Therefore, the use of adjuvant endocrine therapy and the choice of the best treatment strategy are particularly important in premenopausal women with estrogen receptor-positive early breast cancer.

More than 100 years ago, oophorectomy was discovered to have a therapeutic role in premenopausal breast cancer patients [3]. In addition, since many years, chemotherapy-induced amenorrhea is known to have a strong prognostic value in young women with estrogen receptor-positive disease [4,5]. Nevertheless, despite the availability of effective ways to obtain ovarian function suppression both permanently (i.e., bilateral ovarian irradiation or bilateral oophorectomy) or temporarily [i.e., by administering a gonadotropin-releasing hormone agonist (GnRHa)], the benefit of combining it with standard adjuvant endocrine therapy has been an unsolved question for many years [6].

Until recently, tamoxifen alone was the only recommended adjuvant treatment option for premenopausal women with estrogen receptor-positive disease [7▪,8▪▪,9▪]. However, recent important evidence from large randomized trials has contributed to significantly modify the treatment recommendations in this setting.

In this manuscript, we aim at providing an updated overview on the role of adding ovarian function suppression to tamoxifen or an aromatase inhibitor as adjuvant endocrine therapy in premenopausal women with estrogen receptor-positive disease.

Box 1

Box 1

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OVARIAN FUNCTION SUPPRESSION AND TAMOXIFEN

Until 2014, the addition of ovarian function suppression to tamoxifen was not recommended by available guidelines [7▪,8▪▪,9▪]. In a meta-analysis including five randomized trials (n = 1013 patients), no significant benefit in reducing the risk of recurrence [hazard ratio (HR), 0.85; 95% confidence intervals (CI), 0.67–1.09; P = 0.20] or death after recurrence (HR, 0.84; 95% CI, 0.59–1.19; P = 0.33) was observed with the addition of GnRHa to tamoxifen alone [10]. More recently, three randomized trials have better clarified the role of adding ovarian function suppression to tamoxifen in this setting.

The E-3193, INT-0142 trial randomly assigned to tamoxifen with or without ovarian function suppression for 5 years 345 premenopausal women with small node-negative breast cancer (i.e., at low risk of disease recurrence) [11]. Prior (neo)adjuvant chemotherapy was not allowed. The study closed early without reaching the planned accrual of 1600 patients. After a median follow-up of 9.9 years, ovarian function suppression added to tamoxifen neither improve disease-free survival (DFS; adjusted HR, 1.17; 95% CI, 0.64–2.12; P = 0.62) nor overall survival (OS; adjusted HR, 1.19; 95% CI, 0.52–2.70; P = 0.67). The combination of ovarian function suppression and tamoxifen was associated with worse health-related quality of life mainly because of increased menopausal symptoms and lower sexual activity [11].

The SOFT trial randomized 3066 patients to 5 years of endocrine therapy with tamoxifen alone, ovarian function suppression and tamoxifen or exemestane [12]. Patients who received prior chemotherapy (53% of the study population) could be randomized within 8 months after the final dose of cytotoxic therapy only in the presence of premenopausal estradiol levels. Among the 2033 patients included in the primary analysis comparing tamoxifen with or without ovarian function suppression, no difference in DFS (HR, 0.83; 95% CI, 0.66–1.04; P = 0.10), freedom from distant recurrence (HR, 0.88; 95% CI, 0.66–1.18; P = 0.40), or OS (HR, 0.74; 95% CI, 0.51–1.09; P = 0.13) was observed after a median follow-up of 5.6 years. A potential benefit of adding ovarian function suppression to tamoxifen was observed in selected group of patients such as those with prior exposure to chemotherapy, HER2-positive tumors (of note, only 61% of these patients received anti-HER2 adjuvant therapy), or diagnosed at less than 35 years of age [12]. The recently reported updated findings at a median follow-up of 8 years showed more consistent results favoring the addition of ovarian function to tamoxifen [13]. Overall, the combined treatment significantly improved DFS (HR, 0.76; 95% CI, 0.62–0.93; P = 0.009) and OS (HR, 0.67; 95% CI, 0.48–0.92; P = 0.01) with no difference in freedom from distant recurrence (HR, 0.86; 95% CI, 0.66–1.13; P = 0.28; Fig. 1). The DFS benefit was larger and more evident for the patients who received prior chemotherapy, in those with HER2-positive disease and in women diagnosed under the age of 35 (Fig. 2) [13]. At the patient-reported outcomes analysis, endocrine symptoms and sexual functioning (i.e., vaginal dryness, loss of sexual interest, hot flushes, and sleep disturbance) were worsened in patients who received ovarian function suppression particularly in the first 2 years of treatment and in women who did not receive prior chemotherapy [14]. Global cognitive function 1 year after diagnosis was similar in the two treatment arms [15]. Early cessation of ovarian function suppression was observed in approximately 20% of the patients who received GnRHa [13]. Nonadherence with medical ovarian function suppression was significantly higher among women younger than 35 years at diagnosis [16].

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

The ASTRRA study randomized 1282 premenopausal patients with 45 or less years to 5 years of endocrine therapy with tamoxifen alone or added to ovarian function suppression for 2 years [17,18]. All patients received prior chemotherapy; premenopausal status up to 2 years after the end of chemotherapy (defined based on menstrual history or follicle-stimulating hormone levels) was required for being eligible to randomization. After a median follow-up of 5.6 years, the addition of 2 years of ovarian function suppression to 5 years of tamoxifen showed to significantly improve DFS (HR, 0.69; 95% CI, 0.48–0.97; P = 0.033) and OS (HR, 0.31; 95% CI, 0.10–0.94; P = 0.029). The benefit was consistent among all patient subgroups [18]. Full publication is awaited to better interpret the results including the impact of the different timing of ovarian function suppression initiation.

Taken together, data from these three recent randomized trials suggest that the addition of ovarian function suppression to tamoxifen is beneficial in premenopausal women with estrogen receptor-positive breast cancer at intermediate or high risk of disease recurrence such as patients who are often candidates also to receive (neo)adjuvant chemotherapy. On the other hand, for women affected by tumors at low risk of disease recurrence, the addition of ovarian function suppression does not appear to improve outcomes and does not justify the increased risk of its associated adverse events.

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OVARIAN FUNCTION SUPPRESSION AND AN AROMATASE INHIBITOR

When combined with ovarian function suppression in premenopausal patients, aromatase inhibitors showed substantial antitumor activity in the metastatic setting [19,20] as well as neoadjuvant treatment [21]. This combination proved also to be associated with a more profound suppression of hormone serum levels as compared with ovarian function suppression and tamoxifen [22]. The ABCSG 12 study [23], and the joint analysis of the SOFT and TEXT trials [13,24] represent the currently available evidence on the role of combining ovarian function suppression and aromatase inhibitors as adjuvant endocrine treatment in premenopausal women with estrogen receptor-positive early breast cancer.

The ABCSG-12 trial was a randomized study with a 2 × 2 factorial design that included 1803 premenopausal women at low risk of disease relapse (adjuvant chemotherapy was not allowed and only 5.4% received neoadjuvant chemotherapy) [23]. Patients were randomized to 3 years of ovarian function suppression and anastrozole or tamoxifen with or without zoledronic acid. After a median follow-up of approximately 8 years, when considering the comparison between anastrozole and tamoxifen, no difference in DFS was observed (HR, 1.13; 95% CI, 0.88–1.45; P = 0.335); however, OS was significantly worse for patients allocated to anastrozole (HR, 1.63; 95% CI, 1.05–2.52; P = 0.030) [23]. No patient-reported outcomes analysis has been reported for this study. The low-risk population of patients included in this study, the nonstandard 3-year duration of adjuvant endocrine therapy and the use of bisphosphonates in half of the study population should be considered in the interpretation of these findings.

The joint analysis of the TEXT and SOFT trials included 4690 patients that were randomly allocated to ovarian function suppression and exemestane or tamoxifen for 5 years [13,24]. In the primary analysis after a median follow-up of 5.7 years, exemestane showed to significantly improve DFS (HR, 0.72; 95% CI, 0.60–0.85; P < 0.001) and freedom from distant recurrence (HR, 0.78; 95% CI, 0.62–0.97; P = 0.02); however, there was no difference in OS (HR, 1.14; 95% CI, 0.86–1.51; P = 0.37) [24]. Patients affected by tumors with poor prognostic features (e.g., low progesterone receptor and/or high Ki67) and characterized by a high risk of recurrence appeared to derive the greater benefit from the use of ovarian function suppression and exemestane [25,26]. The recently reported updated results of this trial at a median follow-up of 9 years showed similar DFS results favoring the combination of ovarian function suppression with exemestane (HR, 0.77; 95% CI, 0.67–0.90; P < 0.001) and freedom from distant recurrence (HR, 0.80; 95% CI, 0.66–0.96; P = 0.02) but OS remained similar in the two treatment groups (HR, 0.98; 95% CI 0.79–1.22; P = 0.84; Fig. 3) [13]. At the subgroup analysis, the only heterogeneity of treatment effect was observed according to HER2 status: exemestane was superior to tamoxifen only in patients with HER2-negative tumors with an opposite trend in those with HER2-positive disease (Fig. 4) [13]. A recent analysis conducted within the TEXT and SOFT trials has tried to better assess the magnitude of absolute treatment effect based on patients individual risk of recurrence in the overall population of included women with HER2-negative disease [27]. When considering the comparison between ovarian function suppression and exemestane or tamoxifen, the 8-year freedom from distant recurrence favored the use of aromatase inhibitors for patients previously exposed to chemotherapy (absolute improvement of 5.1% in the TEXT trial and 5.9% in the SOFT trial) with no difference in the no chemotherapy cohort (absolute difference of +0.9% in the TEXT trial and +1.0% in the SOFT trial). In the chemotherapy cohort of the TEXT trial, the improvement increased up to 15% in patients characterized by the highest ‘composite risk’ (i.e., in those harboring the worst clinical-pathological features). In the no chemotherapy cohort of the TEXT trial, the benefit favoring exemestane ranged between 2.5 and 4.0% at higher composite risks, with no difference in low-risk patients. Similar results but with a smaller absolute benefit were observed in the SOFT trial [27]. Patient-reported outcomes analysis showed small and similar changes in the global quality of life indicators, but a different toxicity profile of the two treatment options [28]. Vaginal dryness, difficulties in becoming aroused, greater loss of sexual interest, and increased bone or joint pain were more common with ovarian function suppression and exemestane while hot flushes and sweats with ovarian function suppression plus tamoxifen [28]. This led to a greater proportion of patients who prematurely discontinued oral endocrine therapy in the exemestane group as compared with the tamoxifen group (23.7 vs. 19.3%) [13].

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

Based on the available evidence on this regard, the best endocrine agent to be combined with ovarian function suppression appears to be an aromatase inhibitor for premenopausal patients with estrogen receptor-positive/HER2-negative early breast cancer at the highest risk of disease recurrence. On the other hand, tamoxifen alone or combined with ovarian function suppression remains an available option for women with more favorable prognostic features as well as for those who do not tolerate the use of aromatase inhibitors. Final results of the ongoing phase III HOBOE study (ClinicalTrials.gov Identifier: NCT00412022; expected for end of 2018) are awaited to give further insight on the role of ovarian function suppression and aromatase inhibitors [29,30].

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CONCLUSION

In the last few years, we have assisted to a significant change in the endocrine treatment landscape of premenopausal women with estrogen receptor-positive early breast cancer and the choice of the optimal adjuvant endocrine therapy has now become rather complex in this setting [31]. With the only exception of patients with low-risk clinical-pathological features characterized by excellent survival outcomes with tamoxifen alone, the use of ovarian function suppression is to be considered standard of care for most of these premenopausal women. Regarding the choice of its best partner as endocrine agent, the available data suggest that the higher the risk of disease recurrence the larger benefit can be observed with a more profound estrogen deprivation that can be obtained with ovarian function suppression and an aromatase inhibitor as compared with ovarian function suppression and tamoxifen. All the recently updated guidelines support these considerations (Table 1) [32▪▪–35▪▪].

Table 1

Table 1

Despite the significant improvement in our understanding on the role of ovarian function suppression as adjuvant treatment of premenopausal women with estrogen receptor-positive early breast cancer, several unanswered questions remain and further research efforts are needed in the field. First, considering the long-term risk of disease recurrence in women with luminal-like breast cancer [36], updated results from the abovementioned trials are warranted to better understand the magnitude of benefit associated with the use of ovarian function suppression and to better guide the choice between an aromatase inhibitor and tamoxifen as its best adjuvant endocrine partner [31]. Similarly, longer follow-up is needed to better elucidate the potential late negative consequences of such treatments including the need for supportive measures that include the use of bone-modifying agents for bone health preservation [37,38]. Second, for patients who are candidates to receive (neo)adjuvant chemotherapy before starting adjuvant endocrine therapy, the best timing for initiating ovarian function suppression remains controversial. Our preference toward starting ovarian function suppression together with chemotherapy and then continuing the treatment up to 5 years after diagnosis is supported by recent data suggesting both the safety of this approach [39] and its potential utility as a strategy for reducing the risk of premature ovarian failure and infertility linked with the use of systemic cytotoxic therapy [40,41]. Third, despite the recent evidence around the role of ovarian function suppression in premenopausal women with estrogen receptor-positive/HER2-positive early breast cancer [5,13], the best endocrine agent to be combined in this setting remains unknown. Postmenopausal women with estrogen receptor-positive/HER2-positive disease appear to derive a lower benefit with the use of aromatase inhibitors as compared with those with HER2-negative tumors [42], and a trend favoring tamoxifen and ovarian function suppression has been observed in premenopausal patients [13]. However, no solid conclusions can be drawn considering the small numbers of HER2-positive patients included in these studies. Fourth, in premenopausal women for whom an aromatase inhibitor has been chosen as partner of ovarian function suppression, the risk of suboptimal ovarian function suppression exists when GnRHa are used, particularly in patients who are very young, overweight, and not exposed to prior chemotherapy [43,44]. This is an issue of great importance considering also that young patients are characterized by poor treatment compliance [45], often related to concerns about fertility and posttreatment pregnancies [46–48]. However, the utility of estradiol monitoring during treatment remains debatable [49]. Finally, in women exposed to 5 years of ovarian function suppression, and particularly in those who also received an aromatase inhibitor, the choice toward the best type of extended adjuvant endocrine therapy remains challenging. A phase II study that tried to assess the value of combining ovarian function suppression and an aromatase inhibitor after 5 years of tamoxifen in this setting closed prematurely because of poor accrual after including only 16 patients [50]. Although an aromatase inhibitor may be the preferred choice in patients who become definitively postmenopausal after the first 5 years of treatment [51], tamoxifen represents the only option for those who remain premenopausal. In any case, no data support the use of ovarian function suppression beyond 5 years. Importantly, the choice of the optimal endocrine therapy in premenopausal women should be carefully discussed with patients and pros and cons should be taken into account for each strategy.

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Acknowledgements

M.L. acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at the Institut Jules Bordet in Brussels (Belgium).

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Financial support and sponsorship

None.

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Conflicts of interest

M.L. served as a consultant for Teva and received honoraria from Theramex outside the submitted work. E.d.A. received honoraria from Roche-Genentech, research grant from Roche–Genentech (to the insitution) and travel grants from Roche-Genentech and GlaxoSmithKline outside the submitted work. G.V. has no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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Keywords:

breast cancer; endocrine therapy; ovarian function suppression; premenopausal patients

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