The optimal adjuvant endocrine therapy in premenopausal women with early-stage breast cancer is yet to be elucidated. Studies have demonstrated that women who experience cessation of ovarian function after chemotherapy (chemotherapy-induced amenorrhea) may experience improved survival. These findings, however, have not been replicated when pharmacologic or surgical interventions have been used to stop ovarian function (eg, gonadotropin-releasing hormone agonists, oophorectomy, or ovarian irradiation) in combination with an endocrine agent such as tamoxifen or an aromatase inhibitor. Recent large phase III clinical trials, including the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12), Suppression of Ovarian Function Trial (SOFT), and Tamoxifen and Exemestane Trial (TEXT), did not demonstrate an improvement in disease-free survival with ovarian suppression in the overall population. However, subgroup analyses suggest that women at high risk for recurrence, including very young women or those who have received chemotherapy, may benefit from the addition of ovarian suppression. Still, toxicity and adverse effects on patient-reported outcomes were more frequent in patients who received ovarian suppression; these included more menopausal and sexual dysfunction symptoms, diabetes, hypertension, and osteoporosis. This review will summarize the experience with ovarian suppression in the adjuvant setting for the treatment of premenopausal early-stage breast cancer and offer recommendations for clinical management.
The optimal adjuvant endocrine therapy for premenopausal hormone receptor (estrogen receptor [ER], progesterone receptor [PR], or both)–positive breast cancer continues to evolve. Several meta-analyses have demonstrated that endocrine therapy in early-stage breast cancer confers a survival benefit and has a generally favorable toxicity profile.[1,2] At least 5 years of adjuvant tamoxifen has been the standard of care for premenopausal women for more than 2 decades and is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Guidelines in Oncology and the 2014 American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines, based on level 1 evidence.[3,4] The value of adding ovarian suppression is unclear. In premenopausal women, cessation of ovarian function can be achieved on a temporary basis by pharmacologic interventions that inhibit ovarian production of estrogen, such as gonadotropin-releasing hormone (GnRH) agonists, or permanently by surgery (oophorectomy) or pelvic radiation (ovarian ablation). Given the inconclusive evidence supporting the use of ovarian suppression, ASCO has endorsed guidelines recommending that ovarian ablation or suppression not be added routinely to adjuvant therapy in premenopausal women. International consensus guidelines have accepted the addition of GnRH agonists to tamoxifen or tamoxifen alone as standard endocrine therapies in premenopausal women, but they have admitted that evidence is lacking regarding the optimal duration of ovarian function suppression and note that this should be decided on an individual basis after discussion with the patient. Here, we provide an in-depth review of the current evidence for the addition of ovarian suppression to adjuvant endocrine therapy, and we offer recommendations for clinical management.
Chemotherapy-Induced Amenorrhea Is Associated With Improved Survival
Several studies have demonstrated an improvement in survival in women who developed cessation of ovarian function after adjuvant chemotherapy (chemotherapy-induced amenorrhea) for early-stage breast cancer.[7,8] In the International Breast Cancer Study Group (IBCSG) 13-93 trial, 1,246 premenopausal women with axillary node–positive breast cancer were enrolled and received chemotherapy (cyclophosphamide plus either doxorubicin or epirubicin for 4 cycles, followed by immediate or delayed classical cyclophosphamide, methotrexate, and fluorouracil [CMF] for 3 cycles) followed either by tamoxifen for 5 years or no treatment. Amenorrhea in this trial was defined as the absence of menses 15 months following randomization. Patients with ER-positive disease who achieved chemotherapy-induced amenorrhea had a significantly improved disease-free survival (DFS; hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.44–0.86) compared with patients without amenorrhea, whether or not they received tamoxifen.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-30 trial investigated the impact of chemotherapy-induced amenorrhea on survival in 5,351 patients receiving sequential doxorubicin and cyclophosphamide (AC) followed by docetaxel (T); the doxorubicin-docetaxel combination (AT); or concurrent doxorubicin, cyclophosphamide, and docetaxel (TAC). Among the 2,343 premenopausal patients with follow-up menstrual history who developed chemotherapy-induced amenorrhea (defined as no menstruation for at least 6 months during the 24-month follow-up), both overall survival (OS) and DFS were significantly increased (relative risk [RR], 0.76 and 0.70, respectively). In a 12-month landmark analysis, women with ER-positive tumors who had amenorrhea had a significantly better outcome than those who did not develop amenorrhea, with HR for death of 0.52 (P = .002) and HR for disease recurrence, second malignancy, or death of 0.51 (P < .001). Conversely, there was no significant difference in OS or DFS in women with ER-negative disease, regardless of amenorrhea status after chemotherapy. The antitumor effect of a lower estrogen state may offer a biologic basis for the plausibility of these results. Alternatively, chemotherapy-associated amenorrhea may simply represent a pharmacodynamic marker—of a particular patient’s pharmacogenomic variant that happens to affect individual toxicity and susceptibility to treatment.
Ovarian Suppression as a Single-Treatment Modality
To evaluate the role of ovarian suppression as a single agent in the adjuvant setting, the 2005 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a meta-analysis of six trials that included nearly 8,000 women under the age of 50 with ER-positive or ER-unknown early-stage breast cancer, who were randomly assigned to ovarian suppression or no further treatment. The age cut-off of 50 was used as a surrogate marker for menopausal status. Ovarian suppression significantly reduced breast cancer mortality (RR, 0.71) and risk of recurrence (RR, 0.75) at 15 years compared with observation but appeared to do so only in the absence of other systemic treatments. One limitation of this meta-analysis is that ER status was not tested in 63% of the patients who received ovarian ablation and in 26% of those who received ovarian suppression.
In contrast, the 2007 LHRH (luteinizing hormone–releasing hormone)–agonists in Early Breast Cancer Overview group meta-analysis examined 11,906 premenopausal patients with early-stage breast cancer randomized in 16 trials. This analysis focused on the 9,022 patients with ER-positive breast cancer, and patients with ER-unknown status were not included. GnRH agonists were most commonly used for 2 years, although some trials had durations of 18 months, 3 years, or 5 years. When GnRH agonists were used as the only systemic adjuvant treatment (n = 407), there was no significant reduction in recurrence (P = .08) or death (P = .11) in patients with hormone receptor–positive cancers, although the number of patients in this comparison was small and the analysis was likely underpowered for these two outcomes.
While these data suggest that there might be a role for ovarian suppression as a single-treatment modality, it is not commonly used in patients with early-stage breast cancer and is not relevant to modern practice.
Pharmacologic or Surgical Ovarian Suppression After Chemotherapy
The 2005 EBCTCG meta-analysis, which reported significantly improved recurrence rate and survival in patients who received ovarian suppression (compared with those who received no adjuvant ovarian suppression), also assessed efficacy in trials where chemotherapy was equivalent in both arms. There were no significant differences in the chemotherapy-only groups, except in women younger than 40 years, who achieved a significant reduction in recurrence with ovarian suppression (RR, 0.70; 95% CI, 0.39–.996). The reliability of these findings in very young women is limited by the small number of patients in this subgroup analysis. The 2007 LHRH-agonists in Early Breast Cancer Overview group meta-analysis found that the addition of GnRH agonists to tamoxifen, chemotherapy, or both (n = 3,754) significantly reduced recurrence by 12.7% (95% CI, 2.4–21.9) and death by 15.1% (95% CI, 1.8–26.7). Interestingly, GnRH agonists used alone demonstrated an efficacy similar to that of the chemotherapy regimens used in these trials, even though the majority of the chemotherapy regimens used were first-generation (66% of patients received a CMF-based regimen, and only 32% received an anthracycline-based regimen).
Individual studies suggest a benefit from ovarian suppression in patients treated with chemotherapy. In the North American Intergroup Trial (INT 0101, E5188), 1,503 premenopausal women with axillary lymph node–positive, ER-positive breast cancer were randomized to 6 cycles of cyclophosphamide, doxorubicin, and fluorouracil (CAF), CAF followed by 5 years of a GnRH agonist (monthly goserelin; CAF-Z), or CAF-Z with daily tamoxifen (CAF-ZT). After a median follow-up of 9.6 years, there was a trend towards lower risk of mortality with CAF-Z compared with CAF (HR, 0.86; 95% CI, 0.68–1.08); however, with regard to the risk of recurrence, no benefit was seen (HR, 0.91; 95% CI, 0.74–1.11). Of note, there was no arm with tamoxifen only that could have been used to evaluate the impact of adjuvant chemotherapy followed by tamoxifen without ovarian function suppression.
A European multicenter trial evaluated 926 premenopausal women with either axillary node–positive or histologic grade 2 or 3 breast tumors randomized to adjuvant chemotherapy with or without ovarian suppression. Ovarian suppression was achieved by radiation-induced ovarian ablation or triptorelin for 3 years. At a median follow-up of 9.5 years, there was no significant difference in OS (66% for chemotherapy alone vs 68% for chemotherapy plus ovarian suppression; P = .19), except for women in the ovarian suppression arm who were under 40 years of age and who had ER-positive tumors; these women had a significantly decreased risk of recurrence (RR, 0.55; 95% CI, 0.34–0.88). In IBCSG Trial VIII, 1,063 pre- and perimenopausal women with axillary lymph node–negative breast cancer were randomized to receive goserelin alone for 24 months, 6 cycles of classical CMF chemotherapy alone, or 6 cycles of classical CMF followed by 18 months of goserelin. In patients with ER-positive tumors, chemotherapy alone and goserelin alone resulted in similar 5-year DFS, whereas sequential therapy showed a trend for improved DFS compared with either modality alone.
Since most of these studies evaluated ovarian suppression with a first-generation adjuvant chemotherapy regimen (ie, CMF), the relevance of the results in modern practice is limited.
Ovarian Suppression in Combination With Tamoxifen
Although chemotherapy-induced amenorrhea or ovarian suppression used as a single agent was associated with improved survival outcomes, the addition of ovarian suppression to tamoxifen does not confer a survival benefit in most women with ER-positive breast cancer. The 2007 EBGTCG analysis demonstrated no significant difference in either the risk of recurrence (HR, 0.85; 95% CI, 0.67–1.09) or the risk of death (HR, 0.84; 95% CI, 0.59–1.19) when a GnRH agonist was added to tamoxifen, compared with tamoxifen alone. A phase III trial of the Eastern Cooperative Oncology Group (ECOG; E-3193, INT-0142), evaluated 345 premenopausal women with axillary node–negative, hormone receptor–positive breast cancers ≤ 3 cm who were randomized to tamoxifen alone vs tamoxifen plus ovarian function suppression. In this study, adjuvant chemotherapy was not permitted. At a median follow-up of 9.9 years, there was no significant difference between the two arms with regard to DFS (5-year rate: 87.9% for tamoxifen vs 89.7% for tamoxifen plus ovarian suppression; P = .62) or OS (5-year rate: 95.2% vs 97.6%; P = .67). This study was terminated early because of slow accrual, and the sample size resulted in the trial being underpowered to reach a firm conclusion regarding survival. Nonetheless, the study population appeared to be low risk, and it is not surprising that the addition of ovarian suppression was not associated with improved outcomes.
In 2003, the IBCSG initiated two large international phase III trials, the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), to determine the value of adding ovarian suppression to tamoxifen or an aromatase inhibitor (AI), exemestane.[17,18] The primary analysis in SOFT included 2,033 premenopausal women randomized to either tamoxifen for 5 years or tamoxifen plus ovarian function suppression achieved by monthly triptorelin for 5 years, bilateral oophorectomy, or bilateral ovarian irradiation. Patients were stratified by receipt of chemotherapy. Patients who had received chemotherapy required a confirmatory premenopausal estradiol level within 8 months of completing chemotherapy, although adjuvant oral endocrine therapy was allowed before randomization.
At a median follow-up of 67 months, there was no significant difference in the primary endpoint of DFS between the patients receiving tamoxifen and those receiving tamoxifen plus ovarian suppression (5-year DFS, 84.7% vs 86.6%; HR, 0.83; 95% CI, 0.66–1.04; Table 1). However, after adjustment for covariates, tamoxifen plus ovarian suppression significantly reduced the risk of recurrence (HR, 0.78; 95% CI, 0.62–0.98). In particular, women who had not received prior chemotherapy did exceedingly well regardless of which arm they were assigned to; 98.6% of women in the tamoxifen arm and 98.7% of those in the tamoxifen-plus-ovarian-suppression arm were free from distant recurrence at 5 years. These patients were considered to have low-risk disease: 90.7% had node-negative disease, 84.9% had ≤ 2 tumors, 91.9% had grade 1 or 2 tumors, and 90.3% were aged 40 years or older.
Despite the lack of benefit in the overall population, exploratory analyses suggested that patients at higher risk for relapse might derive benefit from the addition of ovarian suppression to tamoxifen, including those treated with chemotherapy and very young women (under the age of 35 at the time of diagnosis of breast cancer). In those who were considered to have sufficient risk of recurrence to warrant chemotherapy and who remained premenopausal, the breast cancer–free interval (BCFI; freedom from invasive recurrence or contralateral breast cancer) at 5 years was 82.5% in the tamoxifen–ovarian suppression group and 78% in the tamoxifen-alone group (HR, 0.78; 95% CI, 0.6–1.02). In the secondary analysis comparing exemestane plus ovarian suppression to tamoxifen alone in patients who had received chemotherapy, the 5-year BCFI was further improved to 85.7% (HR, 0.65; 95% CI, 0.49–0.87). Similarly, most recurrences of breast cancer at distant sites occurred in patients who had received chemotherapy previously. In the chemotherapy cohort, the 5-year OS was significantly better in patients assigned to tamoxifen plus ovarian suppression than in those assigned to tamoxifen alone (95.5% vs 90.9%; HR, 0.64; 95% CI, 0.42–0.96), although these survival data are premature.
The most striking differences in outcomes were seen in the 350 women younger than 35 years of age. Of the women in this subgroup who were included in the primary analysis (n = 223), the 5-year BCFI was 67.7% for women assigned to tamoxifen, 78.9% for those assigned to tamoxifen plus ovarian suppression, and 83.4% for those assigned to exemestane plus ovarian suppression. Notably, 94% of this subgroup had received prior chemotherapy. In conclusion, this study demonstrated that adding ovarian suppression to tamoxifen did not improve DFS in the overall population, but that in certain high-risk cohorts of women, the addition of ovarian suppression might be associated with decreased risk of recurrence.
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