Given a loosely defined target population and a lack of overall survival benefit, the ASCO guideline supporting ovarian suppression in premenopausal women with stage II and III breast cancer should not serve as a mandate, but rather as a guide for discussing its relative risks and benefits with patients.— Katarzyna J. Jerzak, MD, FRCPC (left), and Kathleen I. Pritchard, MD, FRCPC
Oophorectomy was the first proposed form of endocrine therapy for women with breast cancer. Over 100 years ago, Thomas Nunn reported a relationship between menopause and regression of breast cancer.1 This incited interest in the induction of menopause as an anticancer therapy, and in 1986, a report on the efficacy of bilateral oophorectomy in three women with breast cancer was published in The Lancet.2
Several trials have since confirmed a benefit of ovarian ablation or suppression in premenopausal women with breast cancer. An overview conducted by the Early Breast Cancer Trialists’ Collaborative Group demonstrated disease-free survival and overall survival benefits among women < 50 years old treated with ovarian ablation or suppression compared to those receiving no adjuvant endocrine therapy.3 However, ovarian treatments fell out of vogue when an oral endocrine therapy (tamoxifen) was approved in the adjuvant setting.
In light of evidence showing the superiority of aromatase inhibitors over tamoxifen in postmenopausal women with early breast cancer, oncologists have revisited the role of ovarian suppression to optimize outcomes of premenopausal women, either in combination with tamoxifen or to facilitate treatment with an aromatase inhibitor. The 2016 ASCO clinical practice guideline, reported by Burstein et al and reviewed in this issue of The ASCO Post, summarizes the results of four randomized controlled trials that inform the efficacy of ovarian suppression (by surgical oophorectomy, radiation ovarian ablation, or gonadotropin-releasing hormone agonist treatment) in addition to standard endocrine therapy in premenopausal women with estrogen receptor–positive early breast cancer.4
SOFT and TEXT Trials
The largest studies analyzed by Burstein et al were the Suppression of Ovarian Function Trial (SOFT)5 and Tamoxifen and Exemestane Trial (TEXT).6
SOFT compared tamoxifen with the combination of endocrine therapy (tamoxifen or exemestane) plus ovarian suppression among 2,033 women for 5 years. Their median age was 43 years, and 65% were node-positive. Women who did not receive chemotherapy (47%) were deemed premenopausal if they had a menstrual cycle within the past 6 months and/or their serum estradiol levels fell within the premenopausal range. Among the 53% of women receiving chemotherapy, only those who remained premenopausal within 8 months were eligible.
TEXT compared tamoxifen plus ovarian suppression with exemestane plus ovarian suppression in 2,660 women (48% node-positive) with similar eligibility criteria. After accrual to both studies was completed, the data among them were pooled to answer two critical questions: (1) How does the efficacy of tamoxifen alone compare to that of its combination with ovarian suppression, and (2) is exemestane more effective than tamoxifen when added to ovarian suppression?
A relatively large disease-free survival benefit for ovarian suppression was noted among “higher-risk” women who remained premenopausal in spite of adjuvant chemotherapy. The 5-year freedom from breast cancer was a78.0% in the tamoxifen group, 82.5% in the tamoxifen–ovarian suppression group, and 85.7% in the exemestane–ovarian suppression group.6 In comparison to tamoxifen alone, the use of exemestane plus ovarian suppression resulted in a hazard ratio (HR) of 0.65 (95% confidence interval [CI] = 0.49–0.87) for 5-year disease-free survival in this higher-risk subgroup, but tamoxifen plus ovarian suppression was not significantly better.
Other Major Trials
In the Eastern Cooperative Oncology Group trial (E-3193), which enrolled 345 premenopausal and chemotherapy-naive women with node-negative breast cancer, no benefit was seen with the addition of ovarian suppression to tamoxifen.7 Further, the Austrian Breast and Colorectal Cancer Study Group (ABCSG-12) trial failed to demonstrate a benefit of anastrozole over tamoxifen in addition to ovarian suppression.8 In fact, anastrozole resulted in a nonsignificant detriment in 5-year disease-free survival in the overall population and a significantly increased risk of death in a subgroup of overweight women (HR = 3.03, 95% CI = 1.35–6.82).9
It is important to highlight that an overall survival benefit for ovarian suppression was lacking in all four assessed studies (SOFT, TEXT, E-3193, and ABCSG-12), even among the women receiving chemotherapy. Although a survival benefit may emerge with longer-term follow-up, this is certainly not guaranteed.
As recently highlighted by Dowsett and colleagues,10 incomplete ovarian suppression using luteinizing hormone–releasing hormone (LHRH) agonists is a concern, particularly when used in combination with aromatase inhibitors, which are known ovarian stimulants. In fact, in a substudy of the SOFT trial, one-third of the women on exemestane plus triptorelin (Trelstar, n = 86) had estradiol levels above the premenopausal range (2.72 pg/mL) at least once at the 3-, 6-, and 12-month time points.11 Due to the uncertain clinical implications of these findings, however, the evidence is insufficient for monitoring hormone levels in women on ovarian suppression therapy at this time.4
Patients at ‘Higher Risk’
Burstein et al cited intermediate-quality evidence and issued a moderate-strength recommendation for the addition of ovarian suppression to standard endocrine therapy for higher-risk premenopausal women with stage II to III estrogen receptor–positive breast cancer. As the authors acknowledged, the term “higher risk” remains ambiguous.4 While a perceived need for chemotherapy may predict benefit from ovarian suppression, practices regarding the administration of adjuvant chemotherapy vary worldwide, and they have changed with the emergence of the Oncotype DX test.12
In the hormone receptor–positive and HER2-negative SOFT and TEXT trial populations, patients aged < 35 years, those with four or more positive lymph nodes, and those with a grade 2 or 3 tumor were at particularly high risk of breast cancer recurrence.13 In a Cox proportional hazards model, only women aged < 35 years (HR = 2.2, 95% CI = 1.6–3.1) and 35 to 39 years (HR = 1.7, 95% CI = 1.3–2.3) were at higher risk of recurrence compared to the reference group of women aged 45 to 49 years. However, given that recurrence risk was evaluated as a continuous composite of clinicopathologic variables (including Ki67 level, which is not routinely assessed around the world), the implications of this score for day-to-day clinical practice remain unclear.13 Further research to identify predictive biologic and clinical biomarkers for ovarian suppression is needed.
In addition to its efficacy, the side-effect profile of ovarian suppression must also be considered. The combination of ovarian suppression and tamoxifen, as compared to tamoxifen alone, resulted in an impaired overall quality of life, which persisted over the 5-year course of therapy.5 Hot flushes (93.4% vs 79.8%), depression (51.9% vs 46.6%), insomnia (57.2% vs 46.3%), musculoskeletal symptoms (75.1% vs 69.0%), and osteoporosis (20.0% vs 12.3%) were more common in the ovarian suppression arm. Further, in the E-3193 study, grade 3 or higher toxicities were more common in women receiving tamoxifen–ovarian suppression (22%) compared to tamoxifen alone (12%). Implications of irreversible ovarian suppression on fertility must also be considered.14
In light of the potential for incomplete ovarian suppression and challenges in measuring hormonal levels during LHRH agonist therapy, it has been proposed that permanent ovarian ablation via bilateral oophorectomy may be the gold standard therapy for premenopausal women with estrogen receptor–positive breast cancer. However, high-quality evidence to support a recommendation for bilateral oophorectomy as opposed to reversible ovarian suppression with an LHRH agonist is lacking. For example, in SOFT and TEXT, only a minority of women (fewer than one in five) had bilateral oophorectomy or ovarian irradiation during adjuvant therapy, and the outcomes of this subgroup were not reported.5,6 As we await more data, a practical approach may be to commence therapy with an LHRH agonist followed by tamoxifen and, among women for whom an aromatase inhibitor is felt to be warranted, consider surgical oophorectomy if the side-effect profile of chemical ablation is acceptable.
Given a loosely defined target population and a lack of overall survival benefit, the ASCO guideline supporting ovarian suppression in premenopausal women with stage II and III breast cancer should not serve as a mandate, but rather as a guide for discussing its relative risks and benefits with patients. Further insight into the use of ovarian suppression for estrogen receptor–positive breast cancer will likely emerge as available data mature and results of other trials become available. ■
Disclosure: Drs. Jerzak and Pritchard reported no potential conflicts of interest.
4. Burstein HJ, Lacchetti C, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol 34:1689-1701, 2016.
6. Pagani O, Regan MM, Walley BA, et al: TEXT and SOFT Investigators; International Breast Cancer Study Group: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371:107-118, 2014.
7. Tevaarwerk AJ, Wang M, Zhao F, 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 32:3948-3958, 2014.
8. Gnant M, Mlineritsch B, Stoeger H, et al: Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozole plus ovarian function suppression in premenopausal early breast cancer: Final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 26:313-320, 2015.
9. Pfeiler G, Konigsberg R, Fesi C, 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 29:2653-2659, 2011.
10. Dowsett M, Lonning PE, Davidson NE: Incomplete estrogen suppression with gonadotropin-releasing hormone agonists may reduce clinical efficacy in premenopausal women with early breast cancer. J Clin Oncol 34:1580-1583, 2016.
11. Bellet M, Gray KP, Francis PA, et al: Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST substudy. J Clin Oncol 34:1584-1593, 2016.
13. Regan MM, Francis PA, Pagani O, et al: Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer: TEXT and SOFT trials. J Clin Oncol. April 4, 2016 (early release online).
Clinicians should be alert to the possibility of incomplete ovarian suppression with gonadotropin-releasing hormone agonist therapy and evaluate patients for whom there is concern about residual ovarian function.— Harold J. Burstein, MD, PhD and colleagues
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