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.
Ovarian Suppression in Combination With Aromatase Inhibitors
Emerging data support the use of ovarian function suppression in combination with AIs. AIs suppress plasma estrogen levels by inhibiting or inactivating aromatase, which is the enzyme responsible for the peripheral conversion of androgens to estrogens. The standard of care for adjuvant endocrine treatment in postmenopausal women includes AI therapy, based on randomized trials demonstrating a survival benefit for AIs compared with tamoxifen. The efficacy of the various AIs (anastrazole, letrozole, and exemestane) is generally considered comparable.[19-21]
The Austrian Breast and Colorectal Cancer Study Group phase III trial (ABCSG-12) randomized 1,803 premenopausal women with ER-positive breast cancer to receive 3 years of ovarian suppression (goserelin) with tamoxifen or anastrazole, with or without the bisphosphonate zoledronic acid every 6 months. Only 5.8% of patients had received chemotherapy. At a median follow-up of 7.9 years, there was no significant difference in DFS between patients who received ovarian suppression plus anastrazole and those who received ovarian suppression plus tamoxifen (HR, 1.13; 95% CI, 0.88–1.45), but there was a higher risk of death for anastrozole-treated patients (HR, 1.63; 95% CI, 1.05-1.45; Table 1)—findings contrary to those of SOFT. The investigators postulated that inferior survival might be due to acquired AI resistance, which could make post-relapse treatment more challenging.
SOFT and TEXT also addressed the role of AI therapy in combination with ovarian suppression. The SOFT and TEXT results were combined due to fewer events than expected, to allow for earlier reporting of the data. In the combined analysis, 4,690 patients were randomized to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression; 57.4% had received chemotherapy. After a median follow-up of 68 months, the 5-year DFS was improved in the exemestane–ovarian suppression arm compared with the tamoxifen–ovarian suppression arm (91.1% vs 87.3%; HR, 0.72; 95% CI, 0.60–0.85). Patients in the exemestane–ovarian suppression arm had fewer distant recurrences at 5 years than those receiving tamoxifen plus ovarian suppression (93.8% vs 92.0%; HR, 0.78; 95% CI, 0.62–0.97). The difference was even greater in patients who had received prior chemotherapy. Of patients who did not receive chemotherapy and who were randomized to the exemestane-plus-ovarian-suppression group, over 97% remained free from breast cancer at 5 years. There was no significant difference in OS at 5 years between the two groups (95.9% in patients receiving exemestane–ovarian suppression and 96.9% in those receiving tamoxifen–ovarian suppression), although longer follow-up is required. In conclusion, these data indicate improved outcomes for premenopausal women receiving exemestane plus ovarian suppression.
Toxicities Associated With Ovarian Suppression
The addition of ovarian suppression to hormone therapy increased the frequency of toxicities seen in these patients (Table 2). In the patients in the North American Intergroup Trial (E-3193, INT-0142) who received ovarian suppression, grade 3 or higher toxicities were more common—in particular, there were more menopausal symptoms, lower sexual activity, and lower health-related quality of life. ]
Of patients enrolled in SOFT, 16.7% of those in the tamoxifen-plus-ovarian-suppression group discontinued their treatment early compared with 21.7% of those in the tamoxifen-only group, suggesting that the addition of ovarian suppression does not lead to increased discontinuation rates. At 4 years of therapy, 21.9% of patients were not adherent to ovarian suppression, and at 67 months, only 25.8% were continuing some or all of their hormone therapies. Grade 3 or 4 targeted adverse events were more frequently seen in the tamoxifen-plus-ovarian-suppression arm than in the tamoxifen-alone arm (31.3% vs 23.7%). The addition of ovarian suppression led to more frequently reported hot flushes and sweating; decreased libido; and more musculoskeletal complaints, glucose intolerance, osteoporosis, and hypertension.
Patient-reported outcomes were obtained from 1,722 women in SOFT who were assigned to either tamoxifen or tamoxifen plus ovarian function suppression. Patients completed questionnaires every 6 months for the first 24 months and then annually between years 3 and 6. Patients who received ovarian suppression were significantly more affected by hot flushes, sleep problems, and loss of sexual interest, although these all improved over time. These symptoms were less pronounced in patients who had received prior chemotherapy. Vaginal dryness was more frequent in the ovarian suppression group and was sustained over the whole treatment period, whereas more vaginal discharge was seen in those receiving tamoxifen alone. Despite these differences in endocrine and sexual symptoms, changes in global quality of life (mood and physical well-being) were similar between the two arms.
About 14% of patients in TEXT stopped protocol-assigned treatments early, with more patients in the exemestane-plus-ovarian-suppression arm doing so than in the tamoxifen-plus-ovarian-suppression arm (16% vs 11%). Targeted adverse events of grade 3 or 4 were similar between the exemestane arm (30.6%) and the tamoxifen arm (29.4%). Fractures, musculoskeletal symptoms, vaginal dryness, and decreased libido were reported more frequently in the exemestane arm, whereas thromboembolic events, hot flushes, and urinary incontinence were more frequent in the tamoxifen arm. Osteoporosis was more common in the exemestane arm than in the tamoxifen arm (13.2 vs 6.4%). Depression was reported in 50.3% of patients in the exemastane arm and in 50.1% of those in the tamoxifen arm, with 4.1% overall reporting grade 3/4 depression. Changes in quality-of-life indicators and coping were similar between the two groups. The investigators felt that the adverse event profile seen in TEXT was similar to that seen in postmenopausal women generally. Given these data, it is important to consider side effects, their impact on quality of life, and adherence when choosing between tamoxifen, tamoxifen plus ovarian suppression, and an AI plus ovarian suppression.
In light of the recent data from the SOFT and TEXT combined analysis and the ABCSG-12 trial, it is clear that ovarian suppression does not improve outcomes in the overall population of premenopausal women with ER-positive early-stage breast cancer, and particularly in women thought to have low-risk disease (eg, low-grade disease, small tumors, no receipt of chemotherapy). However there does appear to be a role for ovarian suppression in certain subsets. In a preplanned analysis, the SOFT and TEXT data showed us that women who were considered by their providers to harbor sufficient risk of recurrence and who had received chemotherapy derived a benefit in 5-year DFS from the addition of ovarian suppression to either tamoxifen or exemestane. Likewise, patients who were under the age of 35 derived significant benefit from the addition of ovarian suppression, although it is notable that the vast majority of these patients had received chemotherapy and generally had higher-risk disease. TEXT showed us that women had a significant improvement in 5-year DFS if ovarian suppression was combined with an AI as opposed to tamoxifen, although the absolute improvement was small (a 4–percentage point increase in 5-year DFS with exemestane plus ovarian suppression compared with tamoxifen plus ovarian suppression). Conversely, ABCSG-12 did not demonstrate any differences in DFS between the anastrazole and tamoxifen arms, in both of which patients were treated with ovarian function suppression. Moreover, the 5-year OS in patients receiving anastrazole plus ovarian suppression was inferior to the rate in those receiving tamoxifen plus ovarian suppression, whereas the SOFT and TEXT trials showed no difference in OS. Possible reasons for this discordance in results may be the smaller number of patients enrolled in the ABCSG-12 study and the fact that the endocrine therapies were given for a total of 3 years, instead of 5 years as in TEXT. Three years of AI therapy may not have been sufficient—unlike 3 years of tamoxifen, which is known to have a carryover protective effect on breast cancer recurrence. Finally, women in ABCSG-12 who received the bisphosphonate zoledronic acid had a significantly better DFS compared with those who did not receive zolendronic acid; only a minority of patients in SOFT and TEXT received bisphosphonates. The role of bisphosphonates as a component of adjuvant treatment for early-stage breast cancer remains controversial.
Although very young women and those who had received chemotherapy appeared to benefit from the addition of ovarian suppression in SOFT/TEXT, this benefit was associated with additional toxicities. Women who received an AI plus ovarian suppression noted more musculoskeletal complaints, greater loss of sexual interest, and more vaginal dryness, whereas women who received tamoxifen plus ovarian suppression reported more hot flushes and sweats. The tolerability of therapy (eg, toxicity) in an individual patient can have a major impact on adherence to treatment, which may ultimately influence treatment efficacy and outcomes. When balancing efficacy and adverse event profiles, it may be prudent to save ovarian suppression for only those most likely to benefit—higher-risk women. How one defines “high risk” is debatable but would likely include patients with higher-stage disease, lymph node–positive disease, higher histologic grade, and very young age, among other factors.
The recently reported ovarian suppression studies were well conducted and included an enormous number of women recruited on an international platform, although some limitations exist. We do not have long-term follow-up on these studies, and therefore the OS benefit cannot be truly evaluated. It is questionable whether one would subject a young woman to the toxicities of ovarian suppression if it did not translate to an improvement in OS. Likewise, the use of DFS as the primary endpoint is probably not appropriate when evaluating early-stage disease. Also, these studies do not address the question of the optimal duration of therapy, although when they were designed, the results of the Adjuvant Tamoxifen—To Offer More (aTTom) trial and the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, which support the use of 10 years of tamoxifen based on a survival benefit, were unknown.[26,27] In light of the aTTom and ATLAS data, it is questionable whether ovarian suppression with an endocrine agent should be continued past 5 years. The potential long-term consequences and impact on quality of life are not fully characterized at the current time. SOFT and TEXT demonstrated increases in diabetes, heart disease, and osteoporosis, but it is not clear whether these increases will translate to more deaths from these conditions, particularly in very young women. Finally, we do not know how the results of SOFT/TEXT can be integrated into our modern era of genomic testing. It might be of interest to analyze the differences between the effects of ovarian suppression, tamoxifen, and exemestane as these correlate with genomic findings. Much like the way in which we use genomic assays such as the Oncotype DX Recurrence Score to help decide which patients might derive a benefit from chemotherapy, perhaps a similar assay could be used to decipher which endocrine agent(s) should be recommended to our patients.
Progress has been made in our understanding of the role of adjuvant ovarian function suppression in premenopausal women with early-stage breast cancer, but many questions remain. Numerous prior studies have convincingly shown a clear benefit from adjuvant endocrine therapy. For women with low-risk disease, the addition of ovarian suppression to either tamoxifen or an AI does not add a substantial benefit. In the higher-risk subset, ovarian suppression should be considered and discussed with patients. The additional toxicities of ovarian suppression must be kept in mind when deciding whom to treat.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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