Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

Abstract

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.

Keywords:

• Adjuvant
• aromatase inhibitor
• breast cancer
• ER-positive cancer
• estrogen receptor
• exemestane
• hormonal therapy
• premenopausal
• tamoxifen

Breast cancer is the most common cancer diagnosed in women in the United States. The American Cancer Society estimates that 232,670 women will be diagnosed with breast cancer in 2014, with 40,000 deaths expected.¹ Nearly 90% of women will be diagnosed as having early-stage disease. Unfortunately, nearly 30% of women with cancer confined to the breast and 75% of women with nodal involvement will ultimately relapse.² The goal of adjuvant systemic therapy for breast cancer is to prevent the recurrence of the disease by eradicating micrometastatic disease. Tamoxifen, the estrogen receptor (ER) antagonist, is the gold standard for adjuvant endocrine therapy for ER-positive breast cancer in premenopausal women. A compiled analysis was done for 60 randomized trials (n = 80,000 women) of adjuvant tamoxifen therapy with 15 y of follow-up data.³ Tamoxifen administered for 5 y resulted in a 41% reduction in the annual rate of breast cancer recurrence (HR, 0.59) for women with ER-positive breast cancer.

Aromatase inhibitors (AIs) block the enzyme that converts androgens to estrogens. The main source of estrogen in premenopausal women is the ovaries, while in the post-menopausal setting most of the estrogen is produced in peripheral tissues. AIs have traditionally not been used in premenopausal patients, as residual ovarian function can lead to enhanced production of aromatase and thus overcome the effects of AIs.⁴ In postmenopausal patients, AIs effectively lower estrogen concentrations to undetectable levels.

Recent studies have shown that the use of aromatase inhibitors as adjuvant therapy improves outcomes for postmenopausal women with hormone-receptor-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone.⁵ The question has been raised whether or not AIs would have the similar improvements in disease-free survival (DFS) in premenopausal women with hormone-receptor-positive breast cancer. Due to estrogen production by the ovaries in premenopausal women, the ovaries would have to be suppressed with a gonadotropin-releasing-hormone agonist or undergo bilateral oophorectomy inducing a menopausal state for the patients. Two randomized, phase III clinical trials are currently evaluating whether adjuvant therapy with aromatase inhibitors plus ovarian suppression compared to tamoxifen plus ovarian suppression for a period of 5 y will have a significant difference in DFS as the primary endpoint.⁶

Data from the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT) trials were combined for a planned primary analysis that included a total of 4,690 premenopausal women with hormone-receptor-positive breast cancer.⁶ Randomization of adjuvant therapy of exemestane, an irreversible steroidal inhibitor that forms a permanent and deactivating bond with the aromatase enzyme, plus ovarian suppression or tamoxifen plus ovarian suppression occurred at a 1:1 ratio. Specifically in SOFT, a third group received adjuvant therapy with tamoxifen only resulting in a randomization ratio of 1:1:1. Approximately half the patients in both trials received chemotherapy before adjuvant endocrine therapy, during adjuvant endocrine therapy, or as neoadjuvant therapy.

After a median follow-up of 68 months, the combined analysis demonstrated a significant improvement in DFS in the exemestane plus ovarian suppression group at 91.1%, as compared with 87.3% in the tamoxifen plus ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death 0.72; 95% confidence interval [CI], 0.60 to 0.85; P < 0.001). Cumulatively, there were 194 deaths (4.1%) from both trials; and although overall survival did not differ significantly between the 2 groups (hazard ratio for death in exemestane plus ovarian suppression group, 1.14; 95% confidence interval [CI], 0.86 to 1.51; P = 0.37), similar to trials on adjuvant AI versus tamoxifen therapy in the postmenopausal setting, the conclusions are still premature at 68 months of follow-up in the current analysis.

The use of aromatase inhibitors in coordination with ovarian suppression is a new adjuvant treatment option for premenopausal women with hormone-receptor-positive breast cancer and reduces the risk of recurrence. Side effects of grade 3 or 4 were reported in 30.6% of patients in the exemestane-ovarian suppression group and 29.4% in tamoxifen-ovarian suppression group and are similar to those reported in studies of postmenopausal women.⁶ The only side effect that stood out as being of clinical concern for the exemestane plus ovarian suppression was musculoskeletal symptoms (88.7% for the AI plus ovarian suppression vs. 76% for tamoxifen plus ovarian suppression).

When Pagani and colleagues combined data from the 2 trials, there were some discrepancies in eligibility criteria (i.e., start on endocrine therapy and chemotherapy) that may have affected the results. In the SOFT trial, 41.7% patients received tamoxifen 4 months before randomization while awaiting verification of premenopausal status of patient.⁶ We would have also liked to see an analysis of CYP2D6 genotyping status, the enzyme that forms the more potent metabolite endoxifen, for the tamoxifen group.⁷ Is it possible that the disease-free survival in the tamoxifen arm was influenced by genetic polymorphisms in the drug conversion enzyme? Nonetheless, the primary endpoint of disease-free survival showed a significant reduction in risk of recurrence with the use of aromatase inhibitors in premenopausal hormone-receptor-positive breast cancer patients with ovarian suppression. These results could have a significant impact in clinical care assuming medical oncologists are comfortable with the implementation of ovarian suppression in this patient population. Finally, the duration of adjuvant hormonal therapy should also be considered. The most recent guidelines by American Society of Clinical Oncology has extended the recommendation to 10 y of therapy based on the pooled analysis of the 17,477 patients enrolled in aTTom and ATLAS trials showing a 9% reduction in the risk of death after patients received 10 versus 5 y of tamoxifen for the entire follow-up period.⁸

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.