Adjuvant exemestane with ovarian suppression in premenopausal breast cancer

Abstract

Background: Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer.

Methods: In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.

Results: After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-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). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women.

Conclusions: 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. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

Figure 1. Randomization, Treatment, and Follow-up

Of the 383 patients who withdrew consent or were lost to follow-up, 150 consented to the continued submission of disease-recurrence and survival status from medical records or such updates are obtainable from tumor and vital registries according to the protocol follow-up schedule. SOFT denotes Suppression of Ovarian Function Trial, and TEXT Tamoxifen and Exemestane Trial.

Figure 2. Kaplan–Meier Estimates of Disease-free Survival, Freedom from Recurrence of Breast Cancer, Freedom from Recurrence of Breast Cancer at a Distant Site, and Overall Survival after a Median Follow-up of 68 Months, According to Treatment Assignment

The hazard ratio in Panel A is for disease recurrence, second invasive cancer, or death without breast-cancer recurrence or second invasive cancer. The 5-year values are based on Kaplan–Meier estimates of the time to an event. OS denotes ovarian suppression.

Figure 3. Results of the Cox Proportional-Hazards Model for the Comparison of Disease-free Survival, According to Treatment Group, among All Patients and According to Patient Cohort

The solid vertical line at 0.72 indicates the overall hazard-ratio estimate. The x axis is scaled according to the natural logarithm of the hazard ratio. The size of the squares is inversely proportional to the standard error of the hazard ratio. Among patients who received chemotherapy, the patients in TEXT began receiving chemotherapy concurrently with adjuvant ovarian suppression with triptorelin, whereas those in SOFT had completed all chemotherapy before enrollment.