Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer

Abstract

Background: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials.

Methods: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.

Results: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group.

Conclusions: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

Figure 1.. Randomization and Analyses in SOFT and TEXT.

SOFT denotes Suppression of Ovarian Function Trial, and TEXT Tamoxifen and Exemestane Trial.

Figure 2 (facing page).. Kaplan–Meier Estimates of Disease-free Survival after a Median Follow-up of 8 Years in SOFT.

Shown are Kaplan–Meier estimates of the rates of disease-free survival in SOFT according to treatment assignment — tamoxifen alone (T), tamoxifen plus ovarian suppression (T–OS), or exemestane plus ovarian suppression (E–OS) — among all the patients in the trial (Panel A) and according to chemotherapy status (Panels B and C). In Panel A, tamoxifen plus ovarian suppression resulted in a 24% lower relative risk of recurrence, a second invasive cancer, or death than tamoxifen alone (P = 0.009). In each panel, the 8-year data are highlighted by a black vertical line. The hazard ratios are for disease recurrence, a second invasive cancer, or death.

Figure 3.. Disease-free Survival among All Patients and According to HER2 and Chemotherapy Status in SOFT.

Shown are hazard ratios and estimates of 8-year disease-free survival in SOFT comparing patients who received tamoxifen alone with those who received tamoxifen plus ovarian suppression (Panel A) and those who received exemestane plus ovarian suppression (Panel B), according to status with respect to HER2 (human epidermal growth factor receptor 2) and receipt of chemotherapy. The hazard ratios are for disease recurrence, a second invasive cancer, or death. In the comparison involving patients receiving tamoxifen plus ovarian suppression, there was significant interaction according to HER2 status (P = 0.04), but the interaction was not significant in the comparison involving those receiving exemestane plus ovarian suppression (P = 0.44). The 8-year values for disease-free survival are based on Kaplan–Meier estimates. The solid vertical lines at 0.76 in Panel A and at 0.65 in Panel B indicate the overall hazard-ratio estimates for the two comparisons. The comparisons for patients with HER2-positive disease are not presented according to receipt or nonreceipt of chemotherapy because the majority of these patients (86%) had received chemotherapy. Among the patients with HER2-negative disease, testing was not performed for interaction with chemotherapy status. Data are not shown for 95 patients with unknown HER2 status. 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.

Figure 4.. Kaplan–Meier Estimates of Freedom from Distant Recurrence and of Overall Survival in SOFT.

Shown are estimates of rates of freedom from distant recurrence and of overall survival after a median follow-up of 8 years in SOFT among all the patients in the trial (Panels A and B, respectively) and among those who had received chemotherapy before randomization (Panels C and D, respectively). The addition of ovarian suppression to tamoxifen did not result in a significantly lower rate of distant recurrence than that with tamoxifen alone (P = 0.28), but the rate of overall survival was significantly higher (P = 0.01). In Panels A and C, the hazard ratios are for recurrence of breast cancer at a distant site; the hazard ratios in Panels B and D are for death. The 8-year values are based on Kaplan–Meier estimates of the time to an event. The estimates for patients who did not receive chemotherapy are provided in Figure S3B in the Supplementary Appendix; the rates were more than 97% in each treatment group for both end points.

Figure 5.. Kaplan–Meier Estimates of Disease-free Survival, Freedom from Distant Recurrence, and Overall Survival in the Combined SOFT and TEXT Population.

Shown are estimates of disease-free survival (Panel A), freedom from distant recurrence (Panel B), and overall survival (Panel C) among patients who received tamoxifen plus ovarian suppression (T–OS) and those who received exemestane plus ovarian suppression (E–OS) after a median follow-up of 9 years in the combined population. In each panel, the 8-year data are highlighted by a black vertical line. The hazard ratio in Panel A is for disease recurrence, a second invasive cancer, or death. In Panels B and C, the hazard ratios are for distant recurrence of breast cancer and for death, respectively. The 8-year values are based on Kaplan–Meier estimates of the time to an event.

Figure 6.. Estimates of Disease-free Survival, Freedom from Distant Recurrence, and Overall Survival among Patients with HER2-Negative Disease in the Combined SOFT and TEXT Population.

Shown are hazard ratios and estimates of disease-free survival, freedom from distant recurrence, and overall survival among patients with HER2-negative breast cancer who received tamoxifen plus ovarian suppression (OS) and those who received exemestane plus ovarian suppression in the combined SOFT and TEXT population, according to receipt or nonreceipt of chemotherapy. The solid vertical lines at 0.70, 0.69, and 0.86 indicate the overall hazard-ratio estimates for disease-free survival (hazard ratio for disease recurrence, a second invasive cancer, or death), freedom from distant recurrence (hazard ratio for recurrence), and overall survival (hazard ratio for death), respectively, as calculated by means of Cox proportional-hazards models. In the HER2-negative population, inference from the treatment comparisons should be viewed as preliminary, since no testing was performed for heterogeneity of the treatment effects across cohorts. The 8-year values are based on Kaplan–Meier estimates of the time to an event. The size of the squares is inversely proportional to the standard error of the hazard ratio. The median follow-up was 9 years in the combined SOFT and TEXT population. The r esults for patients with HER2-positive disease are provided in Figure S10 in the Supplementary Appendix.