Final outcomes of the SOFT and TEXT phase III trials in premenopausal hormone receptor-positive early breast cancer^☆

Background: The Suppression of Ovarian Function Trial (SOFT) found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. A combined analysis of SOFT and TEXT showed a significant reduction in distant recurrence with E+OFS versus T+OFS. We now report final 15-year outcomes. Patients and methods: Premenopausal women with hormone receptor-positive early breast cancer were enrolled, with 3047 in SOFT and 2660 in TEXT intention-to-treat populations. SOFT randomized to 5 years of T versus T+OFS versus E+OFS. TEXT randomized to 5 years of T+OFS versus E+OFS. Chemotherapy was optional, before SOFT entry with subsequent premenopausal oestradiol or concurrent with OFS in TEXT. Endpoints included disease-free survival, breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), and overall survival (OS). Additionally, 15-year Kaplan–Meier estimates, hazard ratios (HRs), and 95% confidence intervals (CIs) are reported. Results: In SOFT, escalating endocrine therapy (ET) continued to reduce recurrence with 15-year BCFI of 78.6% for E+OFS, 75.7% for T+OFS, and 72.1% for T (T+OFS versus T: HR 0.82, 95% CI, 0.69-0.98, P = 0.03). In the SOFT no-chemotherapy cohort, OFS reduced breast cancer events at 15 years, while DRFI and OS remained high regardless of ET assignment. After prior chemotherapy for HER2-negative tumors (n = 1257), the 15-year OS rate in SOFT was 81.0% with E+OFS, 77.1% with T+OFS and 76.8% with tamoxifen alone. In women under age 35 years with HER2-negative tumors (n = 241), the 15-year OS rate was 82.5% with E+OFS, 77.9% with T+OFS, and 68.1% with tamoxifen. In combined SOFT and TEXT analysis, among those with HER2-negative tumors (n = 4035), E+OFS versus T+OFS reduced distant recurrence (HR 0.75, 95% CI 0.63-0.90), with a smaller reduction in deaths (HR 0.89, 95% CI 0.74-1.06), with absolute survival benefits largest with high-risk features, particularly young age or high-grade tumors. Conclusion: Meaningful OS benefit in hormone receptor-positive, HER2-negative breast cancer from adjuvant exemestane and/or OFS compared with tamoxifen alone is limited to high-risk premenopausal subgroups. Tamoxifen-based ET may not result in optimal outcomes in premenopausal high-grade HER2-negative tumors.