The combination of ovarian suppression and tamoxifen is a standard adjuvant endocrine therapy in premenopausal women with endocrine-responsive breast cancer. Several reports have demonstrated that adjuvant endocrine therapy with aromatase inhibitors is superior to endocrine therapy with tamoxifen in postmenopausal women with endocrine-responsive breast cancer. The benefits of aromatase inhibitors, however, in premenopausal women are largely unknown. Previous studies showing that bisphosphonate therapy with zoledronic acid had antitumor and antimetastatic properties and prevented aromatase inhibitor-associated bone loss were the basis for the Austrian Breast and Colorectal Cancer Study Group trial 12. This randomized trial was part of the Austrian Breast and Colorectal Cancer Study Group trial 12 and investigated the possible benefits of adding zoledronic acid to adjuvant endocrine therapy with either Anastrozole or Tamoxifen in premenopausal women with endocrine-responsive early breast cancer. After primary surgery, 1803 patients were randomized to receive goserelin plus tamoxifen with (n = 449) or without (n = 451) zoledronic acid or goserelin plus anastrozole with (n = 450) or without (n = 453) zoledronic acid for 3 years. The primary end-point was disease-free survival, defined as the first occurrence of one or more of the following event(s): death from any cause, local or regional relapse, distant metastasis, contralateral breast cancer, and a second primary tumor. Secondary end points were recurrence-free survival and overall survival.
At a median follow-up of 47.8 months, 137 events met the criteria for the primary end point. No significant difference in disease-free survival was found between the goserelin/anastrozole and goserelin/tamoxifen groups (92.0% vs. 92.8%, respectively); the hazard ratio (HR) for disease progression was 1.10, with a 95% confidence interval [CI] of 0.78-1.53; P = 0.59. Rates of recurrence-free survival and overall survival also did not differ among the 2 groups. The addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival at 47.8 months; 94.0% of patients receiving zoledronic acid were free of disease compared to 90.8% of those receiving adjuvant endocrine therapy alone (HR, 0.64; 95% CI, 0.46-0.91; P = 0.01). No significant reduction in the risk of death was associated by adding zoledronic acid to adjuvant endocrine treatment (HR, 0.60; 95% CI, 0.32-1.11; P = 0.11). Overall, adverse events were as expected and no increase in serious adverse events or treatment-related deaths occurred.
These data show that addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in a population of premenopausal women with endocrine-responsive early breast cancer.