Abstract S5-05: Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer – The phase III NATAN study (GBG 36/ABCSG XX)

Background: Patients with residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemoresistant breast cancer. Adjuvant treatment with bisphosphonates is considered to reduce the relapse risk predominantly in estrogen-deprivated patients. Methods: Patients who had invasive tumor residuals (ypT1-4 or ypN+) after a minimum of 4 cycles of anthracycline-taxane-containing NACT were eligible to the NATAN study. Patients were randomized within 3 years after surgery to receive zoledronate 4 mg i.v. (plus 1000 mg Ca2+ and 880 I.U. vitamin D daily) for 5 years vs. observation. Zoledronate was given q 4 weeks for the first 6 months, q 3 months the following 2 years, and q 6 months for the last 2.5 years. Patients with hormone receptor (HR)-positive disease received letrozole for 5 years if postmenopausal, or tamoxifen, if premenopausal. Adjuvant trastuzumab for HER2-positive disease was allowed since an amendment in 2007. Stratification factors were HR, time since surgery, age, and center. Primary objective was event-free survival (EFS). 654 patients and 316 events were required to observe an increase of 5yr EFS from 58% to 67.2% (hazard ratio 0.73). Secondary objectives were to determine overall survival, EFS with respect to the interval between surgery and randomization, bone-metastasis-free-survival, toxicity of and compliance to zoledronate, the predictive value of breast tumor response to NACT on the effect of postoperative treatment and the prognostic impact of chemotherapy induced amenorrhea in premenopausal patients. An interim analysis for high efficacy at 158 observed events was planned in the protocol; in agreement with study IDMC a Bayesian analysis for futility with futility boundary of 15% will be performed at the same time. Results: Between 2/2005 and 5/2009 693 patients were enrolled. Time between surgery and randomization was <4 months in 48.4%, 4-12 months in 34.5%, and 13-36 months in 17.1% of patients. The median age was 50.9 yrs (range 33.7-88.2), 72.3% of patients were postmenopausal. 82% had HR-positive and 19% HER2-positive disease. During a median follow up of 48 months 154 events were observed so far. Conclusion: This is the first post-neoadjuvant phase III study. Analysis of the primary endpoint will be presented in case the IDMC will release of the results of the futility analysis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-05.