The Efficacy And Safety Of The Addition Of Ibandronate To Adjuvant Hormonal Therapy In Postmenopausal Women With Hormone-Receptor Positive Early Breast Cancer. First Results Of The Team Iib Trial (Boog 2006-04)

Background: Results of clinical trials concerning adjuvant bisphosphonates for the prevention of (bone) metastases in patients with early breast cancer are conflicting. A recent large meta-analysis, however, suggests that bisphosphonates reduce the incidence of (bone) metastases and improve skeletal-related events in early breast cancer patients. Subgroup analyses show that postmenopausal women seem to benefit the most. In this subgroup a modest overall survival benefit was observed with the addition of adjuvant bisphosphonates to standard adjuvant systemic therapy (EBCTCG, Lancet, 2015). TEAM IIB, a randomized phase III study (ISRCTN17633610), prospectively investigates the value of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Methods: Postmenopausal women with stage I-III breast cancer and an indication for adjuvant hormonal treatment were randomized to receive at least 5 years of hormonal therapy (tamoxifen followed by at least 2-3 years exemestane, or in case of high risk at least 5 years of exemestane) with or without ibandronate 50mg orally, once daily for three years. Primary endpoint was disease-free survival (DFS). Secondary endpoints included time to and rate of bone metastases, other sites of recurrence, overall survival and safety. The study was amended because of slower than anticipated accrual and the sample size calculations were amended accordingly in June 2009. To detect a hazard ratio (HR) of 0.615 with a 2-sided alpha of 0.05 and a power of 0.8, 139 DFS-events were required in the intention-to-treat population. Results: Between February 2007 and May 2014, 1116 patients were enrolled in 37 hospitals in the Netherlands of whom 40% had positive axillary lymph nodes and 56% of all patients received (neo)adjuvant chemotherapy (u003e95% anthracyclines, 69% taxanes). Baseline characteristics were well balanced. At September 9, 2016, 143 DFS events had been reported. Median follow-up was 4.6 years and 80 patients were still on ibandronate treatment. Adherence to 3 years ibandronate was 67%, 21 patients randomized to receive ibandronate never started. 19 patients, of whom 9 in the control group were excluded because of major ineligibility. In the ibandronate treated group 3-year DFS was 94.4% versus 90.8% in the control group (HR 0.84; 95% confidence interval [CI] 0.60-1.17). In total, 48 patients in the ibandronate versus 45 in the control group died, of whom 18 (37,5%) versus 28 (62,2%) of breast cancer. 3 years after randomization 1.6% of ibandronate treated patients developed bone metastases versus 4.6% in patients who were treated with adjuvant hormonal therapy only (HR 0.76; [CI] 0.43-1.32). 14 (29,2%) versus 9 (20%) of patients died because of secondary malignancies respectively. There was no significant difference in creatinine clearance during the first three years after randomization. 36 Serious adverse events (SAEs) were reported in the ibandronate group versus 51 in the control group. Of patients randomized to ibandronate 4 developed osteonecrosis, but without residual complaints. Conclusion: So far, at a median follow-up of 4.6 years there is no statistically significant benefit from adding ibandronate to adjuvant hormonal treatment in postmenopausal women with hormone-receptor positive early breast cancer. However, since hazard rates are in favor of ibandronate longer follow-up is warranted before final conclusions can be drawn. Citation Format: Vliek SB, Meershoek-Klein Kranenbarg E, van Rossum AGJ, Tanis BC, Putter H, van der Velden AWG, Hendriks MP, van Bochove A, van Riet Y, van Leeuwen-Stok AE, Tjan-Heijnen VCG, Kroep JR, Nortier JWR, van de Velde CJH, Linn SC. The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer. First results of the TEAM IIB trial (BOOG 2006-04) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-02.