Two years of adjuvant treatment with ibandronate after dose-dense chemotherapy did not improve survival in a study of more than 3,000 German patients with early stage, node-positive breast cancer.
The results were published online Aug. 26 in the Journal of Clinical Oncology.
Bisphosphonates have been shown to prevent skeletal-related events in patients with metastatic breast cancer, but their effectiveness has not been demonstrated in early breast cancer.
No differences in disease-free survival or overall survival were noted in the GAIN (German Adjuvant Intergroup Node-Positive) study, an open-label, randomized, controlled phase III trial (NCT00196872), reported Dr. Gunter von Minckwitz of the German Breast Group, along with his colleagues in the German Breast Group/Gynecologic Oncology Working Group/North-Eastern Germany Society of Gynecologic Oncology study groups.
In patients randomly assigned to 2 years of ibandronate or observation, there was no difference in disease-free survival (HR, 0.945; 95% CI, 0.768 to 1.161; P equals .589) or in overall survival (HR, 1.040; 95% CI, 0.763 to 1.419; P equals .803). Metastasis to the bone was documented in 31% in the ibandronate arm and in 38% in the observation arm.
Post hoc subgroup analyses of the study data imply that the benefit of adjuvant bisphosphonates was restricted to patients with low estrogen levels, either because of medical ovarian suppression or definite menopause. Future meta-analyses on an individual patient data level may reliably reveal subgroups of early-stage, high-risk breast cancer patients who might benefit from adjuvant bisphosphonates, the researchers noted (J. Clin. Oncol. 2013 Aug. 26 [doi:10.1200/JCO.2012.47.2167]).
In GAIN, patients with node-positive early breast cancer were randomly assigned within 4 weeks after surgery to two different dose-dense chemotherapy regimens and then in 2:1 fashion to ibandronate 50 mg per day orally starting within 4 weeks after last administration of chemotherapy and continuing for 2 years (2,015 patients) or to observation (1,008 patients).
Randomly assigned chemotherapy consisted of three courses of epirubicin 150 mg/m2 followed by three courses of paclitaxel 225 mg/m2 followed by three courses of cyclophosphamide 2,500 mg/m2 (reduced to 2,000 mg/m2 after recruitment of approximately 1,200 patients), all given at 2-week intervals (iddETC regimen) or epirubicin 112.5 mg/m2 and cyclophosphamide 600 mg/m2 for four 2-week courses followed by 10 courses of paclitaxel 67.5 mg/m2 given once per week with capecitabine 2,000 mg/m2 given days 1-14 every 3 weeks (EC-TX regimen).
Radiotherapy, endocrine treatment, and trastuzumab were indicated according to AGO guidelines and, if appropriate, were given in parallel with ibandronate after the end of chemotherapy. All patients received radiotherapy to the affected breast if breast-conserving surgery was performed, the researchers wrote.
Patients with endocrine-sensitive disease received endocrine treatment for 5 years with an aromatase inhibitor either alone or in sequence with tamoxifen if they were postmenopausal. Tamoxifen alone was given for 5 years in some patients together with a luteinizing hormone-releasing hormone (LHRH) analog if they were premenopausal after the end of chemotherapy. Patients with human epidermal growth factor receptor 2–overexpressing tumors received 1 year of adjuvant trastuzumab treatment.
Patients were evaluated every 12 weeks during the first 2 years of treatment and then every 6 months.
A total of 1,421 patients (78.2%) completed ibandronate treatment as planned, 5.8% discontinued treatment due to progression or death, and 16% discontinued treatment for various reasons. There were 405 events, including 186 deaths, after a median of 38.7 months (range, 0-73 months) with a completeness of follow-up of 76.8%.
The study was supported by Amgen, Germany; Bristol-Myers Squibb, Germany; and Roche, Germany, which also provided drugs for the study. Dr. von Minckwitz reported ties with Roche. His colleagues noted ties with numerous drug companies.