The effect of bisphosphonate treatment in early breast cancer is controversial, with some data indicating survival benefit in the adjuvant setting. In a study reported in the Journal of Clinical Oncology (German Adjuvant Intergroup Node-Positive Study, GAIN), Gunter von Minckwitz, MD, PhD, Chairman of the German Breast Group in Neu-Isenberg and Professor of Gynecology at the University of Frankfurt, Germany, and colleagues compared adjuvant oral ibandronate bisphosphonate therapy with observation in women with high-risk early breast cancer.¹ The study found no survival benefit of the addition of ibandronate to dose-dense chemotherapy.

Study Details

In the open-label, 2×2 factorial design GAIN trial, patients with node-positive early breast cancer were randomly assigned between June 2004 and August 2008 to adjuvant dose-dense chemotherapy with either EC-TX (epirubicin and cyclophosphamide for 4 2-week courses followed by 10 courses of paclitaxel combined with weekly capecitabine) or ETC (3 courses of epirubicin, followed by 3 courses of paclitaxel and by 3 courses of cyclophosphamide, all given at 2-week intervals) and randomized 2:1 to ibandronate at 50 mg/d (n = 2,015) or observation (n = 1,008) for 2 years. The primary endpoint was disease-free survival.

The ibandronate and observation groups were well matched for age (median, 49 and 50 years), body mass index, postmenopausal status (52% and 53%), tumor stage (eg, pT2 in 56% in both), tumor laterality (unilateral in 97% in both), histologic type (ductal invasive in 77% in both), tumor grade (G2 in 49.5% and 52%, G3 in 47% and 44%), pN status (pN1 in 38% and 37%, pN2 in 35% and 36%, pN3 in 27% in both), hormone receptor status (positive in 76.5% and 78%), HER2 status (negative in 78% in both), triple-negative status (15% in both), surgery type (breast conservation in 55.5% and 57%), and endocrine adjuvant treatment (tamoxifen alone in 37% and 38%, aromatase inhibitor with/without tamoxifen in 28% and 26%, and luteinizing hormone-releasing hormone and tamoxifen in 5.6% and 6.1%). Both groups had a median of five involved axillary nodes.

A total of 85 of 161 patients receiving adjuvant luteinizing hormone-releasing hormone and tamoxifen were younger than age 40 years, with this total representing 31.5% of patients in this age group with hormone receptor–positive disease.

No Improvement in Disease-Free Survival

In total, 78% of ibandronate patients completed treatment as planned, with 6% discontinuing treatment due to progression or death and 16% discontinuing for other reasons. After a median follow-up of 38.7 months, there was no difference in disease-free survival between the ibandronate group and the observation group (hazard ratio [HR] = 0.945, 95% confidence interval [CI] = 0.768–1.161, P = .589); this prompted release of efficacy data by the independent data monitoring committee due to failure of the difference to cross the futility boundary after 50% of the required disease-free survival events were observed.

There was also no difference in overall survival between the two groups (HR = 1.040, P = .803). Bone metastases were found in 31% of ibandronate patients and 38% of observation patients.

Improvement Trend in Younger and Older Patients

Univariate analysis showed that age, tumor and nodal stage, hormone receptor status, grade, and menopausal status but not body mass index, histologic tumor type, or HER2 status were prognostic for disease-free survival. In multivariate analysis, the same factors except age and menopausal status remained significant. Analysis adjusted by baseline factors confirmed that ibandronate did not improve disease-free survival (HR = 0.912, P = .395) or overall survival (HR = 0.980, P = .899).

Ibandronate was not associated with significant improvement in disease-free survival in any subgroup examined. A trend toward improved disease-free survival was observed with ibandronate in patients aged less than 40 years (HR = 0.70, 95% CI = 0.44–1.13), many of whom were receiving hormone therapy, and in those aged more than 60 years (HR = 0.75, 95% CI = 0.49–1.14, P = .093 for interaction).

Adverse Events

Patients in the ibandronate group had an excess of adverse events of any grade (22% vs 15%, P < .001) and of at least grade 3 (5.3% vs 2.9%, P = .003). The excess was observed in the system categories of infection, cardiac, gastrointestinal, hepatobiliary, and general condition. Osteonecrosis of the jaw was reported in two ibandronate patients. No ibandronate-related deaths were observed.

The investigators concluded:

[Two] years of adjuvant treatment with ibandronate after dose-dense chemotherapy had acceptable adverse effects but did not improve survival in patients with high-risk breast cancer. Post hoc subgroup analyses support the hypothesis that adjuvant bisphosphonate activity is 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 in which this approach has the most efficacy. ■

Disclosure: The study was supported by Amgen, Germany, Bristol-Myers Squibb, Germany, and Roche, Germany. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. von Minckwitz G, Möbus V, Schneeweiss A, et al: German Adjuvant Intergroup Node-Positive Study:
A phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer. J Clin Oncol 31:3531-3539, 2013.