German Adjuvant Intergroup Node-Positive Study: A Phase III Trial to Compare Oral Ibandronate Versus Observation in Patients With High-Risk Early Breast Cancer Gunter von Minckwitz, Volker Mo ¨bus, Andreas Schneeweiss, Jens Huober, Christoph Thomssen, Michael Untch, Christian Jackisch, Ingo J. Diel, Dirk Elling, Bettina Conrad, Rolf Kreienberg, Volkmar Mu ¨ller, Hans-Joachim Lu ¨ck, Ingo Bauerfeind, Michael Clemens, Marcus Schmidt, Stefanie Noeding, Helmut Forstbauer, Jana Barinoff, Antje Belau, Valentina Nekljudova, Nadia Harbeck, and Sibylle Loibl Author affiliations appear at the end of this article. Published online ahead of print at www.jco.org on August 26, 2013. Supported by Amgen, Germany; Bristol- Myers Squibb, Germany; and Roche, Germany which also provided drugs for this study. Written on behalf of the German Breast Group/Arbeitsgemeinschaft fu ¨r Gyna ¨ kologische Onkologie-B/Nord- Ostdeutsche Gesellschaft fu ¨ r Gyna ¨ kolo- gische Onkologie (GBG/AGO-B [Gynecologic Oncology Working Group]/ NOGGO [North-East Society for Gyne- cologic Oncology]) study groups. G.V.M., V.M., N.H., and S.L. contrib- uted equally to this work. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical trial information: NCT00196872. Corresponding author: Gunter von Minckwitz, MD, German Breast Group, c/o GBG Forschungs GmbH, Martin- Behaim-Str 12, 63263 Neu-Isenburg, Germany; e-mail: gunter.vonminckwitz@ germanbreastgroup.de. © 2013 by American Society of Clinical Oncology 0732-183X/13/3128w-3531w/$20.00 DOI: 10.1200/JCO.2012.47.2167 A B S T R A C T Purpose Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. Patients and Methods The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2  2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided  = .05 and 1- of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Results Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Conclusion Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy. J Clin Oncol 31:3531-3539. © 2013 by American Society of Clinical Oncology INTRODUCTION Several systemic medical treatments have proven, clinically relevant, long-term survival effects if given after surgery to patients with early-stage breast can- cer. 1 Targeted agents like tamoxifen, aromatase in- hibitors, and trastuzumab 2-4 do have favorable efficacy and toxicity profiles, but they can be used only in certain subsets of patients. Nontargeted cy- totoxic treatments, however, show similar relative risk reductions in all disease subtypes, but their use is associated with significant toxicities and is therefore limited to patients with substantial risks for relapse and death. In addition, resistance to all of these treat- ment options has been observed. Hence, preferably nontoxic, adjuvant treatment options are required to improve survival. Bisphosphonates have been successfully used for the treatment of bone metastasis in patients with advanced breast cancers because they inhibit osteoclast-mediated bone resorption. 5 In addition, direct anticancer mechanisms such as activating an- ticancer immune responses, inhibiting angiogene- sis, and inhibiting interactions with mesenchymal stem cells are postulated. 6-8 When the GAIN (Ger- man Adjuvant Intergroup Node-Positive) study was designed, three previous studies had investigated the use of a nonamino-bisphosphonate clodronate in JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 31  NUMBER 28  OCTOBER 1 2013 © 2013 by American Society of Clinical Oncology 3531 Downloaded from ascopubs.org by 35.175.195.222 on June 14, 2022 from 035.175.195.222 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.