Daily Oral Ibandronate With Adjuvant Endocrine Therapy in Postmenopausal Women With Estrogen Receptor–Positive Breast Cancer (BOOG 2006–04)

Randomized Phase III TEAM-IIB Trial

Sonja B. Vliek, MD; Iris Noordhoek, BSc; Elma Meershoek-Klein Kranenbarg, MSc; Annelot G.J. van Rossum, MD, PhD; Vincent O. Dezentje, MD, PhD; Agnes Jager, MD, PhD; J.W. Esmeralda Hokken, MD, PhD; Hein Putter, PhD; Annette W.G. van der Velden, MD, PhD; Mathijs P. Hendriks, MD, PhD; Sandra D. Bakker, MD, PhD; Yvonne E.A. van Riet, MD, PhD; Vivianne C.G. Tjan-Heijnen, MD, PhD; Johanneke E.A. Portielje, MD, PhD; Judith R. Kroep, MD, PhD; Johan W.R. Nortier, MD, PhD; Cornelis J.H. van de Velde, MD, PhD; Sabine C. Linn, MD, PhD


J Clin Oncol. 2022;40(25):2934-2945. 

In This Article

Abstract and Introduction


Purpose: For postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen-containing bisphosphonates such as ibandronate is unclear in this setting. TEAM-IIB investigates adjuvant ibandronate in postmenopausal women with estrogen receptor–positive (ER+) breast cancer.

Methods: TEAM-IIB is a randomized, open-label, multicenter phase III study. Postmenopausal women with stage I-III ER+ breast cancer and an indication for adjuvant endocrine therapy (ET) were randomly assigned 1:1 to 5 years of ET with or without oral ibandronate 50 mg once daily for 3 years. Major ineligibility criteria were bilateral breast cancer, active gastroesophageal problems, and health conditions that might interfere with study treatment. Primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population.

Results: Between February 1, 2007, and May 27, 2014, 1,116 patients were enrolled, 565 to ET with ibandronate (ibandronate arm) and 551 to ET alone (control arm). Median follow-up was 8.5 years. DFS was not significantly different between the ibandronate and control arms (HR, 0.97; 95% CI, 0.76 to 1.24; log-rank P = .811). Three years after random assignment, DFS was 94% in the ibandronate arm and 91% in the control arm. Five years after random assignment, this was 89% and 86%, respectively. In the ibandronate arm, 97/565 (17%) of patients stopped ibandronate early because of adverse events. Significantly more patients experienced GI issues, mainly dyspepsia, in the ibandronate arm than in the control arm (89 [16%] and 54 [10%], respectively; P < .003). Eleven patients in the ibandronate arm developed osteonecrosis of the jaw.

Conclusion: In postmenopausal women with ER+ breast cancer, adjuvant ibandronate 50 mg once daily does not improve DFS and should not be recommended as part of standard treatment regimens.


Metastatic spread of breast cancer is still the leading cause of cancer-related mortality in women.[1] Because hormone receptor–positive breast cancer cells prefer an osseous microenvironment, about 70% of breast cancer metastases are bone recurrences.[2,3] Nitrogen-containing bisphosphonates such as ibandronate affect bone metabolism by inhibiting key enzymes of the intracellular mevalonate pathway.[4] This decreases osteoclast-mediated bone resorption and osteoclast survival, causing an increase in bone density and a decreased release of cytokines and growth factors.[5] Preclinical studies suggest a direct antitumor effect by inhibition of tumor proliferation, induction of apoptosis, and enhanced immunosurveillance.[6] However, the exact anticancer mechanism of bisphosphonates is still unclear.

Several trials have investigated the effect of (neo)adjuvant bisphosphonates on cancer recurrence.[7–9] In 2015, a meta-analysis of 26 trials comparing patients treated with and without adjuvant bisphosphonates showed a reduction in breast cancer recurrence and mortality in the subgroup of women who were postmenopausal at the onset of treatment, but not in the premenopausal subgroup.[10] Thus far, the use of nitrogen-containing bisphosphonates has not been studied in exclusively postmenopausal patients.

The randomized TEAM-IIB trial investigates the addition of daily oral ibandronate to adjuvant endocrine therapy (ET) in postmenopausal women with estrogen receptor–positive (ER+) breast cancer. The registered dose of ibandronate to reduce skeletal events in the metastatic setting was used (50 mg once daily). This paper describes the results of the TEAM-IIB trial, including safety and toxicity.