Publications 2009

Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer

Michael Gnant, M.D., Brigitte Mlineritsch, M.D., Walter Schippinger, M.D., Gero Luschin-Ebengreuth, M.D., Sabine Pöstlberger, M.D., Christian Menzel, M.D., Raimund Jakesz, M.D., Michael Seifert, M.D., Michael Hubalek, M.D., Vesna Bjelic-Radisic, M.D., Hellmut Samonigg, M.D., Christoph Tausch, M.D., Holger Eidtmann, M.D., Günther Steger, M.D., Werner Kwasny, M.D., Peter Dubsky, M.D., Michael Fridrik, M.D., Florian Fitzal, M.D., Michael Stierer, M.D., Ernst Rücklinger, Ph.D., and Richard Greil, M.D., for the ABCSG-12 Trial Investigators

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Abstract

BACKGROUND: Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties.

METHODS: We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points.

RESULTS: After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles.

CONCLUSIONS: The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)

N Engl J Med 2009;360:679-91

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Maintaining Bone Density in Patients Undergoing Treatment for Breast Cancer: Is There an Adjuvant Benefit?

Michael Gnant, Peter Dubsky, Florian Fitzal, Peter Blaha, Sebastian Schoppmann, Günther Steger, Christian Marth, Hellmut Samonigg, Katharina Hüttner, Hannes Fohler, Ernst Rücklinger, Raimund Jakesz, Richard Greil, on behalf of the Austrian Breast and Colorectal Cancer Study Group

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Abstract

Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures.

Many small studies have demonstrated that cancer therapy-induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting.

Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of early-stage breast cancer.

Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.

Clinical Breast Cancer, Vol. 9, Suppl. 1, S18-S27, 2009

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