Endocrine Therapy Plus Zoledronic Acid in Premenopausal Breast Cancer

N Engl J Med. 2009 Feb 12;360(7):679-91. doi: 10.1056/NEJMoa0806285.

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.)

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anastrozole
  • Antineoplastic Agents, Hormonal / adverse effects
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Aromatase Inhibitors / adverse effects
  • Aromatase Inhibitors / therapeutic use
  • Bone Density Conservation Agents / adverse effects
  • Bone Density Conservation Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / surgery
  • Chemotherapy, Adjuvant
  • Diphosphonates / adverse effects
  • Diphosphonates / therapeutic use*
  • Disease-Free Survival
  • Drug Therapy, Combination
  • Estrogen Antagonists / adverse effects
  • Estrogen Antagonists / therapeutic use
  • Female
  • Follow-Up Studies
  • Goserelin / therapeutic use*
  • Humans
  • Imidazoles / adverse effects
  • Imidazoles / therapeutic use*
  • Middle Aged
  • Nitriles / adverse effects
  • Nitriles / therapeutic use
  • Premenopause*
  • Receptors, Estrogen / analysis
  • Tamoxifen / adverse effects
  • Tamoxifen / therapeutic use
  • Triazoles / adverse effects
  • Triazoles / therapeutic use
  • Zoledronic Acid

Substances

  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Bone Density Conservation Agents
  • Diphosphonates
  • Estrogen Antagonists
  • Imidazoles
  • Nitriles
  • Receptors, Estrogen
  • Triazoles
  • Tamoxifen
  • Goserelin
  • Anastrozole
  • Zoledronic Acid

Associated data

  • ClinicalTrials.gov/NCT00295646