Endocrine therapy plus zoledronic acid in premenopausal breast cancer.
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.)
Gnant
Michael
M
Medical University of Vienna, Austria. michael.gnant@meduniwien.ac.at
Mlineritsch
Brigitte
B
Schippinger
Walter
W
Luschin-Ebengreuth
Gero
G
Pöstlberger
Sabine
S
Menzel
Christian
C
Jakesz
Raimund
R
Seifert
Michael
M
Hubalek
Michael
M
Bjelic-Radisic
Vesna
V
Samonigg
Hellmut
H
Tausch
Christoph
C
Eidtmann
Holger
H
Steger
Günther
G
Kwasny
Werner
W
Dubsky
Peter
P
Fridrik
Michael
M
Fitzal
Florian
F
Stierer
Michael
M
Rücklinger
Ernst
E
Greil
Richard
R
Marth
C
C
D000328:Adult; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D004965:Estrogen Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D017273:Goserelin / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use; D017697:Premenopause; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000009:adverse effects / Q000627:therapeutic use; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use; D000077211:Zoledronic Acid
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004965:Estrogen Antagonists; D007093:Imidazoles; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D013629:Tamoxifen; D017273:Goserelin; D000077384:Anastrozole; D000077211:Zoledronic Acid