[Rich66]

Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer
http://content.nejm.org/cgi/content/abstract/360/7/679
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 [ClinicalTrials.gov] .)


^{critiques/responses:}

http://content.nejm.org/cgi/content/full/360/22/2367

The author replies: In response to Wenz, Gelber and Aebi, Katz et al., Li and Dong, and Reimer and Gerber: according to St. Gallen and National Comprehensive Cancer Network guidelines, goserelin plus tamoxifen is an accepted treatment for premenopausal patients with endocrine-responsive breast cancer, and luteinizing hormone–releasing hormone agonists alone are associated with a strong trend toward reduced rates of recurrence and death.¹ In the ABCSG-12 study, the selection of 3 years of endocrine therapy was based on the findings of the ABCSG-5 trial (ClinicalTrials.gov number, NCT00309478 [ClinicalTrials.gov] ) (which examined 3 years of goserelin, then 5 years of tamoxifen).² However, 5 years of continuous endocrine therapy may not be necessary in this low-risk population, since it would be difficult to improve the 98.2% 4-year overall survival achieved in the group receiving zoledronic acid in the ABCSG-12 trial. We agree that long-term follow-up of SOFT and Triptorelin with Exemestane on Tamoxifen (TEXT) (NCT00066703 [ClinicalTrials.gov] ) may provide more definitive guidance on the use of aromatase inhibitors in premenopausal patients with breast cancer.
The ABCSG-12 study was designed and powered to show whether the addition of zoledronic acid to endocrine therapy improved outcomes, as compared with endocrine therapy alone. A specific interaction test did not reveal any difference in the treatment effect between the group receiving anastrozole plus zoledronic acid and the group receiving tamoxifen plus zoledronic acid. Therefore, at this time, it is not possible to conclude that the effect of zoledronic acid was driven primarily by the findings in one cohort. Longer follow-up of the zoledronic acid effect may help to determine whether meaningful differences exist.
Reimer and Gerber are correct in pointing out that there was a nonsignificant trend favoring tamoxifen over anastrozole for survival, and both P values in Figure 2E should be 0.07 rather than 0.70. (The article has been corrected at NEJM.org.)
In response to Li and Dong: we did not prospectively determine the HER-2/neu status of patients in our study. However, since patients underwent randomization, the proportion of HER-2/neu–positive patients is likely to have been balanced among the study groups and is unlikely to have confounded the trial outcomes.
In response to Berruti et al.: vitamin D levels and vitamin D supplementation were not part of our protocol and therefore were not prospectively recorded. However, we agree that this could be an important factor and should be elucidated in future trials of adjuvant bisphosphonates.
We agree with De Luca and Normanno that the antitumor effects of zoledronic acid may be mediated by preventing the secretion of angiogenic factors by mesenchymal stem cells in bone marrow. This is entirely consistent with the idea that zoledronic acid makes the bone-and-marrow microenvironment less favorable "soil" for tumor-cell growth. One hypothesis is that bone may provide a sanctuary for dormant micrometastases that may later seed distant metastases. Preliminary clinical data suggest that the antitumor activity of zoledronic acid may include the inhibition of angiogenesis, immunostimulatory effects through the activation of gamma delta T cells,³ and a reduction in the number of disseminated tumor cells in bone marrow.⁴ In addition, recent results from the neoadjuvant subgroup analysis of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) (NCT00072020 [ClinicalTrials.gov] ) trial indicate that zoledronic acid has direct antitumor activity.⁵ Therefore, stimulation of a wide array of antitumor effects by zoledronic acid may inhibit disease progression in areas other than bone in patients with breast cancer.
Michael Gnant, M.D.
Medical University of Vienna
A-1090 Vienna, Austria
michael.gnant@meduniwien.ac.at