Zoledronic Acid Update

Adjuvant therapy with non-nitrogenous bisphosphonates has not been shown to improve progression free survival (PFS) and overall survival (OS) in estrogen positive breast cancer patients. A clinical trial meta analysis of adjuvant clodronate therapy found no evidence of any statistically significant difference in OS, bone metastasis-free survival or non-skeletal metastasis-free survival in early or advanced breast cancer patients receiving adjuvant clodronate treatment compared with those who did not receive any active treatment (Ha & Li., 2007).

However, nitrogen-containing bisphosphonates such as zoledronic acid have been shown to produce significant improvements in PFS and OS in pre-menopausal woman undergoing estrogen suppression and post-menopausal woman treated with aromatase inhibitors (Benzaïd et al., 2011).

Furthermore, zoledronic acid inhibits metastasis to the bone and reduces epithelial to mesenchymal transition (EMT) by reducing the occurrence of disseminated tumour cells. Treatment with zoledronic acid has been shown to significantly reduce the ability of mesenchymal stem cells to migrate by reducing the secretion of factors such as RANTES/chemokine (C—C motif) ligand 5 (CCL5) and interleukin 6, which induce breast cancer cell migration (Normanno et al., 2011).

Results from Clinical Trials:

The results from the recent AZURE trial have shown significant benefits with adjuvant zoledronic acid treatment. Among postmenopausal patients, the rates of invasive disease free survival (DFS) were 78.2% in the zoledronic acid group and 71.0% in the control group (adjusted hazard ratio with zoledronic acid, 0.75; 95% CI, 0.59 to 0.96; P = 0.02). In addition, among patients who had undergone menopause more than 5 years earlier, the 5-year OS rate was 84.6% in the zoledronic acid group and 78.7% in the control group (adjusted hazard ratio, 0.74; 95% CI, 0.55 to 0.98; P = 0.04). In this group, there was a 29% reduction in the risk of death (hazard ratio, 0.71; P = 0.17) (Coleman et al., 2011).

The following figure is a summary of disease free survival from the ZO-FAST, AZURE and ABCSG-12 clinical trials. See Gnant, (2011).

FIG. 1: Zoledronic acid (ZOL) significantly improves disease-free survival in postmenopausal women with early breast cancer (BC) (ZO-FAST and AZURE) and in premenopausal women with early BC receiving goserelin therapy (ABCSG-12), compared with no ZOL (or delayed ZOL). ABCSG-12, Austrian Breast and Colorectal Cancer Study Group trial 12; AZURE, Adjuvant Zoledronic Acid to Reduce Recurrence; ZO-FAST, Zometa-Femara Adjuvant Synergy Trial.

The following table is a summary of disease free survival from the ZO-FAST, AZURE and ABCSG-12 clinical trials (Gnant et al., 2011; Coleman et al., 2010; de Boer et al., 2010). 

TABLE 1: Effects of zoledronic acid on disease-free survival and overall survival in 3 large phase 3 clinical trials in patients with early breast cancer. See Gnant, (2011).

ABCSG-12 AZURE ZO-FAST
Total population Subset > 40 years of age Total population Subset of PMWa Total population
Patients, n 1803 1390 3360 1101 1065
Menopausal status Pre + ovarian suppression Any Post Post
Median follow-up months 76 76 59 59 60
Comparator No ZOL No ZOL Delayed ZOL
End point
Disease Free  

Survival

HR, 0.73; P = 0.021 HR, 0.66; P = 0.013 HR, 0.98; P = 0.79 HR, 0.76; P < 0.05 (n = 1,041b) HR, 0.66; P = 0.0375
No. DFS events 213 144 752 263a; 247b 104
No. events in bone 57 NR 240 69a NR
No. events outside bone 156 NR 512 194a NR
Overall Survival HR, 0.59; P = 0.042 HR, 0.51; P = 0.018 HR, 0.85; P = 0.07 HR, 0.71; P = 0.017 (n = 1101a) N/A

aWomen who were > 5 years postmenopausal or of unknown menopausal status but > 60 years of age at baseline. bWomen who were > 5 years postmenopausal only. ABCSG-12 Austrian Breast and Colorectal Cancer Study Group trial 12, AZURE Adjuvant Zoledronic Acid to Reduce Recurrence, DFS disease-free survival, HR hazard ratio, NR not reported, OS overall survival, PMW postmenopausal women, ZO-FAST Zometa-Femara Adjuvant Synergy Trial, ZOL zoledronic acid.

REFERENCES:

Benzaïd et al., (2011). High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res; 71: 4562-4572.

Brufsky et al., (2011). Final 5-year results of Z-FAST trial: Adjuvant Zoledronic Acid Maintains Bone Mass in Postmenopausal Breast Cancer Patients Receiving Letrozole. Cancer; doi: 10.1002/cncr.26313. [Epub ahead of print]

Coleman et al., (2011). Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med; 365(15): 1396-405.

Coleman et al., (2010). Adjuvant treatment with zoledronic acid in stage II/III breast cancer. The AZURE trial (BIG 01/04). Presented at 33rd Annual San Antonio Breast Cancer Symposium;

de Boer et al., (2010). The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: The ZO-FAST study 5-year final follow-up [poster]. Presented at 33rd Annual San Antonio Breast Cancer Symposium; December 8–12, 2010; San Antonio, TX. Poster P5-11-01.

Gnant, (2011). Zoledronic Acid in the Treatment of Early-Stage Breast Cancer: Is There a Final Verdict? Curr Oncol Rep; Nov 24. [Epub ahead of print]

Gnant et al., (2011). Overall survival with adjuvant zoledronic acid in premenopausal breast cancer patients with complete endocrine blockade—long-term results from ABCSG-12 [poster]. Presented at Annual Meeting of the American Society of Clinical Oncology; June 3–7, 2011; Chicago, IL. Abstract 520.

Ha & Li., (2007). Meta-analysis of clodronate and breast cancer survival. British Journal of Cancer; 96: 1796–1801.

Normanno et al., (2011). Zoledronic acid in early-stage breast cancer. The Lancet Oncology; 12 (11): 991.

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