Bisphosphonates and Breast Cancer: Good News and Bad News
Bisphosphonates and Breast Cancer: Good News and Bad News
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Two recent reports relate to the expanded use of zoledronic acid or other bisphosphonate in current oncologic practice. A report of a randomized, clinical trial demonstrated a small but clear benefit of a combination of endocrine therapy with zoledronic acid compared to endocrine therapy alone for early-stage, hormone-responsive breast cancer patients. In a separate article, the prevalence of the untoward bisphosphonate treatment-related osteonecrosis of the jaw was estimated to be approximately 5% in patients with advanced breast cancer. Interestingly, osteonecrosis of the jaw was not observed in the larger randomized trial in which early-stage breast cancer patients were enrolled.
Sources: Gnant M, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009; 360:679-691; Walter C, et al. Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer. 2009;115:1631-1637.
Skeletal metastases remain the most common site of distant metastases in breast cancer patients. There is now expanding literature on the potential antineoplastic effect of certain bisphosphonates1,2 which strengthen the rationale for the inclusion of such an agent in early management of this disease. In recent issues of the New England Journal of Medicine and Cancer, we learned of a clinical demonstration of such a salutary effect, but are reminded of one important concern, that of osteonecrosis of the jaw.
Gnant et al, representing the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12), 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. For this, 1,803 patients were randomly assigned to receive goserelin (3.6 mg subcutaneously every 28 days) plus tamoxifen (20 mg/day given orally) or anastrozole (1 mg/day given orally) with or without zoledronic acid (4 mg given intravenously every six months) for three years. The primary endpoint was disease-free survival; recurrence-free survival and overall survival were secondary endpoints.
After a median follow-up of 47.8 months, the disease-free survival (DFS) rate for those who received tamoxifen was 92.8%, compared with 92% for those who received anastrozole. For those who received endocrine therapy alone, the DFS was 90.8%, whereas for those who received zoledronic acid plus endocrine therapy, DFS was 94.0%. Thus, there was no significant difference in DFS 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). Nonetheless, the addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2% 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). However, 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).
In this trial, the addition of zoledronic acid was not associated with significant adverse events. Patients receiving anastrozole experienced more arthralgias and bone discomfort than those receiving tamoxifen and, in both groups, these symptoms increased for those receiving zoledronic acid. It was notable, however, that none of the 1,803 patients were found to have suffered osteonecrosis of the jaw.
In this light, the article published in Cancer by Walter et al was of interest. They performed a retrospective analysis of metastatic breast cancer patients treated with bisphosphonates at the breast unit of the Dr. Horst Schmidt hospital in Wiesbaden, Germany from January of 2000 to March of 2006. All patients were contacted, and missing data were completed through structured interviews with their dentists and physicians (n = 75). Primary outcome was the development of bisphosphonate-associated osteonecrosis of the jaw and the detection of possible additional trigger factors for the development of this untoward outcome.
Of the 117 patients who fulfilled the inclusion criteria, information was available for 75 who were still living. Of these, four patients had developed ONJ, resulting in a prevalence of 5.3%. Of these, three patients received zoledronate only and one patient had pamidronate followed by zoledronate and ibandronate. A tooth extraction could be identified as an additional trigger factor for two patients.
Commentary
These papers highlight the rapidly developing interest and concern regarding zoledronic acid and other drugs in this class amongst oncologists. These drugs are known to inhibit bone resorption due to their direct cytotoxic effect on osteoclasts.3,4 Whether that mechanism alone is sufficient to account for the previously reported reduction in bone metastases5 or the improvement in DFS found in the current study, is a point of conjecture. Certainly, other effects, such as that on angiogenesis2 or on anti-tumor immune responses could be equally relevant.6,7
The similar rates of disease-free survival found by Gnant et al comparing anastrozole with tamoxifen for early-stage breast cancer in premenopausal women is notable in light of the superiority of aromatase inhibitors over tamoxifen in post-menopausal patients.8,9 As Gnant et al suggest, this may relate to the dominant effect of ovarian suppression on estrogen and androgen levels in premenopausal women, limiting the availability of substrate for aromatase activity.
These data from a large, randomized, multicenter trial clearly demonstrate a small but significant improvement in DFS by the addition of zoledronic acid to adjuvant endocrine therapy in premenopausal patients with estrogen-responsive early breast cancer. This also has been observed in similarly treated post-menopausal breast cancer patients.5 The concern over osteonecrosis of the jaw, although not observed among the patients on the clinical trial, remains relevant, occurring in about 5% of cases in the series reported from Germany. Why the occurrence of osteonecrosis of the jaw was not observed in the current trial, or in the earlier trial of post-menopausal women5 remains conjecture, although it might relate to the more debilitated condition of patients with metastatic disease, such as those included in the German report.
References
1. Daubine F, et al. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007; 99:322-330.
2. Santini D, et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007;13:4482-4486.
3. Amin D, et al. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res. 1992;33:1657-1663.
4. Rogers MJ, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000;88:2961-78.
5. Brufsky A, et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist. 2008;13:503-14.
6. Dieli F, et al. Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res. 2007;67:7450-7457.
7. Kunzmann V, et al. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood. 2000;96:384-92.
8. Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008;9:45-53.
9. Goss PE, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-1802.
Two recent reports relate to the expanded use of zoledronic acid or other bisphosphonate in current oncologic practice.Subscribe Now for Access
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