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Bisphosphonates Should Not Be Routine in Early Breast Cancer

TOP - February 2013 VOL 6, NO 1

For preventing bone metastases in women with early breast cancer, the current body of evidence does not support the use of osteoclast-targeting agents, ie, bisphosphonates, according to Julie Gralow, MD, director of Breast Medical Oncology at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Gralow presented her thoughts on this controversial topic at the American Society of Clinical Oncology 2012 Breast Cancer Symposium, held in San Francisco, California.1

“There is no question that breast cancer treatment can cause accelerated bone loss, most commonly among patients receiving aromatase inhibitors,” she acknowledged. But studies have failed to show significant differences in the occurrence of the more clinically relevant end point of fracture, and the prevention of recurrences and deaths from breast cancer, she noted.

To the point, Gralow reviewed key data from several important trials evaluating the benefit of adjuvant bisphosphonates.

No Real Benefit for Fracture Prevention

The Z-FAST trial compared upfront use of zoledronic acid with its delayed use in postmenopausal women receiving adjuvant letrozole. Whereas bone mineral density (BMD) was better with the immediate use of zoledronic acid—with gain observed with upfront use and decline observed without it—fracture rates were similar between the arms: approximately 6% at 36 months and 9% to 11% at 61 months, the recent update showed.2

“Zoledronic acid preserved BMD but did not impact fractures,” she said.

“There is also a rebound effect in BMD that is important,” Gralow noted. In the ABCSG-12 trial, premenopausal patients received ovarian suppression for 3 years plus adjuvant hormonal therapy, with or without zoledronic acid.3 The bisphosphonate was protective against BMD loss. However, a natural rebound in BMD occurred once the ovarian suppression was stopped, she said.

“Just because we are suppressing the ovaries, especially temporarily, or starting an aromatase inhibitor, we don’t need to impact on BMD immediately,” she explained. “There’s a significant rebound of BMD once you take away the pressures from these treatments.”
Although zoledronic acid did reduce recurrences by 28% and deaths by 36%, the death rate at 84 months was already very low (6%) among patients not receiving chemotherapy or zoledronic acid (and in spite of allowing up to 10 positive nodes).

A task force of the National Com­p­rehensive Cancer Network, led by Gralow, defined patients who may be at increased risk for fracture and who therefore might be candidates for bisphosphonates. The algorithm suggests that drug therapy be considered for patients with a T-score between -1.5 and -2.0, and that it be initiated in those with a T-score ≤-2.0 or who have a 10-year risk >20% for a major fracture or >3% for a hip fracture by FRAX analysis (WHO Fracture Risk Assessment Tool).

“The task force clearly did not say that all patients should start drug therapy up front,” she emphasized.

No Real Protection From Recurrence

Studies investigating whether bisphosphonates can prevent bone metastases and improve survival have produced conflicting results. Two randomized trials of oral clodronate showed a reduction in bone metastases, while a third demonstrated an equivalent rate of bone metastases between the arms. A meta-analysis using the 5-year data from these 3 adjuvant clodronate trials failed to show a statistically significant difference in overall survival or bone metastasis-free survival,4 although heterogeneity among the trial was noted, she said.

“The largest and most recently reported trial of clodronate, NSABP B-345 (the 2011 San Antonio Breast Cancer Symposium), was flat-out negative for the primary end point, disease-free survival,” she added.

The German GAIN trial of ibandronate6 also was completely negative for a benefit in terms of recurrence or survival, she added.

Trials of the more potent aminobisphosphonate, zoledronic acid, also have produced conflicting results. Whereas the ABCSG-12 trial3 and the ZO-FAST trial7 both showed improvements in disease-free survival in patients receiving zoledronic acid, the Z-FAST trial, with the same design as ZO-FAST, did not.2 The AZURE trial, which evaluated an “intensive” adjuvant zoledronic acid regimen, also failed to show a disease- free or overall survival benefit.8

“The largest trial in the highest risk patients using the most intensive dosing (AZURE) was flat-out negative,” Gralow emphasized.
There was a suggestion of an overall survival benefit among women who were 5 years past menopause prior to randomization—a statistically significant 25% risk reduction—suggesting that an estrogen-deficient environment might be more susceptible to the effect of zoledronic acid, but these results must be interpreted with caution, she said.

Gralow added, “If there is a direct antitumor effect, I don’t know why we have not seen a hint of this in metastat­ic studies.”

A number of ongoing trials are further evaluating clodronate, ibandronate, zoledronic acid, and the newest osteoclast inhibitor denosumab. “The results of these trials will be critical in better defining the efficacy of bone-modifying agents for preventing recurrence and may provide data regarding which patients and tumors are most likely to benefit from treatment,” Gralow said. l

1. Gralow J. Debate: bone health/role of bisphosphonates in early-stage breast cancer—con. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA.
2. Brufsky AM, Harker WG, Beck JT, et al. Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer. 2012;118(5):
3. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S1-2.
4. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer. 2007;96(12):1796-1801.
5. Paterson AHG, Anderson SJ, Lembersky BC, et al. NSABP protocol B-34: a clinical trial comparing adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy—final analysis. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S2-3.
6. Möbus V, Diel IJ, Harbeck N, et al. GAIN (German Adjuvant Intergroup Node Positive) study: a phase-III multicenter trial to compare dose dense, dose intense ETC (iddETC) vs. EC-TX and ibandronate vs. observation in patients with node-positive primary breast cancer—1st interim EFFICACY analysis. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S2-4.
7. de Boer R, Bundred N, Eidtmann H, et al. Long-term survival outcomes among postmenopausal women with hormone receptor-positive early breast cancer receiving adjuvant letrozole and zoledronic acid: 5-year follow-up of ZO-FAST. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S1-3.
8. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365(15):1396-1405.

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