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Can Bone-Targeted Therapy Reduce Recurrence and Improve Survival in Early-Stage Breast Cancer?

Can Bone-Targeted Therapy Reduce Recurrence and Improve Survival in Early-Stage Breast Cancer?

Although the majority of women diagnosed with early-stage breast cancer will be cured, the risk of recurrence remains even after optimal therapy, with bone being the most common distant site. Based on preclinical studies suggesting that osteoclast-targeted therapy may inhibit critical steps in the development of bone metastases, adjuvant bisphosphonates have been studied as a means to reduce breast cancer recurrences. The studies reported to date have produced conflicting results.

Four randomized clodronate trials used a dose of 1600 mg daily, a dose approved in many non-US countries to treat bone metastases.[1-4] Although two early trials showed a survival benefit for clodronate, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 trial, the largest and most recent, did not show benefit for clodronate in its primary endpoint, disease-free survival (DFS).[4] The only secondary endpoint that met statistical significance was the non–bone metastases–free interval, while the bone metastases–free interval did not. A subset analysis of B-34 suggested possible benefit among patients aged 50 years or older. In the German Intergroup Node-Positive (GAIN) study, patients receiving dose-dense chemotherapy were randomized to ibandronate (Boniva) 50 mg orally daily, a dose approved outside of the US for treatment of bone metastases, or placebo.[5] In the first interim efficacy analysis, the GAIN trial showed no difference in DFS or overall survival (OS).

Several trials of adjuvant zoledronic acid have shown conflicting results.[6-10] The Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, which randomized patients receiving adjuvant systemic therapy to 5 years of an intensive dosing schedule of zoledronic acid or not, showed no benefit for zoledronic acid.[6] In a subgroup analysis of patients more than 5 years from menopause, the 5-year OS rate favored zoledronic acid. AZURE was the largest adjuvant zoledronic acid trial, enrolling higher-risk patients and using the most intensive dosing regimen. Other adjuvant zoledronic acid trials used dosing intervals of 6 months, a regimen optimized for prevention of bone loss. In the Austrian Breast Cancer Study Group (ABCSG)-12 trial, premenopausal women with estrogen receptor (ER)-positive breast cancer receiving ovarian suppression were randomized in a 2 × 2 design to receive tamoxifen or anastrozole, and zoledronic acid or not.[7] ABCSG-12 showed a reduced risk of recurrence, the primary study endpoint, and a reduction in risk of death in the zoledronic acid arm. The Zometa-Femara Adjuvant Synergy studies, Z-FAST, ZO-FAST, and EZO –FAST,[8-10] focused on loss of bone mineral density in postmenopausal women receiving letrozole (Femara), with zoledronic acid used in an upfront or delayed fashion.[8-10] A post hoc analysis of ZO-FAST showed an improvement in DFS favoring upfront zoledronic acid, while Z-FAST and EZO-FAST were unable to show a DFS or OS benefit of zoledronic acid.

The positive adjuvant bisphosphonate trials had higher percentages of ER-positive disease, higher numbers of women with a low-estrogen state, and less chemotherapy. Subset analyses have suggested differential benefits based on menopausal status and age. Is this due to serum estrogen levels, the state of bone resorption, or other factors? Does chemotherapy eliminate the possible benefit of adjuvant bisphosphonates, by preventing the same potential recurrences?

Can we identify tumor-related factors that predict benefit—such as expression of ER?

Also, what is the mechanism of action? While the original hypothesis for these studies was based on a presumption of disruption of interaction between cancer and bone, reductions in bone-specific metastases have not been predominant across the trials.

At present, caution is urged in use of osteoclast-targeted therapy in early-stage breast cancer patients. Not all are at risk for therapy-induced bone loss, and the majority are not at risk for recurrence following adjuvant therapy. Toxicities exist, and there is financial cost to consider. While a subset of early-stage breast cancer patients may benefit from adjuvant bone-targeted therapy, this group has not yet been adequately defined. The Early Breast Cancer Clinical Trialists’ Collaborative Group will undertake a meta-analysis of the adjuvant bisphosphonate trials in the near future. Additionally, trials that have yet to report will provide further data, and ongoing correlative studies will help define the role of bone-targeted therapy. These drugs offer promise in the treatment of early-stage breast cancer patients, but it is clear that not all will benefit.

Financial Disclosure: Dr. Gralow receives research funding from Amgen, Novartis, Genentech, and Roche.

References

REFERENCES

1. Powles T, Paterson A, McCloskey E, et al: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Res. 2006;8:R13.

2. Diel IJ, Jaschke A, Solomayer EF, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol. 2008;19:2007-11.

3. Saarto T, Vehmanen L, Virkkunen P, et al. Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol. 2004;43:650-6.

4. 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. San Antonio Breast Cancer Symposium 2011. San Antonio, TX, Dec 6-10, 2011; abstr S2-3.

5. Möbus V DI, Elling D, Harbeck N, et al. GAIN study: a phase III trial to compare ETC vs EC-TX and ibandronate vs observation in patients with node positive primary breast cancer – 1st interim efficacy analysis. San Antonio Breast Cancer Symposium 2011. San Antonio, TX, Dec 6-10, 2011; abstr S2-4.

6. Coleman R, Cameron D, Dodwell D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365:1396-405.

7. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360:679-91.

8. de Boer RH, Eidtmann H, Neven P, 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. San Antonio Breast Cancer Symposium 2011. San Antonio, TX, Dec 6-10, 2011; abstr S1-3.

9. 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;118:1192-201.

10. Llombart A, Frassoldati A, Paija O, et al. Zoledronic acid prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: E-ZO-FAST 36-month follow-up. American Society of Clinical Oncology Breast Cancer Symposium 2009. Orlando, FL, May 29–June 2, 2009; abstr 213.

 
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