Where Is Adjuvant Bisphosphonate Therapy Now? 

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Debu Tripathy, MD

The adjuvant use of bisphosphonates in breast cancer continues to yield seemingly contradictory data despite a sound biologic basis and smaller pilot studies suggesting that dampening bone turnover with bisphosphonates can lessen the bone reservoir of micrometastases.1,2 Early adjuvant trials with the weaker earlier-generation non-amino bisphosphonate clodronate, though not all consistent, provided promising data and suggested that this issue would be settled quickly with adequately powered studies.3-5

A decade later, larger pivotal trials continue to show mixed results, although their larger sizes have raised new hypotheses. For example, the benefit of adjuvant zoledronic acid may be significant in low-estrogen environments—either with ovarian ablation or in the postmenopausal subset as observed in the ABCSG-12, AZURE, and ZO-FAST trials.6-8

GAIN Trial

The GAIN Trial tested the oral amino-bisphosphonate ibandronate for 2 years in patients not restricted by menopausal or hormone receptor status and for whom chemotherapy was appropriate adjuvant treatment. An unplanned Bayesian futility analysis was added to the planned interim analysis, showing it was unlikely that a difference would be seen after the target number of events.

No difference in disease-free survival was seen with ibandronate at the time of this prespecified analysis, but subset analysis revealed a trend toward benefit in younger patients (most of whom had ovarian blockade in the case of hormone receptor–positive disease) as well as in those over age 60. However, no difference was seen in the estrogen receptor–positive subset. There were not enough events in subsets of interest—for example, postmenopausal patients with hormone receptor–positive tumors—to verify the findings of other studies.

ABCSG-12 Trial

The ABCSG-12 trial is the only contemporary trial to show a benefit in its primary endpoint in the overall population. It remains unclear whether the benefit in a low-estrogen state also requires hormone receptor–positive breast cancer. In fact, one randomized neoadjuvant zoledronic acid study showed a disease-free and overall survival benefit in the estrogen receptor–negative subset only.9

Nevertheless, in the general population of early-stage breast cancer patients, recent meta-analyses of randomized zoledronic acid studies (either as adjuvant therapy or to inhibit bone loss) have shown no impact on disease-free or overall survival. That said, the first cited study did show benefits for the postmenopausal subsets in disease-free (including both distant and locoregional disease) and overall survival.10,11

Further Considerations

Given the known pitfalls of subset analyses, what are we to make of the collective data on adjuvant bisphosphonates? Is there enough support to change practice in the case of ovarian blockade or menopause for hormone-responsive breast cancer?

Some have postulated that these findings could be explained by estrogen-mediated effects on the bone microenvironment via transforming growth factor (TGF)-β family members and the receptor activator of nuclear factor-kappaB (RANK) signaling system, both of which affect bone modeling.12 Additionally, zoledronic acid may have direct effects on cancer cells as evidenced by higher complete pathologic complete response rates seen in both randomized groups and uncontrolled series of patients on bisphosphonate therapy.13,14

A small randomized biomarker trial demonstrated enhanced tumor recovery of cell proliferation and apoptosis and lowered post-treatment serum vascular endothelial growth factor (VEGF) with zoledronic acid.15 Explanations for this effect include direct inhibition of the mevalonic acid pathway and subsequent inhibition of the prenylation (and activation) of signal transduction proteins involved in growth factor receptor pathways.16


All things considered, adjuvant bisphosphonate therapy—and its accompanying real but small rate of osteonecrosis of the jaw and other side effects—is not quite ready for broad application. Ideally, corroborating data from trials designed with specific subsets of patients may answer the many questions regarding the optimal agent, receptor subtype, and estrogenic milieu (eg, menopausal status, use of tamoxifen or aromatase inhibitors). ■

Dr. Tripathy is Professor of Medicine, Keck School of Medicine and USC/Norris Comprehensive Cancer Center, University of Southern California.

Disclosure: Dr. Tripathy reported no potential conflicts of interest.


1. Aft R, Naughton M, Trinkaus K, et al: Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: An open label, randomised, phase 2 trial. Lancet Oncol 11:421–428, 2010.

2. Solomayer EF, Gebauer G, Hirnle P, et al: Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol 23:2271-2277, 2012.

3. 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 19:2007-2011, 2008.

4. Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002.

5. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C: Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol 43:650-656, 2004.

6. Gnant M, Mlineritsch B, Stoeger H, et al: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12:631-641, 2011.

7. Coleman RE, Marshall H, Cameron D, et al: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365:1396-1405, 2011.

8. Coleman R, de Boer R, Eidtmann H, et al: Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): Final 60-month results. Ann Oncol 24:398-405, 2013.

9. Aft RL, Naughton M, Trinkaus K, et al: Effect of (neo)adjuvant zoledronic acid on disease-free and overall survival in clinical stage II/III breast cancer. Br J Cancer 107:7-11, 2012.

10. Yan T, Yin W, Zhou Q, et al: The efficacy of zoledronic acid in breast cancer adjuvant therapy: A meta-analysis of randomised controlled trials. Eur J Cancer 48:187-195, 2012.

11. Valachis A, Polyzos NP, Coleman RE, et al: Adjuvant therapy with zoledronic acid in patients with breast cancer: A systematic review and meta-analysis. Oncologist 18:353-361, 2013.

12. Hadji P, Coleman R, Gnant M, et al: The impact of menopause on bone, zoledronic acid, and implications for breast cancer growth and metastasis. Ann Oncol 23:2782-2790, 2012.

13. Coleman RE, Winter MC, Cameron D, et al: The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: Exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 102:1099-1105, 2010.

14. Chavez-Macgregor M, Brown E, Lei X, et al: Bisphosphonates and pathologic complete response to taxane- and anthracycline-based neoadjuvant chemotherapy in patients with breast cancer. Cancer 118:326-232, 2012.

15. Winter MC, Wilson C, Syddall SP, et al: Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer—a randomized biomarker pilot study. Clin Cancer Res 19:2755-2765, 2013.

16. Rogers MJ, Gordon S, Benford HL, et al: Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88:2961-2978, 2010.

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