The development of effective systemic therapies to reduce the risk of disease recurrence or metastases in early-stage breast cancer remains an important challenge. The use of bone-modifying agents (BMAs), including the bisphosphonates (BPs) and the monoclonal antibody denosumab (Xgeva), is well established for metastatic bone disease. In the adjuvant setting, some studies have shown provocative findings with some of these agents for the prevention of future breast cancer–related events, with improved survival in some subgroups. The most compelling results have been seen with clodronate and zoledronic acid. In this review we describe the current evidence for use of BPs as part of the adjuvant treatment of patients with early-stage breast cancer.
The bisphosphonate (BP) drugs have a long established role in the management of osteoporosis, hypercalcemia of malignancy, and bone metastases from solid tumors and multiple myeloma. In the breast cancer population, zoledronic acid (ZA) and pamidronate have been widely used for over a decade in patients with bone metastases as an adjunct to radiotherapy, hormonal therapy, and chemotherapy, based on trials that have shown a reduction in skeletal-related events (SREs), including fractures, spinal cord compression, and worsening pain necessitating radiotherapy. In addition, these agents are being suggested for premenopausal patients with bone loss from premature ovarian failure due to chemotherapy and in postmenopausal patients treated with aromatase inhibitors (AIs). There is increasing interest in using these drugs to reduce the risk of breast cancer metastases, both bone and non-bone, independent of the established uses for bone-related indications; this is in light of a plausible mechanism of action based on preclinical evidence, some compelling observational data, and results from several interventional trials suggesting a role in some subpopulations of breast cancer patients. However, trial results with BPs are conflicting, and currently none of these agents have been designated by the US Food and Drug Administration (FDA) as being indicated for reducing breast cancer recurrence or improving disease-free survival (DFS) and overall survival (OS), so any use for this purpose in the US must be considered off-label and experimental.
This manuscript will review the preclinical and clinical data for the use of bone-modifying agents (BMAs) in the adjuvant treatment of early breast cancer. We will examine clinical trial results for these agents and will address issues of toxicity and cost-effectiveness. We will attempt to offer a perspective on their use in the absence of existing guidelines for the primary purpose of reducing breast cancer recurrence.
Bone-Modifying Agents and Early Breast Cancer: Preclinical Observations
In normal bone, particularly in young adults, there is a balance between osteoclastic bone resorption and osteoblastic bone formation. This can be altered by the presence of tumor cells in bone, which accelerate resorption by promoting osteoclast formation and activity through the release of tumor cell–derived factors, such as parathyroid hormone–related peptide (PTHrP), prostaglandin-E, and bone sialoprotein. PTHrP binds to receptors on osteoblasts, enhancing production of receptor activator of nuclear factor κβ ligand (RANKL). This pathway results in the differentiation of osteoclasts and their activation. On osteoclasts, RANKL binds to its receptor, RANK, promoting an increase in bone resorption.
Osteoclast inhibition induced by bisphosphonates (BPs) can alter the bone microenvironment, making it less supportive of tumor cell proliferation, and preclinical data suggest that BPs can reduce the likelihood of developing bone metastases. The mechanisms of antitumor activity of BPs have not been fully elucidated, but it is proposed that these drugs exert both indirect and direct antitumor effects. One potential indirect mechanism of action would be inhibition of bone resorption, in which BPs reduce the release of cytokines and other growth factors. This makes the bone environment less hospitable for tumor cell migration, decreasing the likelihood of cell adhesion and proliferation. Another indirect antitumor effect is the induction of a T cell–mediated immune response, in which BPs may inhibit angiogenesis by activating T-effector cells producing interferon-gamma.
A potential direct mechanism of BPs is the inhibition of angiogenesis, as shown in particular with ZA.[5,6] The BPs also decrease the adhesion, invasion, and proliferation of tumor cells. Moreover, they may have synergistic antitumor activity with cytotoxic agents, mainly with taxanes and anthracyclines. For instance, the combination of ZA and doxorubicin produced synergistic antitumor activity in a primary breast cancer murine model without extraskeletal disease. Additionally, antitumor effects appear to be dose-dependent, and in some in vitro studies BPs may directly and dose-dependently induce apoptosis in breast cancer cell lines.[8-11]
The hypothesis of the “seed and soil” described by Paget may further elucidate the antitumor properties of BPs. The “seed” represents the tumor cell and the “soil” represents the bone marrow, which would have the ideal microenvironment to receive tumor cells. Supportive stromal cells, growth factors, and other components of the extracellular matrix, including the vasculature, make the bone marrow microenvironment a favorable milieu for cancer cell proliferation and propagation. Some preclinical evidence also suggests that the bone marrow is a “premetastatic niche,” and the engraftment of tumor cells onto a favorable bone marrow microenvironment would begin the evolution of micrometastasis, to macrometastasis, to distant, non-bone metastasis. Thus, early intervention such as the use of BPs in the adjuvant setting may interfere with the formation of this premetastatic niche.
1. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003; 98:1735-44.
2. Hadji P. Reducing the risk of bone loss associated with breast cancer treatment. Breast. 2007;16(Suppl 3):S10-5.
3. Winter MC, Holen I, Coleman RE. Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev. 2008;34:453-75.
4. Hall DG, Stoica G. Effect of the bisphosphonate risedronate on bone metastases in a rat mammary adenocarcinoma model system. J Bone Miner Res. 1994;9:221-30.
5. Bezzi M, Hasmim M, Bieler G, et al. Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J Biol Chem. 2003;278:43603-14.
6. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055-61.
7. Ottewell PD, Monkkonen H, Jones M, et al. Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst. 2008;100:1167-78.
8. Fromigue O, Lagneaux L, Body JJ. Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res. 2000;15:2211-21.
9. Senaratne SG, Pirianov G, Mansi JL, et al. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000;82:1459-68.
10. Verdijk R, Franke HR, Wolbers F, Vermes I. Differential effects of bisphosphonates on breast cancer cell lines. Cancer Lett. 2007;246:308-12.
11. Jagdev SP, Coleman RE, Shipman CM, et al. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer. 2001;84:1126-34.
12. Paget S. The distribution of secondary growths in cancer of the breast. 1989. Cancer Metastasis Rev. 1989;8:98-101.
13. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9:285-93.
14. Tabane K, Vorobiof DA. Bone targeted therapies in early breast cancer. Curr Treat Options Oncol. 2011;
15. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998;339:357-63.
16. 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.
17. Powles T, Paterson S, Kanis JA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol. 2002;
18. Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol. 2001;19:10-7.
19. 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. 2004;43:650-6.
20. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer. 2007;96:1796-801.
21. Paterson A, Anderson S, Lembersky B, 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. CTRC-AACR San Antonio Breast Cancer Symposium. 2011; abstr S2-3.
22. Mobus V, Diel I, Elling D, 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. CTRC-AACR San Antonio Breast Cancer Symposium. 2011; abstr S2-4.
23. Kokufu I, Kohno N, Takao S, et al. Adjuvant pamidronate (PMT) therapy for the prevention of bone metastasis in breast cancer (BC) patients (pts) with four or more positive nodes. J Clin Oncol. 2004;22(14s):abstr 530.
24. Jung J, Hwang G, Lee Y, et al. Pamidronate as adjuvant treatment for prevention of bone metastasis in breast cancer. ASCO Annual Meeting. 2005; abstr 888.
25. Brufsky A, Harker WG, Beck JT, et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol. 2007;25:829-36.
26. Bundred NJ, Campbell ID, Davidson N, et al. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST study results. Cancer. 2008;
27. Brufsky A, Bundred N, Coleman R, 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.
28. 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.
29. Eidtmann H, de Boer R, Bundred N, et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol. 2010;21:2188-94.
30. 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. CTRC-AACR San Antonio Breast Cancer Symposium 2011; abstr S1-3.
31. 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.
32. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365:1396-405.
33. 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. 2011;12:631-41.
34. 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. CTRC-AACR San Antonio Breast Cancer Symposium. 2011; abstr S1-2.
35. Lipton A, Uzzo R, Amato RJ, et al. The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors. J Natl Compr Canc Netw. 2009;7(Suppl 7):S1-29.
36. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-9.
37. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-65.
38. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26:4875-82.
39. Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745-55.
40. Goss P, Barrios C, Bell R, et al. Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): an international, randomized, double-blind, placebo-controlled phase III clinical trial. J Clin Oncol. 2012;30(suppl): abstr TPS670.
41. Papapetrou PD. Bisphosphonate-associated adverse events. Hormones (Athens). 2009;8:96-110.
42. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007;25:4431-7.
43. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-91.
44. Ruggiero S, Gralow J, Marx RE, et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract. 2006;2:7-14.
45. Mauri D, Valachis A, Polyzos IP, et al. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat. 2009;116:433-9.
46. Coleman R, Woodward E, Brown J, et al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast Cancer Res Treat. 2011;127:429-38.
47. El-Ouagari K, Taneja C, Sofrygin O, et al. Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with early breast cancer: Canadian perspective. ASCO Breast Cancer Symposium 2009; abstr 184.
48. Logman JF, Heeg BM, Botteman MF, et al. Economic evaluation of zoledronic acid for the prevention of osteoporotic fractures in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the UK. Ann Oncol. 2010;21:1529-36.
49. Southwest Oncology Group: Zoledronate, clodronate, or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer. S0307. [Updated May 19, 2012.] Available from: www.clinicaltrials.gov.
50. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2: CD003474.