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Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer

  • Breast Cancer (ML Telli, Section Editor)
  • Published:
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Opinion statement

Bone health and breast cancer are two connected subjects, because breast cancer patients have a higher prevalence of osteopenia/osteoporosis and reduced bone health parameters than healthy woman of the same age. Therefore, the positive effect of adjuvant bisphosphonate therapy plays an important role in breast cancer treatment. Several randomized trials have studied bisphosphonates in the adjuvant setting in postmenopausal woman and demonstrated their potential to prevent treatment-induced bone loss. The prevention of fractures and the subsequent preservation of patients’ quality of life are important arguments for the use of adjuvant bisphosphonates in postmenopausal breast cancer patients. In addition, trials of adjuvant bone-targeted agents showed a reduction of recurrences in and outside bone and an improved outcome in patients treated with bisphosphonates.

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  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    Article  CAS  PubMed  Google Scholar 

  2. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol. 2014;32(21):2255–69.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dubsky PC, Jakesz R, Mlineritsch B, Postlberger S, Samonigg H, Kwasny W, et al. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012;30(7):722–8.

    Article  CAS  PubMed  Google Scholar 

  4. Jakesz R, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 2007;99(24):1845–53.

    Article  CAS  PubMed  Google Scholar 

  5. Bartlett JMS, Ahmed I, Regan MM, Sestak I, Mallon EA, Dell’Orto P, et al. HER2 status predicts for upfront AI benefit: A TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1-98 and TEAM with centrally determined HER2. Eur J Cancer 2017; 79:129–138.

  6. • Jacobs C, Amir E, Paterson A, Zhu X, Clemons M. Are adjuvant bisphosphonates now standard of care of women with early stage breast cancer? A debate from the Canadian Bone and the Oncologist New Updates meeting. J Bone Oncol. 2015;4(2):54–8. This recent Work shows the benefit of bisphosphonates in relation to the estrogen level and the menopausal status.

    Article  PubMed  PubMed Central  Google Scholar 

  7. •• Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. New England J Med. 2009;360(7):679–91. The ABCSG-12 trial demonstrated a significant outcome benefit for advuvant zoledronic acid in premenopausal hormone-receptor positive breast cancer patients on ovarian function suppression therapy.

    Article  CAS  Google Scholar 

  8. Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, 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(7):631–41.

    Article  CAS  PubMed  Google Scholar 

  9. • Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015;26(2):313–20. This study underlines the superior effect of adjuvant bisphosphonate therapy in woman with early-stage breast cancer, who have a low estrogen level induced through ovarian function suppression or by nature.

    Article  CAS  PubMed  Google Scholar 

  10. Naume B, Borgen E, Kvalheim G, Karesen R, Qvist H, Sauer T, et al. Detection of isolated tumor cells in bone marrow in early-stage breast carcinoma patients: comparison with preoperative clinical parameters and primary tumor characteristics. Clin Cancer Res. 2001;7(12):4122–9.

    CAS  PubMed  Google Scholar 

  11. Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139(7):1315–26.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.

    CAS  PubMed  Google Scholar 

  13. Brown HK, Ottewell PD, Evans CA, Holen I. Location matters: osteoblast and osteoclast distribution is modified by the presence and proximity to breast cancer cells in vivo. Clin Exp Metastasis. 2012;29(8):927–38.

    Article  CAS  PubMed  Google Scholar 

  14. Kaplan RN, Rafii S, Lyden D. Preparing the “soil”: the premetastatic niche. Cancer Res. 2006;66(23):11089–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80(8 Suppl):1546–56.

    Article  CAS  PubMed  Google Scholar 

  16. Gnant M, Clezardin P. Direct and indirect anticancer activity of bisphosphonates: a brief review of published literature. Cancer Treat Rev. 2012;38(5):407–15.s.

    Article  CAS  PubMed  Google Scholar 

  17. Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, et al. Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res. 2014;20(11):2922–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. •• Early Breast Cancer Trialists’ Collaborative G. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386(10001):1353–61. The EBCTCG meta-analysis confirms a significant outcome benefit for adjuvant bisphosphonates in postmenopausal women, both in terms of breast cancer recurrences and overall survival.

    Article  Google Scholar 

  19. Rennert G, Pinchev M, Rennert HS, Gruber SB. Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol. 2011;29(9):1146–50.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hue TF, Cummings SR, Cauley JA, Bauer DC, Ensrud KE, Barrett-Connor E, et al. Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med. 2014;174(10):1550–7.

    Article  PubMed  PubMed Central  Google Scholar 

  21. • Early Breast Cancer Trialists’ Collaborative G, Dowsett M, Forbes JF, Bradley R, Ingle J, Aihara T, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–52. AI shows a significant benefit on overall survival compared with tamoxifen; this makes bone protection with bisphosphonate an important issue.

    Article  Google Scholar 

  22. Becker T, Lipscombe L, Narod S, Simmons C, Anderson GM, Rochon PA. Systematic review of bone health in older women treated with aromatase inhibitors for early-stage breast cancer. J Am Geriatr Soc. 2012;60(9):1761–7.

    Article  PubMed  Google Scholar 

  23. Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26(7):1051–7.

    Article  CAS  Google Scholar 

  24. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kassmann H, Piswanger-Solkner JC, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. The Lancet Oncology. 2008;9(9):840–9.

    Article  CAS  PubMed  Google Scholar 

  25. Brufsky AM, Harker WG, Beck JT, Bosserman L, Vogel C, Seidler C, 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):1192–201.

    Article  CAS  PubMed  Google Scholar 

  26. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. New England J Med. 1998;339(6):357–63.

    Article  CAS  Google Scholar 

  27. Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res: BCR. 2006;8(2):R13.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Diel IJ, Jaschke A, Solomayer EF, Gollan C, Bastert G, Sohn C, 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: Off J Eur Soc Med Oncol. 2008;19(12):2007–11.

    Article  CAS  Google Scholar 

  29. Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, et al. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. The Lancet Oncol. 2012;13(7):734–42.

    Article  CAS  PubMed  Google Scholar 

  30. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer. 2007;96(12):1796–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rogers MJ, Chilton KM, Coxon FP, Lawry J, Smith MO, Suri S, et al. Bisphosphonates induce apoptosis in mouse macrophage-like cells in vitro by a nitric oxide-independent mechanism. J Bone Miner Res: Off J Am Soc Bone Miner Res. 1996;11(10):1482–91.

    Article  CAS  Google Scholar 

  32. Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, et al. Breast-cancer adjuvant therapy with zoledronic acid. New England J Med. 2011;365(15):1396–405.

    Article  CAS  Google Scholar 

  33. Santini D, Martini F, Fratto ME, Galluzzo S, Vincenzi B, Agrati C, et al. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol Immunother: CII. 2009;58(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  34. Zocchi MR, Ferrarini M, Rugarli C. Selective lysis of the autologous tumor by delta TCS1+ gamma/delta+ tumor-infiltrating lymphocytes from human lung carcinomas. Eur J Immunol. 1990;20(12):2685–9.

    Article  CAS  PubMed  Google Scholar 

  35. Bagot M, Heslan M, Dubertret L, Roujeau JC, Touraine R, Levy JP. Antigen-presenting properties of human epidermal cells compared with peripheral blood mononuclear cells. Br J Dermatol. 1985;113(Suppl 28):55–60.

    Article  PubMed  Google Scholar 

  36. Morita CT, Jin C, Sarikonda G, Wang H. Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev. 2007;215:59–76.

    Article  CAS  PubMed  Google Scholar 

  37. Clezardin P. Bisphosphonates’ antitumor activity: an unravelled side of a multifaceted drug class. Bone. 2011;48(1):71–9.

    Article  CAS  PubMed  Google Scholar 

  38. Holen I, Coleman RE. Anti-tumour activity of bisphosphonates in preclinical models of breast cancer. Breast Cancer Res: BCR. 2010;12(6):214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gnant M, Hadji P. Prevention of bone metastases and management of bone health in early breast cancer. Breast Cancer Res: BCR. 2010;12(6):216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, 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. 2010;11(5):421–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ubellacker JM, Haider MT, DeCristo MJ, Allocca G, Brown NJ, Silver DP, et al. Zoledronic acid alters hematopoiesis and generates breast tumor-suppressive bone marrow cells. Breast Cancer Res: BCR. 2017;19(1):23.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Coleman R, de Boer R, Eidtmann H, Llombart A, Davidson N, Neven P, et al. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol: Off J Eur Soc Med Oncol. 2013;24(2):398–405.

    Article  CAS  Google Scholar 

  43. Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol. 2014;15(9):997–1006.

    Article  CAS  PubMed  Google Scholar 

  44. Hadji P, Aapro MS, Body JJ, Gnant M, Brandi ML, Reginster JY, et al. Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7:1–12.

    Article  PubMed  PubMed Central  Google Scholar 

  45. •• Dhesy-Thind S, Fletcher GG, Blanchette PS, Clemons MJ, Dillmon MS, Frank ES, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol: Off J Am Soc Clin Oncol. 2017;35(18):2062–81. The most recent ASCO guideline suggests adjuvant bone-targeted therapy for all breast cancer patients who are postmenopausal or premenopausal women on ovarian function suppression therapy.

    Article  Google Scholar 

  46. Cramer JA, Amonkar MM, Hebborn A, Altman R. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin. 2005;21(9):1453–60.

    Article  CAS  PubMed  Google Scholar 

  47. Cramer JA, Lynch NO, Gaudin AF, Walker M, Cowell W. The effect of dosing frequency on compliance and persistence with bisphosphonate therapy in postmenopausal women: a comparison of studies in the United States, the United Kingdom, and France. Clin Ther. 2006;28(10):1686–94.

    Article  CAS  PubMed  Google Scholar 

  48. Julie Gralow, WEB, Alexander H. G. Paterson, Danika Lew, Alison Stopeck, Daniel F. Hayes ... Dawn L. Hershman, et al. SWOG S0307 phase III trial of bisphosphonates as adjuvant therapy in primary breast cancer: comparison of toxicities and patient-stated preference for oral versus intravenous delivery. J Clin Oncol 32, no 15_suppl (May 2014) 558–558. 2014.

  49. Hadji P, Aapro M, Costa L, Gnant M. Antiresorptive treatment options and bone health in cancer patients-safety profiles and clinical considerations. Cancer Treat Rev. 2012;38(6):815–24.

    Article  CAS  PubMed  Google Scholar 

  50. Bounameaux HM, Schifferli J, Montani JP, Jung A, Chatelanat F. Renal failure associated with intravenous diphosphonates. Lancet. 1983;1(8322):471.

    Article  CAS  PubMed  Google Scholar 

  51. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Safety. 1999;21(5):389–406.

    Article  CAS  PubMed  Google Scholar 

  52. Berenson JR, Vescio RA, Rosen LS, VonTeichert JM, Woo M, Swift R, et al. A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res: Off J Am Assoc Cancer Res. 2001;7(3):478–85.

    CAS  Google Scholar 

  53. Launay-Vacher V, Spano JP, Janus N, Gligorov J, Ray-Coquard I, Oudard S, et al. Renal insufficiency and anticancer drugs in elderly cancer patients: a subgroup analysis of the IRMA study. Crit Rev Oncol/Hematol. 2009;70(2):124–33.

    Article  Google Scholar 

  54. Lipton A. The safety of zoledronic acid. Expert Opin Drug Saf. 2007;6(3):305–13.

    Article  CAS  PubMed  Google Scholar 

  55. Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. The Oncologist. 2004;9(Suppl 4):28–37.

    Article  CAS  PubMed  Google Scholar 

  56. Hadji P, Gnant M, Aapro M, Lipton A, Coleman R. Dosing of zoledronic acid throughout the treatment continuum in breast cancer. Crit Rev Oncol/Hematol. 2011;79(2):175–88.

    Article  Google Scholar 

  57. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev. 2000;42(3):175–95.

    Article  CAS  PubMed  Google Scholar 

  58. Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. Bmj. 2010;341:c4444.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. Jama. 2010;304(6):657–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gnant M PG, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, et al. The impact of adjuvant denosumab on disease-free survival: results from 3425 postmenopausal patients of the ABCSG-18 trial. San Antonio Breast Cancer Symposium: 2015 Dec 8–12; San Antonio, TX2015.

  61. •• Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–43. ABCSG-18 demonstrates in the primary end point analysis that adjuvant denosumab (60 mg s.c. twice yearly) reduced treatment-induced clinical fractures by 50% in postmenopausal women on adjuvant aromatase inhibitor treatment.

    Article  CAS  PubMed  Google Scholar 

  62. Azim HA, Kamal NS, Malak RA. Bisphosphonates in the adjuvant treatment of young women with breast cancer: the estrogen rich is a poor candidate! J Thorac Dis. 2013;5(Suppl 1):S27–35.

    PubMed  PubMed Central  Google Scholar 

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Correspondence to Michael Gnant MD, FACS.

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Stephanie Strobl declares that she has no conflict of interest. Kerstin Wimmer has received a congress fee from Pfizer. Ruth Exner declares that she has no conflict of interest. Yelena Devyatko declares that she has no conflict of interest. Michael Bolliger declares that he has no conflict of interest. Florian Fitzal has received financial support for meetings from Novartis, Roche, Pfizer, and AstraZeneca, and has received honoraria from Roche and Pfizer. Michael Gnant has received research support through grants from AstraZeneca, Roche, Novartis, and Pfizer; and has received compensation from AstraZeneca, Roche, Novartis, Pfizer, Accelsiors, Amgen, Celgene, and OBI Pharma for service as a consultant.

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Strobl, S., Wimmer, K., Exner, R. et al. Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer. Curr. Treat. Options in Oncol. 19, 18 (2018). https://doi.org/10.1007/s11864-018-0535-z

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