Adjuvant Bisphosphonate Therapy in Postmenopausal Breast Cancer

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance.

1. 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.PubMedCrossRefGoogle Scholar
2. 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.PubMedPubMedCentralCrossRefGoogle Scholar
3. 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.PubMedCrossRefGoogle Scholar
4. 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.PubMedCrossRefGoogle Scholar
5. 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.Google Scholar
6. 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.PubMedPubMedCentralCrossRefGoogle Scholar
7. 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.CrossRefGoogle Scholar
8. 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.PubMedCrossRefGoogle Scholar
9. 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.PubMedCrossRefGoogle Scholar
10. 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.PubMedGoogle Scholar
11. 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.PubMedPubMedCentralCrossRefGoogle Scholar
12. 12.
    Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.PubMedGoogle Scholar
13. 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.PubMedCrossRefGoogle Scholar
14. 14.
    Kaplan RN, Rafii S, Lyden D. Preparing the “soil”: the premetastatic niche. Cancer Res. 2006;66(23):11089–93.PubMedPubMedCentralCrossRefGoogle Scholar
15. 15.
    Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80(8 Suppl):1546–56.PubMedCrossRefGoogle Scholar
16. 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.PubMedCrossRefGoogle Scholar
17. 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.PubMedPubMedCentralCrossRefGoogle Scholar
18. 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.CrossRefGoogle Scholar
19. 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.PubMedPubMedCentralCrossRefGoogle Scholar
20. 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.PubMedPubMedCentralCrossRefGoogle Scholar
21. 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.CrossRefGoogle Scholar
22. 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.PubMedCrossRefGoogle Scholar
23. 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.CrossRefGoogle Scholar
24. 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.PubMedCrossRefGoogle Scholar
25. 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.PubMedCrossRefGoogle Scholar
26. 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.CrossRefGoogle Scholar
27. 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.PubMedPubMedCentralCrossRefGoogle Scholar
28. 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.CrossRefGoogle Scholar
29. 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.PubMedCrossRefGoogle Scholar
30. 30.
    Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer. 2007;96(12):1796–801.PubMedPubMedCentralCrossRefGoogle Scholar
31. 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.CrossRefGoogle Scholar
32. 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.CrossRefGoogle Scholar
33. 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.PubMedCrossRefGoogle Scholar
34. 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.PubMedCrossRefGoogle Scholar
35. 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.PubMedCrossRefGoogle Scholar
36. 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.PubMedCrossRefGoogle Scholar
37. 37.
    Clezardin P. Bisphosphonates’ antitumor activity: an unravelled side of a multifaceted drug class. Bone. 2011;48(1):71–9.PubMedCrossRefGoogle Scholar
38. 38.
    Holen I, Coleman RE. Anti-tumour activity of bisphosphonates in preclinical models of breast cancer. Breast Cancer Res: BCR. 2010;12(6):214.PubMedPubMedCentralCrossRefGoogle Scholar
39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
40. 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.PubMedPubMedCentralCrossRefGoogle Scholar
41. 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.PubMedPubMedCentralCrossRefGoogle Scholar
42. 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.CrossRefGoogle Scholar
43. 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.PubMedCrossRefGoogle Scholar
44. 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.PubMedPubMedCentralCrossRefGoogle Scholar
45. 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.CrossRefGoogle Scholar
46. 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.PubMedCrossRefGoogle Scholar
47. 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.PubMedCrossRefGoogle Scholar
48. 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.Google Scholar
49. 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.PubMedCrossRefGoogle Scholar
50. 50.
    Bounameaux HM, Schifferli J, Montani JP, Jung A, Chatelanat F. Renal failure associated with intravenous diphosphonates. Lancet. 1983;1(8322):471.PubMedCrossRefGoogle Scholar
51. 51.
    Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Safety. 1999;21(5):389–406.PubMedCrossRefGoogle Scholar
52. 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.Google Scholar
53. 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.CrossRefGoogle Scholar
54. 54.
    Lipton A. The safety of zoledronic acid. Expert Opin Drug Saf. 2007;6(3):305–13.PubMedCrossRefGoogle Scholar
55. 55.
    Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. The Oncologist. 2004;9(Suppl 4):28–37.PubMedCrossRefGoogle Scholar
56. 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.CrossRefGoogle Scholar
57. 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.PubMedCrossRefGoogle Scholar
58. 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.PubMedPubMedCentralCrossRefGoogle Scholar
59. 59.
    Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. Jama. 2010;304(6):657–63.PubMedPubMedCentralCrossRefGoogle Scholar
60. 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.Google Scholar
61. 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.PubMedCrossRefGoogle Scholar
62. 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.PubMedPubMedCentralGoogle Scholar