Repurposing denosumab in breast cancer beyond prevention of skeletal related events: Could nonclinical data be translated into clinical practice?

References

• McCabe B, Liberante F, Mills KI. Repurposing medicinal compounds for blood cancer treatment. Ann Hematol. 2015;94(8):1267–1276.
   PubMed Web of Science ®Google Scholar
• Peters S, Clézardin P, Márquez-Rodas I, et al. The RANK-RANKL axis: an opportunity for drug repurposing in cancer? Clin Transl Oncol. 2019;21(8):977–991.
   PubMed Web of Science ®Google Scholar
• [ cited 2020 Feb]. Available from: https://www.drugs.com/history/prolia.html
   Google Scholar
• Martin TJ. Historically significant events in the discovery of RANK/RANKL/OPG. World J Orthop. 2013;4(4):186–197.
   PubMedGoogle Scholar
• Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139–146.
   PubMed Web of Science ®Google Scholar
• Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29(2):155–192.
   PubMed Web of Science ®Google Scholar
• Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390(6656):175–179.
   PubMed Web of Science ®Google Scholar
• Hanada R, Hanada T, Sigl V, et al. RANKL/RANK-beyond bones. J Mol Med (Berl). 2011;89(7):647–656.
   PubMed Web of Science ®Google Scholar
• de Groot AF, Appelman-Dijkstra NM, van der Burg SH, et al. The anti-tumor effect of RANKL inhibition in malignant solid tumors—a systematic review. Cancer Treat Rev. 2018;62:18–28.
   PubMed Web of Science ®Google Scholar
• Renema N, Navet B, Heymann MF, et al. RANK–RANKL signalling in cancer. Biosci Rep. 2016;36(4):pii: e00366.
   PubMed Web of Science ®Google Scholar
• Yu X, Kong W, Zheng K. Expression of osteoprotegerin and osteoprotegerin ligand in giant cell tumor of bone and its clinical significance. Oncol Lett. 2013;5(4):1133–1139.
   PubMed Web of Science ®Google Scholar
• Molyneux SD, Di Grappa MA, Beristain AG, et al. Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. J Clin Invest. 2010;120(9):3310–3325.
   PubMed Web of Science ®Google Scholar
• Navet B, Ando K, Vargas-Franco JW, et al. The intrinsic and extrinsic implications of RANKL/RANK signaling in osteosarcoma: from tumor initiation to lung metastases. Cancers (Basel). 2018;10(11):pii: E398.
   PubMed Web of Science ®Google Scholar
• [ cited 2020 Mar]. Available from: https://clinicaltrials.gov/
   Google Scholar
• Lipton A, Jacobs I. Denosumab: benefits of RANK ligand inhibition in cancer patients. Curr Opin Support Palliat Care. 2011;5(3):258–264.
   PubMedGoogle Scholar
• Gaston CL, Puls F, Grimer RJ. The dilemma of denosumab: salvage of a femoral head giant cell tumour. Int J Surg Case Rep. 2014;5(11):783–786.
   PubMedGoogle Scholar
• Branstetter DG, Nelson SD, Manivel JC, et al. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012;18(16):4415–4424.
   PubMed Web of Science ®Google Scholar
• Egerdie B, Saad F, Smith MR, et al. Responder analysis of the effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. Prostate Cancer Prostatic Dis. 2012;15(3):308–312.
   PubMed Web of Science ®Google Scholar
• Smith MR, Egerdie B, Toriz NH, et al. For the denosumab HALT prostate cancer study group C. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745–755.
   PubMed Web of Science ®Google Scholar
• 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(30):4875–4882.
   PubMed Web of Science ®Google Scholar
• Jiang Z, Shao Z, Zhang Q, et al. Efficacy and safety of denosumab from a phase III, randomized, active-controlled study compared with ZA in patients of Asian ancestry with bone metastases from solid tumors. J Clin Oncol. 2016;34(15):S10116.
   Web of Science ®Google Scholar
• Smith MR, Saad F, Coleman R, et al. Denosumab and bone metastasis-free survival in men with castration-resistant prostate cancer: results of a global phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39–46.
   PubMed Web of Science ®Google Scholar
• Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis–free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31(30):3800–3806.
   PubMed Web of Science ®Google Scholar
• Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19(3):370–381.
   PubMed Web of Science ®Google Scholar
• Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14(9):901–908.
   PubMed Web of Science ®Google Scholar
• [ cited 2020 June 28]. Available from: https://www.drugs.com/history/xgeva.html
   Google Scholar
• Infante M, Fabi A, Cognetti F, et al. RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives. J Exp Clin Cancer Res. 2019;38(1):12.
   PubMed Web of Science ®Google Scholar
• Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Suarez E, Jacob AP, Jones J, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–107.
   PubMed Web of Science ®Google Scholar
• Schramek D, Leibbrandt A, Sigl V, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98–102.
   PubMed Web of Science ®Google Scholar
• Jones DH, Nakashima T, Sanchez OH. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440(7084):692–696.
   PubMed Web of Science ®Google Scholar
• Walsh MC, Choi Y. Biology of the RANKL–RANK–OPG system in immunity, bone, and beyond. Front Immunol. 2014;5:511.
   PubMed Web of Science ®Google Scholar
• Chu GC, Chung LW. RANK-mediated signaling network and cancer metastasis. Cancer Metastasis Rev. 2014;33(2–3):497–509.
   PubMed Web of Science ®Google Scholar
• Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 2007;9(Suppl 1):S1.
   PubMed Web of Science ®Google Scholar
• Luo J, Yang Z, Ma Y, et al. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016;22(5):539–546.
   PubMed Web of Science ®Google Scholar
• Yue Z, Yuan Z, Zeng L, et al. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. Faseb J. 2018;32(5):2422–2437.
   PubMed Web of Science ®Google Scholar
• Cheng ML, Fong L. Effects of RANKL-targeted therapy in immunity and cancer. Front Oncol. 2014;3:329.
   PubMedGoogle Scholar
• Ahern E, Smyth MJ, Dougall WC, et al. Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy. Nat Rev Clin Oncol. 2018;15(11):676–693.
   PubMed Web of Science ®Google Scholar
• Loi S. The ESMO clinical practise guidelines for early breast cancer: diagnosis, treatment and follow-up: on the winding road to personalized medicine. Ann Oncol. 2019;30(8):1183–1184.
   PubMed Web of Science ®Google Scholar
• Cardoso F, Kyriakides S, Ohno S, et al.; on behalf of the ESMO guidelines committee. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;2019(30):1194–1220.
   Web of Science ®Google Scholar
• Diep CH, Daniel AR, Mauro LJ, et al. Progesterone action in breast, uterine, and ovarian cancers. J Mol Endocrinol. 2015;54(2):R31–53.
   PubMed Web of Science ®Google Scholar
• Daniel AR, Hagan CR, Lange CA. Progesterone receptor action: defining a role in breast cancer. Expert Rev Endocrinol Metab. 2011;6(3):359–369.
   PubMedGoogle Scholar
• Tanos T, Sflomos G, Echeverria PC, et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med. 2013;5(182):182ra55.
   PubMed Web of Science ®Google Scholar
• Joshi PA, Jackson HW, Beristain AG. Progesterone induces adult mammary stem cell expansion. Nature. 2010;465(7299):803–807.
   PubMed Web of Science ®Google Scholar
• Macedo GS, Alemar B, Ashton-Prolla P. Reviewing the characteristics of BRCA and PALB2-related cancers in the precision medicine era. Genet Mol Biol. 2019;42(1 suppl 1):215–231.
   PubMed Web of Science ®Google Scholar
• Venkitaraman AR. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science. 2014;343(6178):1470–1475.
   PubMed Web of Science ®Google Scholar
• Armstrong N, Ryder S, Forbes C, et al. A systematic review of the international prevalence of BRCA mutation in breast cancer. Clin Epidemiol. 2019;11:543–561.
   PubMed Web of Science ®Google Scholar
• Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–2416.
   PubMed Web of Science ®Google Scholar
• Widschwendter M, Rosenthal AN, Philpott S, et al. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol. 2013;14(12):1226–1232.
   PubMed Web of Science ®Google Scholar
• Nolan E, Lindeman GJ, Visvader JE. Out-RANKing BRCA1 in mutation carrier. Cancer Res. 2017;77(3):595–600.
   PubMed Web of Science ®Google Scholar
• Cuyàs E, Corominas-Faja B, Muñoz-San María M, et al. BRCA1 haploinsufficiency cell-autonomously activates RANKL expression and generates denosumab-responsive breast cancer-initiating cells. Oncotarget. 2017;8(21):35019–35032.
   PubMedGoogle Scholar
• Kiechl S, Schramek D, Widschwendter M. Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer. Oncotarget. 2017;8(3):3811–3825.
   PubMedGoogle Scholar
• Widschwendter M, Burnell M, Fraser L, et al. Osteoprotegerin (OPG), the endogenous inhibitor of receptor activator of NF-κB Ligand (RANKL), is dysregulated in BRCA mutation carriers. EMBioMedicine. 2015;2(10):1331–1339.
   PubMed Web of Science ®Google Scholar
• Zaman T, Sun P, Narod SA, et al. Plasma RANKL levels are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Oncotarget. 2019;10(25):2475–2483.
   PubMedGoogle Scholar
• Wood CE, Branstetter D, Jacob AP. Progestin effects on cell proliferation pathways in the postmenopausal mammary gland. Breast Cancer Res. 2013;15(4):R62.
   PubMed Web of Science ®Google Scholar
• Sigl V, Owusu-Boaitey K, Joshi PA, et al. RANKL/RANK control Brca1 mutation. Cell Res. 2016;26(7):761–774.
   PubMed Web of Science ®Google Scholar
• Nolan E, Vaillant F, Branstetter D, et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med. 2016;22(8):933–939.
   PubMed Web of Science ®Google Scholar
• [ cited 2020 Mar]. Available from: http://purl.org/au-research/grants/nhmrc/1140715 nhmrc:1140715
   Google Scholar
• Odén L, Akbari M, Zaman T, et al. Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Oncotarget. 2016;7(52):86687–86694.
   PubMedGoogle Scholar
• Vik A, Brodin EE, Mathiesen EB. Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromso study. Eur J Epidemiol. 2015;30(3):219–230.
   PubMed Web of Science ®Google Scholar
• Sanger N, Ruckhaberle E, Bianchini G. OPG and PgR show similar cohort specific effects as prognostic factors in ER positive breast cancer. Mol Oncol. 2014;8(7):1196–1207.
   PubMed Web of Science ®Google Scholar
• Park HS, Lee A, Chae BJ, et al. Expression of receptor activator of nuclear factor kappa-B as a poor prognostic marker in breast cancer. J Surg Oncol. 2014;110(7):807–812.
   PubMed Web of Science ®Google Scholar
• Singer CF. Nonsurgical prevention strategies in BRCA1 and BRCA2 mutation carriers. Breast Care. 2020;1–5. DOI:https://doi.org/10.1159/000507503
   Google Scholar
• [ cited Oct 2020 11]. Available from: https://www.abcsg.com/studies/open-trials/mammacarzinom/abcsg-50-brca-p/abcsg-50-brca-p-details/
   Google Scholar
• Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386(10001):1353–1361.
   PubMed Web of Science ®Google Scholar
• Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol. 2016;27(3):379–390.
   PubMed Web of Science ®Google Scholar
• Gnant M, Pfeiler G, Dubsky PC, et al.; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–443.
   PubMed Web of Science ®Google Scholar
• Gnant M, Pfeiler G, Steger GG, et al.; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20(3):339–351.
   PubMed Web of Science ®Google Scholar
• Coleman RE, Finkelstein D, Barrios CH, et al. Adjuvant denosumab in early breast cancer: first results from the international multicenter randomized phase III placebo-controlled D-CARE study. J Clin Oncol. 2018;36(15):S501.
   Web of Science ®Google Scholar
• Coleman R, Finkelstein DM, Barrios C, et al. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(1):60–72.
   PubMed Web of Science ®Google Scholar
• Nguyen B, Maetens M, Salgado R, et al. Abstract CT101: D-BEYOND: a window of opportunity trial evaluating denosumab, a RANK-ligand (RANKL) inhibitor and its biological effects in young pre-menopausal women diagnosed with early breast cancer. Cancer Res. 2018;78(13 Supplement):CT101–CT101.
   Web of Science ®Google Scholar
• Gnant M, Harbeck N, Thomssen C. St. Gallen/ Vienna 2017: a brief summary of the consensus discussion about escalation and de-escalation of primary breast cancer treatment. Breast Care (Basel). 2017;12(2):102–107.
   PubMed Web of Science ®Google Scholar
• Curigliano G, Burstein HJ, Winer P, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28(8):1700–1712.
   PubMed Web of Science ®Google Scholar
• Thill M, Liedtke C, Solomayer EF, et al. AGO recommendations for the diagnosis and treatment of patients with advanced and metastatic breast cancer: update 2017. Breast Care (Basel). 2017;12(3):184–191.
   PubMed Web of Science ®Google Scholar
• Thill M, Liedtke C, Müller V, et al.; AGO Breast Committee. AGO recommendations for the diagnosis and treatment of patients with advanced and metastatic breast cancer: update 2018. Breast Care (Basel). 2018;13(3):209–215.
   PubMed Web of Science ®Google Scholar
• [ cited 2020 Mar]. Available from: https://www.xgeva.com/hcp/solid-tumors/pivotal-trial-safety
   Google Scholar
• Laskowski LK, Goldfarb DS, Howland MA, et al. A RANKL wrinkle: denosumab-induced hypocalcemia. J Med Toxicol. 2016;12(3):305–308.
   PubMed Web of Science ®Google Scholar
• Pittman K, Antill YC, Goldrick A, et al. Denosumab: prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures. Asia Pac J Clin Oncol. 2017;13(4):266–276.
   PubMed Web of Science ®Google Scholar
• Yerram P, Kansagra S, Abdelghany O. Incidence of hypocalcemia in patients receiving denosumab for prevention of skeletal-related events in bone metastasis. J Oncol Pharm Pract. 2016;23(3):179–184.
   PubMed Web of Science ®Google Scholar
• Jalleh R, Basu G, Le Leu R, et al. Denosumab-induced severe hypocalcaemia in chronic kidney disease. Case Rep Nephrol. 2018;2018:7384763.
   PubMedGoogle Scholar
• Thongprayoon C, Acharya P, Acharya C, et al. Hypocalcemia and bone mineral density changes following denosumab treatment in end-stage renal disease patients: a meta-analysis of observational studies. Osteoporos Int. 2018;29(8):1737–1745.
   PubMed Web of Science ®Google Scholar
• [ cited 2020 June 26]. Available from: https://www.medicines.org.uk/emc/product/4675/smpc
   Google Scholar
• Lombard T, Neirinckx V, Rogister B, et al. Medication-related osteonecrosis of the jaw: new insights into molecular mechanisms and cellular therapeutic approaches. Stem Cells Int. 2016;2016:8768162.
   PubMed Web of Science ®Google Scholar
• Ruggiero SL, Dodson TB, Fantasia J, et al. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw – 2014 update. J Oral Maxillofac Surg. 2014;72:1938–1956.
   PubMed Web of Science ®Google Scholar
• Khan AA, Morrison A, Hanley DA, et al.; International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30:3–23.
   PubMed Web of Science ®Google Scholar
• Nifosì AF, Zuccarello M, Nifosì L, et al. Osteonecrosis of the jaw in the era of targeted therapy and immunotherapy in oncology. J Korean Assoc Oral Maxillofac Surg. 2019;45(1):3–8.
   PubMed Web of Science ®Google Scholar
• Svejda B, Muschitz C, Gruber R, et al. Position paper on medication-related osteonecrosis of the jaw (MRONJ). Wien Med Wochenschr. 2016;166(1–2):68–74.
   PubMed Web of Science ®Google Scholar
• Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. J Bone Miner Res. 2014;29(1):1–23.
   PubMed Web of Science ®Google Scholar
• Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013;98(11):4483–4492.
   PubMed Web of Science ®Google Scholar
• Henry D, Vadhan-Raj S, Hirsh V, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer. 2014;22(3):679–687.
   PubMed Web of Science ®Google Scholar
• Yang SP, Kim TW, Boland PJ, et al. a retrospective review of atypical femoral fracture in metastatic Bone disease patients receiving Denosumab therapy. Oncologist. 2017;22(4):438–444.
   PubMed Web of Science ®Google Scholar
• Dennison EM, Cooper C, Kanis JA, et al. Fracture risk following intermission of osteoporosis therapy. Osteoporos Int. 2019;30(9):1733–1743.
   PubMed Web of Science ®Google Scholar
• Lamy O, Stoll D, Aubry-Rozier B, et al. Stopping denosumab. Curr Osteoporos Rep. 2019;17(1):8–15.
   PubMed Web of Science ®Google Scholar
• von Keyserlingk C, Hopkins R, Anastasilakis A, et al. Clinical efficacy and safety of denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis. Semin Arthritis Rheum. 2011;41(2):178–186.
   PubMed Web of Science ®Google Scholar
• Tovazzi V, Dalla Volta A, Pedersini R, et al. Excess of second tumors in denosumab-treated patients: a metabolic hypothesis. Future Oncol. 2019;15(20):2319–2321.
   PubMed Web of Science ®Google Scholar
• Sachdev JC, Sandoval AC, Jahanzeb M. Update on precision medicine in breast cancer. Cancer Treat Res. 2019;178:45–80.
   PubMedGoogle Scholar
• Peters N, Michael Conroy M, O’Reilly S. Adjuvant denosumab in early breast cancer. Lancet Oncol. 2020;21(3):e121.
   PubMed Web of Science ®Google Scholar
• Scimeca M, Bonfiglio R, Urbano N, et al. Adjuvant denosumab in early breast cancer. Lancet Oncol. 2020;21(3):e122.
   PubMed Web of Science ®Google Scholar
• Coleman R, Ying Zhou Y, Chan A. for the D-CARE investigators. Adjuvant denosumab in early breast cancer. Authors’ reply [www.thelancet. Lancet Oncol. 2020;21(3):e125.
   PubMed Web of Science ®Google Scholar
• Hein A, Bayer CM, Schrauder MG, et al. Polymorphisms in the RANK/RANKL genes and their effect on bone specific prognosis in breast cancer patients. Biomed Res Int. 2014;2014:842452.
   PubMed Web of Science ®Google Scholar
• Ferreira A, Alho I, Vendrell I, et al. The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases. Oncotarget. 2016;7(27):41380–41389.
   PubMedGoogle Scholar
• Deligiorgi MV, Panayiotidis MI, Griniatsos J, et al. Harnessing the versatile role of OPG in bone oncology: counterbalancing RANKL and TRAIL signaling and beyond. Clin Exp Metastasis. 2020;37(1):13–30.
   PubMed Web of Science ®Google Scholar
• Deligiorgi MV, Panayiotidis MI, Trafalis DT. Combining immune checkpoint inhibitors with denosumab: a new era in repurposing denosumab in oncology? JBUON. 2020;25(1):1–14.
   Google Scholar
• Schneeweiss A, Hartkopf AD, Müller V, et al. Update breast cancer 2020 part 1 - early breast cancer: consolidation of knowledge about known therapies. Geburtshilfe Frauenheilkd. 2020;80(3):277–287.
   PubMed Web of Science ®Google Scholar
• Cuyàs E, Martin-Castillo B, Bosch-Barrera J, et al. Metformin inhibits RANKL and sensitizes cancer stem cells to denosumab. Cell Cycle. 2017;16(11):1022–1028.
   PubMed Web of Science ®Google Scholar
• Timotheadou E, Kalogeras KT, Koliou GA, et al. Evaluation of the prognostic value of RANK, OPG, and RANKL mRNA expression in early breast cancer patients treated with anthracycline-based adjuvant chemotherapy. Transl Oncol. 2017;10(4):589–598.
   PubMed Web of Science ®Google Scholar
• Owen S, Ye L, Sanders AJ, et al. Expression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. Anticancer Res. 2013;33(1):199–206.
   PubMed Web of Science ®Google Scholar
• Bhatia P, Sanders MM, Hansen MF. Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin Cancer Res. 2005;11(1):162–165.
   PubMed Web of Science ®Google Scholar
• Papanastasiou AD, Sirinian C, Kalofonos HP. Identification of novel human receptor activator of nuclear factor-kB isoforms generated through alternative splicing: implications in breast cancer cell survival and migration. Breast Cancer Res. 2012;14(4):R112.
   PubMed Web of Science ®Google Scholar
• Gnant M, Pfeiler G, Frantal S; Austrian breast and colorectal cancer study group. Denosumab in early-stage breast cancer - authors’ reply. Lancet Oncol. 2019;20(5):236.
   PubMed Web of Science ®Google Scholar