Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18

C Minichsdorfer, T Fuereder, M Leutner, C F Singer, S Kacerovsky-Strobl, D Egle, R Greil, M Balic, F Fitzal, G Pfeiler, S Frantal, R Bartsch, M Gnant, C Minichsdorfer, T Fuereder, M Leutner, C F Singer, S Kacerovsky-Strobl, D Egle, R Greil, M Balic, F Fitzal, G Pfeiler, S Frantal, R Bartsch, M Gnant

Abstract

Background: Statins are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, statins may possess anticancer properties and interact with receptor activator of nuclear factor κB ligand expression. We aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18.

Patients and methods: ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor-positive BC receiving a nonsteroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post hoc analysis, we investigated the effects of concomitant statin therapy on recurrence risk (RR) of BC, fracture risk and bone mineral density (BMD).

Results: In the study population (n = 3420), statin therapy (n = 824) was associated with worse disease-free survival (DFS) [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.04-1.75; P = 0.023]. While no significant effect of lipophilic statins (n = 710) on RR was observed (HR 1.30, 95% CI 0.99-1.72; P = 0.062), patients on hydrophilic statins (n = 87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; P = 0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21-5.68; P = 0.014). However, this effect subsided after correction for confounders in the sensitivity analysis. No association between statin use and fracture risk or osteoporosis was observed.

Conclusion: According to this analysis, hydrophilic statins showed a detrimental effect on DFS in the main model, which was attenuated after correction for confounders. Our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins.

Keywords: ABCSG-18; breast cancer; disease-free survival; hormone receptor positive; postmenopausal osteoporosis; statins.

Conflict of interest statement

Disclosure CM: Honoraria from Boehringer Ingelheim, MSD, Amgen and Sandoz. Travel grants from MSD, Merck. TF: Honoraria from MSD; Merck Darmstadt, Roche, BMS, Accord; Sanofi, Boehringer Ingelheim; Amgen, Pfizer. CFS: Grant support, travel grants and speaker honoraria from Novartis, Astra Zeneca, Amgen, Roche, Daiichi-Sankyo, Seagen. DE: Grant support, honoraria from Astra-Zeneca, Daiichi-Sankyo, MSD, Novartis, Pfizer, Pierre Fabre, Roche. RG: Honoraria, Consulting Advisory Role, Research Funding, Travel expenses, Accommodations, Expenses from AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Daiichi Sankyo, Roche, Gilead, Merck, MSD, Novartis, Sandoz, Takeda. MB: Grant support, honoraria from Amgen, Astra-Zeneca, Celgene, Daiichi Sankyo, Eli-Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Samsung. FF: Grant support, honoraria from Myriad, Comesa, Nanostring, Bondimed, Astra-Zeneca, Eli-Lilly, Hoffmann-La Roche, Novartis, Pfizer. Founder: Breast analyzing tool, Editor oncoplastic surgery I+II: Springer. GP: Honoraria and funding from: Amgen, Pfizer, Roche, Eli-Lilly, Daiichi, Astra-Zeneca, Accord, Bondimed, Novartis, MSD. SF: Funding from Amgen. RB: Research support from Daiichi Sankyo, Novartis, Roche and honoraria from Astra-Zeneca, Celgene, Daiichi, Eli-Lilly, MSD, Novartis, Pfizer, Roche, Samsung, BMS and Sandoz. MG: Personal fees from Amgen, personal fees from AstraZeneca, personal fees from Eli-Lilly, personal fees from Novartis, personal fees from DaiichiSankyo, personal fees from Veracyte, personal fees from Tolmar, personal fees from Lifebrain, outside the submitted work; and an immediate family member is employed by Sandoz. All other authors have declared no conflicts of interest. Data sharing Data and materials supporting the results are available upon reasonable request from the corresponding author RB (rupert.bartsch@meduniwien.ac.at).

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Consolidated Standards of Reporting Trials (CONSORT) diagram. The number of statin patients is based on receiving statins at any point in time during the study. aPatients who switched their statin treatment (from hydrophilic to lipophilic or vice versa) were excluded from the detailed statin group analysis. bFive patients started statin after disease recurrence and are therefore considered in the ‘no statin’ group for survival analyses.
Figure 2
Figure 2
Effect of statin co-medication on disease free survival. (A) Effect of statin treatment on disease-free survival in the general population. (B) Detailed statin groups. Curves and numbers at risk are based on Simon–Makuch method. Patients who switch between statins and non-statins or between lipophilic, hydrophilic and non-statins, respectively, are counted in the according risk set for each time point. ORs and P values are based on Mantel–Byar tests accounting for the time-dependent factor statin groups (statins versus non-statins or lipophilic and hydrophilic versus non-statins, respectively). An OR >1.0 indicates a higher average event rate and a shorter disease-free time for statins or the different statin groups, respectively, relative to non-statins. CI, confidence interval; OR, odds ratio.
Figure 3
Figure 3
Effect of statins on disease-free survival in subgroups with or without denosumab. (A) Statin effect in patients receiving denosumab. (B) Detailed statin analysis in patients receiving denosumab. (C) Effect of statins in patients not receiving denosumab. (D) Detailed statin analysis in patients not receiving denosumab. Curves and numbers at risk are based on the Simon–Makuch method. Patients who switch between statins and non-statins or between lipophilic, hydrophilic and non-statins, respectively, are counted in the corresponding risk set for each time point. ORs and P values are based on Mantel–Byar tests accounting for the time-dependent factor statin groups (statins versus non-statins or lipophilic and hydrophilic versus non-statins, respectively). An OR >1.0 indicates a higher average event rate and a shorter disease-free time for statins or the different statin groups, respectively, relative to non-statins. CI, confidence interval; OR, odds ratio.

References

    1. Burstein H.J., Curigliano G., Thurlimann B., et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021;32(10):1216–1235.
    1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–1352.
    1. Breast International Group 1-98 Collaborative Group. Thurlimann B., Keshaviah A., et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
    1. Howell A., Cuzick J., Baum M., et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453):60–62.
    1. Goss P.E., Ingle J.N., Martino S., et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97(17):1262–1271.
    1. Coleman R.E., Banks L.M., Girgis S.I., et al. Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol. 2007;8(2):119–127.
    1. Goldstein J.L., Brown M.S. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425–430.
    1. Shibata M.A., Ito Y., Morimoto J., Otsuki Y. Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: a p53-independent mitochondrial-mediated apoptotic mechanism. Carcinogenesis. 2004;25(10):1887–1898.
    1. Alonso D.F., Farina H.G., Skilton G., Gabri M.R., De Lorenzo M.S., Gomez D.E. Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis. Breast Cancer Res Treat. 1998;50(1):83–93.
    1. Mandal C.C., Ghosh-Choudhury N., Yoneda T., Choudhury G.G., Ghosh-Choudhury N. Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44. J Biol Chem. 2011;286(13):11314–11327.
    1. Mundy G., Garrett R., Harris S., et al. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286(5446):1946–1949.
    1. Ahn K.S., Sethi G., Chaturvedi M.M., Aggarwal B.B. Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway. Int J Cancer. 2008;123(8):1733–1740.
    1. Yamashita M., Otsuka F., Mukai T., et al. Simvastatin antagonizes tumor necrosis factor-alpha inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway. J Endocrinol. 2008;196(3):601–613.
    1. Yamashita M., Otsuka F., Mukai T., et al. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept. 2010;162(1-3):99–108.
    1. Shellman Y.G., Ribble D., Miller L., et al. Lovastatin-induced apoptosis in human melanoma cell lines. Melanoma Res. 2005;15(2):83–89.
    1. Sivaprasad U., Abbas T., Dutta A. Differential efficacy of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors on the cell cycle of prostate cancer cells. Mol Cancer Ther. 2006;5(9):2310–2316.
    1. Mueck A.O., Seeger H., Wallwiener D. Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells. Menopause. 2003;10(4):332–336.
    1. Seeger H., Wallwiener D., Mueck A.O. Statins can inhibit proliferation of human breast cancer cells in vitro. Exp Clin Endocrinol Diabetes. 2003;111(1):47–48.
    1. Delmas P.D. Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases. J Clin Densitom. 2008;11(2):325–338.
    1. Egerdie R.B., Saad F., Smith M.R., 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.
    1. Gnant M., Pfeiler G., Dubsky P.C., et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–443.
    1. Gnant M., Pfeiler G., Steger G.G., et al. 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.
    1. Kim J.Y., Lee E.Y., Lee E.B., et al. Atorvastatin inhibits osteoclastogenesis by decreasing the expression of RANKL in the synoviocytes of rheumatoid arthritis. Arthritis Res Ther. 2012;14(4):R187.
    1. Gopalan A., Yu W., Sanders B.G., Kline K. Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol. Cancer Lett. 2013;328(2):285–296.
    1. Gopalan A., Yu W., Sanders B.G., Kline K. Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway. Cancer Lett. 2013;329(1):9–16.
    1. Muck A.O., Seeger H., Wallwiener D. Inhibitory effect of statins on the proliferation of human breast cancer cells. Int J Clin Pharmacol Ther. 2004;42(12):695–700.
    1. Ahern T.P., Pedersen L., Tarp M., et al. Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 2011;103(19):1461–1468.
    1. Kwan M.L., Habel L.A., Flick E.D., Quesenberry C.P., Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat. 2008;109(3):573–579.
    1. Manthravadi S., Shrestha A., Madhusudhana S. Impact of statin use on cancer recurrence and mortality in breast cancer: a systematic review and meta-analysis. Int J Cancer. 2016;139(6):1281–1288.
    1. Mansourian M., Haghjooy-Javanmard S., Eshraghi A., Vaseghi G., Hayatshahi A., Thomas J. Statins use and risk of breast cancer recurrence and death: a systematic review and meta-analysis of observational studies. J Pharm Pharm Sci. 2016;19(1):72–81.
    1. Kumar A.S., Benz C.C., Shim V., Minami C.A., Moore D.H., Esserman L.J. Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1028–1033.
    1. Woditschka S., Habel L.A., Udaltsova N., Friedman G.D., Sieh W. Lipophilic statin use and risk of breast cancer subtypes. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2479–2487.
    1. Desai P., Chlebowski R., Cauley J.A., et al. Prospective analysis of association between statin use and breast cancer risk in the women’s health initiative. Cancer Epidemiol Biomarkers Prev. 2013;22(10):1868–1876.
    1. Desai P., Lehman A., Chlebowski R.T., et al. Statins and breast cancer stage and mortality in the Women’s Health Initiative. Cancer Causes Control. 2015;26(4):529–539.
    1. Borgquist S., Djerbi S., Ponten F., et al. HMG-CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors. Int J Cancer. 2008;123(5):1146–1153.
    1. Borgquist S., Jogi A., Ponten F., Ryden L., Brennan D.J., Jirstrom K. Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer. Breast Cancer Res. 2008;10(5):R79.
    1. Sun L., Zhu Y., Qian Q., Tang L. Body mass index and prognosis of breast cancer: an analysis by menstruation status when breast cancer diagnosis. Medicine (Baltimore) 2018;97(26)
    1. Zhao X.B., Ren G.S. Diabetes mellitus and prognosis in women with breast cancer: a systematic review and meta-analysis. Medicine (Baltimore) 2016;95(49)
    1. Kiderlen M., de Glas N.A., Bastiaannet E., et al. Diabetes in relation to breast cancer relapse and all-cause mortality in elderly breast cancer patients: a FOCUS study analysis. Ann Oncol. 2013;24(12):3011–3016.
    1. Jakobsen M., Kolodziejczyk C., Jensen M.S., et al. Cardiovascular disease in women with breast cancer - a nationwide cohort study. BMC Cancer. 2021;21(1):1040.
    1. An T., Hao J., Sun S., et al. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int. 2017;28(1):47–57.
    1. Leutner M., Matzhold C., Bellach L., et al. Diagnosis of osteoporosis in statin-treated patients is dose-dependent. Ann Rheum Dis. 2019;78(12):1706–1711.
    1. Cheng K.C., Liao K.F., Lin C.L., Lin C.C., Lai S.W. Case-control study examining the association between hip fracture risk and statins therapy in old people. Medicine (Baltimore) 2019;98(41)
    1. Lin S.M., Wang J.H., Liang C.C., Huang H.K. Statin use is associated with decreased osteoporosis and fracture risks in stroke patients. J Clin Endocrinol Metab. 2018;103(9):3439–3448.
    1. Lin T.K., Chou P., Lin C.H., Hung Y.J., Jong G.P. Long-term effect of statins on the risk of new-onset osteoporosis: a nationwide population-based cohort study. PLoS One. 2018;13(5)
    1. Lin T.K., Liou Y.S., Lin C.H., Chou P., Jong G.P. High-potency statins but not all statins decrease the risk of new-onset osteoporotic fractures: a nationwide population-based longitudinal cohort study. Clin Epidemiol. 2018;10:159–165.
    1. Pena J.M., Aspberg S., MacFadyen J., Glynn R.J., Solomon D.H., Ridker P.M. Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial. JAMA Intern Med. 2015;175(2):171–177.
    1. van Staa T.P., Wegman S., de Vries F., Leufkens B., Cooper C. Use of statins and risk of fractures. JAMA. 2001;285(14):1850–1855.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir