, Volume 36, Issue 9, pp 1113–1124 | Cite as

Cost-Effectiveness of Second-Line Endocrine Therapies in Postmenopausal Women with Hormone Receptor–positive and Human Epidermal Growth Factor Receptor 2–negative Metastatic Breast Cancer in Japan

  • Verin Lertjanyakun
  • Nathorn Chaiyakunapruk
  • Susumu Kunisawa
  • Yuichi Imanaka
Original Research Article



Exemestane (EXE), exemestane + everolimus (EXE + EVE), toremifene (TOR), and fulvestrant (FUL) are second-line endocrine therapies for postmenopausal hormone receptor–positive (HR +)/human epidermal growth factor receptor 2–negative (HER2 −) metastatic breast cancer (mBC) in Japan. Although the efficacy of these therapies has been shown in recent studies, cost-effectiveness has not yet been determined in Japan.


This study aimed to examine the cost-effectiveness of second-line endocrine therapies for the treatment of postmenopausal women with HR + and HER2 − mBC.


A Markov model was developed to analyze the cost-effectiveness of the therapies over a 15-year time horizon from a public healthcare payer’s perspective. The efficacy and utility parameters were determined via a systematic search of the literature. Direct medical care costs were used. A discount rate of 2% was applied for costs and outcomes. Subgroup analysis was performed for non-visceral metastasis. A series of sensitivity analyses, including probabilistic sensitivity analysis (PSA) and threshold analysis were performed.


Base-case analyses estimated incremental cost-effectiveness ratios (ICERs) of 3 million and 6 million Japanese yen (JPY)/quality-adjusted life year (QALY) gained for TOR and FUL 500 mg relative to EXE, respectively. FUL 250 mg and EXE + EVE were dominated. The overall survival (OS) highly influenced the ICER. With a willingness-to-pay (WTP) threshold of 5 million JPY/QALY, the probability of TOR being cost-effective was the highest. Subgroup analysis in non-visceral metastasis revealed 0.4 and 10% reduction in ICER from the base-case results of FUL5 500 mg versus EXE and TOR versus EXE, respectively, while threshold analysis indicated EVE and FUL prices should be reduced 73 and 30%, respectively.


As a second-line therapy for postmenopausal women with HR +/HER2 − mBC, TOR may be cost-effective relative to other alternatives and seems to be the most favorable choice, based on a WTP threshold of 5 million JPY/QALY. FUL 250 mg is expected to be as costly and effective as EXE. The cost-effectiveness of EXE + EVE and FUL 500 mg could be improved by a large price reduction. However, the results are highly sensitive to the hazard ratio of OS. Policy makers should carefully interpret and utilize these findings.



The authors would like to thank Rosarin Sruamsiri, a former staff member at the Center of Pharmaceutical Outcomes Research, Naresuan University, Thailand, for providing technical guidance regarding economic evaluation model development, and Takeru Shiroiwa, Senior researcher at the Department of Health and Welfare Services, National Institute of Public Health, for his review and comments on the methodology of this study. The model used in this study was provided to the journal’s peer reviewers for their reference when reviewing the manuscript. Verin Lertjanyakun was supported by the 2017 Kyoto University School of Public Health—Super Global Course’s travel scholarship to Naresuan University, Phitsanulok, Thailand through the Top Global University Project “Japan Gateway: Kyoto University Top Global Program,” sponsored by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This study was supported by a JSPS Grant-in-Aid Scientific Research (A) (16H02634).

Author Contributions

VL participated in the design of the study, developed the cost-effectiveness model, conducted the expert meetings, searched input parameters, conducted the cost-effectiveness analyses, and drafted the manuscript. NC and YI participated in the design of the study, developed the cost-effectiveness models, and drafted the manuscript. KS participated in the design of the study and searched input parameters. Each author also contributed to the interpretation of data and results, critically reviewing the manuscript for important issues, and has approved the final version.

Compliance with Ethical Standards

Conflicts of interest

V.L., N.C., S.W., and Y.I. declare that they have no conflicts of interest. No sponsors were involved in this study.

Supplementary material

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  1. 1.
    Bray F, Ren JS, Masuyer E, et al. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013;132(5):1133–45.CrossRefPubMedGoogle Scholar
  2. 2.
    Cancer statistics in Japan’16. Foundation for Promotion of Cancer Research (FPCR); 2016.Google Scholar
  3. 3.
    Cancer statistics in Japan’15. Foundation for Promotion of Cancer Research (FPCR); 2015.Google Scholar
  4. 4.
    Kourlaba G, Rapti V, Alexopoulos A, et al. Everolimus plus exemestane versus bevacizumab-based chemotherapy for second-line treatment of hormone receptor-positive metastatic breast cancer in Greece: An economic evaluation study. BMC Health Serv Res. 2015;15:307.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yamashita H, Iwase H, Toyama T, et al. Estrogen receptor-positive breast cancer in Japanese women: trends in incidence, characteristics, and prognosis. Ann Oncol. 2011;22(6):1318–25.CrossRefPubMedGoogle Scholar
  6. 6.
    Aihara T, Toyama T, Takahashi M, et al. The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer, 2015 edition. Breast Cancer. 2016;23(3):329–42.CrossRefPubMedGoogle Scholar
  7. 7.
    Network NCC. NCCN Guideline Version 2.2017 of Invasive breast cancer.Google Scholar
  8. 8.
    Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol. 2017;28(1):16–33.PubMedGoogle Scholar
  9. 9.
    Yamamoto Y, Ishikawa T, Hozumi Y, et al. Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer. BMC Cancer. 2013;13:239.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    National Institute for Health and Care Excellence: Everolimus in combination with exemestane for treating advanced HER2-negative hormone-receptor positive breast cancer after endocrine therapy. NICE technology appraisal guidance 421; 2016.
  11. 11.
    Siebert U, Alagoz O, Bayoumi AM, et al. State-transition modeling: a report of the ISPOR-SMDM modeling good research practices task force-3. Value Health 2012;15:812–20.CrossRefPubMedGoogle Scholar
  12. 12.
    Shiroiwa T, Igarashi A, Fukuda T, et al. WTP for a QALY and health states: more money for severer health states? Cost Eff Resour Alloc. 2013;11:22.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shiroiwa T, Fukuda T, Ikeda S, et al. Development of an official guideline for the economic evaluation of drugs/medical devices in Japan. Value Health 20(3):372–8.CrossRefGoogle Scholar
  14. 14.
    Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Value Health. 2013;16(2):e1–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Le QA. Structural uncertainty of Markov models for advanced breast cancer: a simulation study of lapatinib. Med Decis Making. 2016;36(5):629–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Das R, Cope S, Ouwens M, et al. Economic evaluation of fulvestrant 500 mg versus generic nonsteroidal aromatase inhibitors in patients with advanced breast cancer in the United Kingdom. Clin Ther. 2013;35(3):246–60.CrossRefPubMedGoogle Scholar
  17. 17.
    Mouri M, Fukuda T, Taira N, et al. Cost-effectiveness analysis of bevacizumab in combined chemotherapy for human epidermal growth factor receptor 2-negative metastatic breast cancer in Japan. Jpn J Pharmacoepidemiol Yakuzai ekigaku. 2013;18(1):1–12.CrossRefGoogle Scholar
  18. 18.
    Rugo HS, Pritchard KI, Gnant M, et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014;25(4):808–15.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Delea TE, Amdahl J, Chit A, et al. Cost-effectiveness of lapatinib plus letrozole in her2-positive, hormone receptor-positive metastatic breast cancer in Canada. Curr Oncol. 2013;20(5):e371–87.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ito Y, Masuda N, Iwata H, et al. Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer—Japanese subgroup analysis of BOLERO-2. Gan To Kagaku Ryoho. 2015;42(1):67–75.PubMedGoogle Scholar
  21. 21.
    Campone M, Bachelot T, Gnant M, et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. Eur J Cancer. 2013;49(12):2621–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870–84.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013;14(10):989–98.CrossRefPubMedGoogle Scholar
  25. 25.
    Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26(10):1664–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594–600.CrossRefPubMedGoogle Scholar
  27. 27.
    Bucher HC, Guyatt GH, Griffith LE, et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6):683–91.CrossRefPubMedGoogle Scholar
  28. 28.
    Hoyle MW, Henley W. Improved curve fits to summary survival data: application to economic evaluation of health technologies. BMC Med Res Methodol. 2011;11:139.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol. 2014;25(12):2357–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Thompson Coon J, Hoyle M, Green C, et al. Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Health Technol Assess. 2010;14(2):1–184 (iii-iv).CrossRefPubMedGoogle Scholar
  31. 31.
    Peasgood T, Ward SE, Brazier J. Health-state utility values in breast cancer. Expert Rev Pharmacoecon Outcomes Res. 2010;10(5):553–66.CrossRefPubMedGoogle Scholar
  32. 32.
    Paracha N, Thuresson PO, Moreno SG, et al. Health state utility values in locally advanced and metastatic breast cancer by treatment line: a systematic review. Expert Rev Pharmacoecon Outcomes Res. 2016;16(5):549–59.CrossRefPubMedGoogle Scholar
  33. 33.
    Lloyd A, Nafees B, Narewska J, et al. Health state utilities for metastatic breast cancer. Br J Cancer. 2006;95(6):683–90.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Shiroiwa T, Fukuda T, Shimozuma K, et al. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017;26(2):445–53.CrossRefPubMedGoogle Scholar
  35. 35.
    Simons WR. Standard gamble techniques for the measurement of treatment related toxicity in oncology: application to breast cancer. Value Health 2007;10(3):A5.CrossRefGoogle Scholar
  36. 36.
    Sruamsiri R, Dilokthornsakul P, Pratoomsoot C, et al. A cost-effectiveness study of intravenous immunoglobulin in childhood idiopathic thrombocytopenia purpura patients with life-threatening bleeding. Pharmacoeconomics. 2014;32(8):801–13.CrossRefPubMedGoogle Scholar
  37. 37.
    Doyle S, Lloyd A, Walker M. Health state utility scores in advanced non-small cell lung cancer. Lung Cancer. 2008;62(3):374–80.CrossRefPubMedGoogle Scholar
  38. 38.
    Shiroiwa T, Fukuda T, Ikeda S, et al. Japanese population norms for preference-based measures: EQ-5D-3L, EQ-5D-5L, and SF-6D. Qual Life Res. 2016;25(3):707–19.CrossRefPubMedGoogle Scholar
  39. 39.
    2016 National Health Insurance Drug Price Standard. Ministry of Health, Labour and Welfare. 2016. 2017/01.
  40. 40.
    2016 Social insurance reimbursement schedule. Health Insurance Claims Review & Reimbursement Services. 2016. 2017/01.
  41. 41.
    Shiroiwa T, Shimozuma K, Fukuda T. Treatment costs for breast cancer in Japan: large claim database analysis. Value Health. 2017;17(7):A735.CrossRefGoogle Scholar
  42. 42.
    Annual report of trend in medical dispensing. Ministry of Health, Labour and Welfare. 2016. 2018.
  43. 43.
    Okubo I, Kondo M, Toi M, et al. Cost-effectiveness of letrozole versus tamoxifen as first-line hormonal therapy in treating postmenopausal women with advanced breast cancer in Japan. Gan To Kagaku Ryoho. 2005;32(3):351–63.PubMedGoogle Scholar
  44. 44.
    Tange C, Kunisawa S, Maeda S, et al. Cost-effectiveness analysis of pertuzumab for metastatic HER2-positive breast cancer in Japan. Value Health. 2015;18(7):A456–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Xie J, Hao Y, Zhou ZY, et al. Economic evaluations of everolimus versus other hormonal therapies in the treatment of HR +/HER2- advanced breast cancer from a US payer perspective. Clin Breast Cancer. 2015;15(5):e263–76.CrossRefPubMedGoogle Scholar
  46. 46.
    Kinjo K, Sairenji T, Koga H, et al. Cost of physician-led home visit care (Zaitaku care) compared with hospital care at the end of life in Japan. BMC Health Serv Res. 2017;17(1):40.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. National Cancer Institute. 2017.Google Scholar
  48. 48.
    NCCN Guidelines Version 1.2017 of Survivorship. National Comprehensive Cancer Network. 2017.
  49. 49.
    White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010;182(3):396–403.CrossRefPubMedGoogle Scholar
  50. 50.
    Peterson ME. Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial. Support Care Cancer. 2013;21(8):2341–9.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig. 2013;51(4):260–77.CrossRefPubMedGoogle Scholar
  52. 52.
    Peddi PF, Shatsky RA, Hurvitz SA. Noninfectious pneumonitis with the use of mTOR inhibitors in breast cancer. Cancer Treat Rev. 2014;40(2):320–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Briggs AH, Weinstein MC, Fenwick EA, et al. Model parameter estimation and uncertainty analysis: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force Working Group-6. Med Decis Making. 2012;32(5):722–32.CrossRefPubMedGoogle Scholar
  54. 54.
    Briggs A, Sculpher M, Claxton K. Decision modelling for health economic evaluation. New York: Oxford University Press; 2006.Google Scholar
  55. 55.
    Woods B, Sideris E, Palmer S, et al. Partitioned survival analysis for decision modelling in health care: a critical review. In: NICE DSU Technical Support Document 19. 2017.
  56. 56.
    Diaby V, Adunlin G, Zeichner SB, et al. Cost-effectiveness analysis of everolimus plus exemestane versus exemestane alone for treatment of hormone receptor positive metastatic breast cancer. Breast Cancer Res Treat. 2014;147(2):433–41.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Verin Lertjanyakun
    • 1
  • Nathorn Chaiyakunapruk
    • 2
    • 3
    • 4
    • 5
  • Susumu Kunisawa
    • 1
  • Yuichi Imanaka
    • 1
  1. 1.Department of Healthcare Economics and Quality Management, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.School of PharmacyMonash University MalaysiaSubang JayaMalaysia
  3. 3.Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Center of Pharmaceutical Outcomes ResearchNaresuan UniversityPhitsanulokThailand
  4. 4.School of PharmacyUniversity of Wisconsin-MadisonWisconsinUSA
  5. 5.Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes, Health and Well-being Cluster, Global Asia in the 21st Century (GA21) PlatformMonash University MalaysiaSubang JayaMalaysia

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