Breast Cancer

, Volume 24, Issue 3, pp 345–352 | Cite as

Fulvestrant plus targeted agents versus fulvestrant alone for treatment of hormone-receptor positive advanced breast cancer progressed on previous endocrine therapy: a meta-analysis of randomized controlled trials

  • Wen-Zhao Lin
  • Qi-Ni Xu
  • Hong-Biao Wang
  • Xu-Yuan Li
Review Article


To compare the addition of targeted agents to fulvestrant with fulvestrant alone in hormone-receptor positive advanced breast cancer progressed on previous endocrine therapy; a meta-analysis of all relevant randomized controlled trials was performed. The PubMed, Embase databases and the Cochrane Central Register of Controlled Trials were searched for relevant publications reporting randomized controlled trials between January 2000 and June 2016. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity were assessed. Eight trials with a total of 2,470 patients were included in this meta-analysis. Compared with fulvestrant alone, combination therapy improved PFS (HR = 0.79; 95% CI 0.72–0.87; P = 0.00), increased ORR (RR = 1.70; 95% CI 1.30–2.21; P = 0.00), and showed a trend of increase in DCR (RR = 1.27; 95% CI 0.96–1.69, P = 0.09). In network analysis, only CD4/6 and PI3K/m-TOR inhibitors showed significant treatment effects with a P-score of 0.9999 and 0.7615, respectively. Patients treated with combination therapy developed more grade 3 or greater toxic effects (RR = 1.24; 95% CI 1.13–1.36; P = 0.00). Combining targeted agents with fulvestrant showed benefit but with increased toxicity in patients with advanced breast cancer compared with fulvestrant alone. Biomarkers for treatment optimization are lacking. The CD4/6 and PI3K/m-TOR pathways merit further investigation.


Breast cancer Fulvestrant Targeted therapy Meta-analysis 


Compliance with ethical standards

Conflict of interest

The authors declared no potential conflicts of interest.


  1. 1.
    Yang XR, Chang-Claude J, Goode EL, Couch FJ, Nevanlinna H, et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst. 2011;103:250–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Sini V, Cinieri S, Conte P, De Laurentiis M, Leo AD, et al. Endocrine therapy in post-menopausal women with metastatic breast cancer: from literature and guidelines to clinical practice. Crit Rev Oncol Hematol. 2016;100:57–68.CrossRefPubMedGoogle Scholar
  3. 3.
    Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thürlimann B, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001;92:2247–58.CrossRefPubMedGoogle Scholar
  4. 4.
    Mouridsen H, Sun Y, Gershanovich M, Perez-Carrion R, Becquart D, et al. Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability. Oncologist. 2004;9:489–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Chia S, Gradishar W, Mauriac L, Bines J, Amant F, 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;26:1664–70.CrossRefPubMedGoogle Scholar
  6. 6.
    Cope S, Ouwens MJNM, Jansen JP, Schmid P. Progression-free survival with fulvestrant 500 mg and alternative endocrine therapies as second-line treatment for advanced breast cancer: a network meta-analysis with parametric survival models. Value Health. 2013;16:403–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, 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;28:4594–600.CrossRefPubMedGoogle Scholar
  8. 8.
    Johnston SRD, Kilburn LS, Ellis P, Dodwell D, Cameron D, 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;14:989–98.CrossRefPubMedGoogle Scholar
  9. 9.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.CrossRefPubMedGoogle Scholar
  11. 11.
    Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bergh J, Jonsson PE, Lidbrink EK, Trudeau M, Eiermann W, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919–25.CrossRefPubMedGoogle Scholar
  13. 13.
    Howell A, Robertson JFR, Abram P, Lichinitser MR, Elledge R, et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004;22:1605–13.CrossRefPubMedGoogle Scholar
  14. 14.
    Johnston SRD, Kilburn LS, Ellis P, Dodwell D, Cameron D, 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;14:989–98.CrossRefPubMedGoogle Scholar
  15. 15.
    Leo AD, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2013;106:djt337.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367:435–44.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Robertson JF, Dixon JM, Sibbering DM, Jahan A, Ellis IO, et al. A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer. Breast Cancer Res. 2013;15:R18.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Martin M, Loibl S, von Minckwitz G, Morales S, Martinez N, et al. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the Letrozole/Fulvestrant and Avastin (LEA) study. J Clin Oncol. 2015;33:1045–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Turner NC, Ro J, André F, Loi S, Verma S, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209–19.CrossRefPubMedGoogle Scholar
  20. 20.
    Baselga J, Im SA, Iwata H, Clemons M, Ito Y, et al. PIK3CA status in circulating tumor DNA predicts efficacy of buparlisib plus fulvestrant in postmenopausal women with endocrine-resistant HR+/HER2− advanced breast cancer: first results from the randomized, Phase III BELLE-2 trial. Program and abstracts of the San Antonio Breast Cancer Symposium (SABCS) S6-01. 2015Google Scholar
  21. 21.
    Hyams DM, Chan A, de Oliveira C, Snyder R, Vinholes J, et al. Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study. Invest New Drugs. 2013;31:1345–54.CrossRefPubMedGoogle Scholar
  22. 22.
    Robertson JFR, Ferrero J-M, Bourgeois H, Kennecke H, de Boer RH, et al. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol. 2013;14:228–35.CrossRefPubMedGoogle Scholar
  23. 23.
    Clemons MJ, Cochrane B, Pond GR, Califaretti N, Chia SKL, et al. Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study. Breast Cancer Res Treat. 2014;146:153–62.CrossRefPubMedGoogle Scholar
  24. 24.
    Zaman K, Winterhalder R, Mamot C, Hasler-Strub U, Rochlitz C, et al. Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: a multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08. Eur J Cancer. 2015;51:1212–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:811–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Burstein HJ, Cirrincione CT, Barry WT, Chew HK, Tolaney SM, et al. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III Trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer—CALGB 40302 (alliance). J Clin Oncol. 2014;32:3959–66.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425–39.CrossRefPubMedGoogle Scholar
  28. 28.
    Brodie A, Sabnis G. Adaptive changes result in activation of alternate signaling pathways and acquisition of resistance to aromatase inhibitors. Clin Cancer Res. 2011;17:4208–13.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Arpino G, Green SJ, Allred DC, Lew D, Martino S, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. Clin Cancer Res. 2004;10:5670–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Lauring J, Park BH, Wolff AC. The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J Natl Compr Canc Netw. 2013;11:670–8.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Nichols M. New directions for drug-resistant breast cancer: the CDK4/6 inhibitors. Future Med Chem. 2015;7:1473–81.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. Clin Invest. 2010;120:2406–13.CrossRefGoogle Scholar
  33. 33.
    Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nature Commun. 2016;7:11579.CrossRefGoogle Scholar
  34. 34.
    Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2015;21:4760–6.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2017

Authors and Affiliations

  • Wen-Zhao Lin
    • 1
  • Qi-Ni Xu
    • 2
  • Hong-Biao Wang
    • 2
  • Xu-Yuan Li
    • 1
  1. 1.Department of Medical OncologyShantou Central HospitalShantouChina
  2. 2.Department of Respiratory Medical OncologyCancer Hospital of Shantou University Medical CollegeShantouChina

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