Skip to main content

Advertisement

SpringerLink
Log in

Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

To compare the efficacy and toxicity of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and nonsteroidal aromatase inhibitors (AI) versus AI alone as first-line therapy for patients with advanced hormone receptor-positive breast cancer.

Materials and methods

Phase III randomized clinical trials (RCT) were identified after a systematic review of electronic databases. A random-effect model was used to determine the pooled hazard ratio (HR) for progression-free survival (PFS) using the inverse-variance method. The Mantel–Haenszel method was used to calculate the pooled odds ratio (OR) for overall response, clinical benefit rate and treatment-related side effects. Heterogeneity was measured using the tau-squared and I2 statistics.

Results

After a systematic search, three phase III RCT (n = 1827) were included. The use of CDK 4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) in combination with an AI was significantly associated with longer PFS compared to the use of letrozole or anastrozole alone (HR: 0.57; 95% CI 0.50–0.65; p < 0.00001), with no significant heterogeneity among trials. Similarly, overall response rate and clinical benefit rate were higher for patients who received the combination therapy than for patients allocated to AI alone. Grade 3 or higher treatment-related side effects were more frequently reported for patients who received CDK 4/6 inhibitors (OR: 7.51; 95% CI 6.01–9.38; p < 0.00001), these included mainly neutropenia, leukopenia and anemia.

Conclusion

The addition of CDK 4/6 inhibitors (either abemaciclib, palbociclib, or ribociclib) to an AI (anastrozole or letrozole) significantly improved PFS, overall response rate, and clinical benefit rate in comparison with a nonsteroidal AI alone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  2. Migliaccio I, Malorni L, Hart CD, Guarducci C, Di Leo A. Endocrine therapy considerations in postmenopausal patients with hormone receptor positive, human epidermal growth factor receptor type 2 negative advanced breast cancers. BMC Med. 2015;13(1):1–6. https://doi.org/10.1186/s12916-015-0280-0.

    Article  CAS  Google Scholar 

  3. Group EBCTC, (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.

    Article  CAS  Google Scholar 

  4. Cardoso F, Costa A, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Bhattacharyya G, Biganzoli L, Cardoso MJ, Carey L, et al. 3rd ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol. 2017;28:16–33. https://doi.org/10.1093/annonc/mdw544.

    Article  PubMed  CAS  Google Scholar 

  5. Rugo HS, Rumble B, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34:3069–103.

    Article  PubMed  CAS  Google Scholar 

  6. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.

    Article  PubMed  CAS  Google Scholar 

  7. Lu J. Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer. J Hematol Oncol. 2015;8:98.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Coudreuse D, Nurse P. Driving the cell cycle with a minimal CDK control network. Nature. 2010;468(7327):1074–9.

    Article  PubMed  CAS  Google Scholar 

  9. Xu, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol. 2017;10:97. https://doi.org/10.1186/s13045-017-0467-2.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bilgin B, Sendur MAN, Sener Dede D, et al. A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer. Curr Med Res Opin. 2017;33:1559–69.

    Article  PubMed  CAS  Google Scholar 

  11. Wesierska-Gadek J, Hajek SB, Sarg B, et al. Pleiotropic effects of selective CDK inhibitors on human normal and cancer cells. Biochem Pharmacol. 2008;76:1503–14.

    Article  PubMed  CAS  Google Scholar 

  12. Higgins JP, Green S. Cochrane collaboration. Cochrane handbook for systematic reviews of interventions. 1st ed. Hoboken: Wiley; 2008.

    Book  Google Scholar 

  13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;445:228–47.

    Article  Google Scholar 

  14. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–934.

    Article  PubMed  CAS  Google Scholar 

  15. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.

    Article  PubMed  CAS  Google Scholar 

  16. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive advanced breast cancer. N Engl J Med. 2016;375:1738–48.

    Article  PubMed  CAS  Google Scholar 

  17. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638–46.

    Article  PubMed  Google Scholar 

  18. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18:3758–67.

    Article  PubMed  CAS  Google Scholar 

  19. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001;19:2596–606.

    Article  PubMed  CAS  Google Scholar 

  20. Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26:4883–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009;27:4530–5.

    Article  PubMed  CAS  Google Scholar 

  22. Hu W, Sung T, Jessen BA, et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res. 2016;22(8):2000–8.

    Article  PubMed  CAS  Google Scholar 

  23. Costa R, Gradishar WJ. Differences are important: breast cancer therapy in different ethnic groups. J Glob Oncol. 2017;3:281–4.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lin Gomez S, Clarke CA, Shema SJ, et al. Disparities in breast cancer survival among asian women by ethnicity and immigrant status: a population-based study. Am J Public Health. 2010;100:861–9.

    Article  Google Scholar 

  25. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18:17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Departamento de Oncología Médica, Hospital San Juan de Dios, PO BOX: 1000-SJO, San Jose, Costa Rica

    Allan Ramos-Esquivel & Hellen Hernández-Steller

  2. Escuela de Medicina, Universidad de Costa Rica, San Jose, Costa Rica

    Allan Ramos-Esquivel & Denis Ulises Landaverde

  3. Department of Oncology, McGill University, Montreal, QC, Canada

    Marie-France Savard

  4. Departamento de Oncología Médica, Hospital México, San Jose, Costa Rica

    Denis Ulises Landaverde

Authors
  1. Allan Ramos-Esquivel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hellen Hernández-Steller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-France Savard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Denis Ulises Landaverde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Allan Ramos-Esquivel.

Ethics declarations

Conflict of interest

There are no conflicts of interest to disclose.

Electronic supplementary material

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramos-Esquivel, A., Hernández-Steller, H., Savard, MF. et al. Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials. Breast Cancer 25, 479–488 (2018). https://doi.org/10.1007/s12282-018-0848-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-018-0848-6

Keywords

Search

Navigation