Skip to main content

Advertisement

Springer Nature Link
Log in

Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Lapatinib is a tyrosine kinase inhibitor that targets the human epidermal growth factor receptor 2 (HER2) and the epidermal growth factor receptor (EGFR/HER1), and there are concerns about its cardiac toxicity. Recent studies of lapatinib have reported cardiac adverse events; however, the results have been inconsistent among the studies. The aim of our study was to estimate the cardiac toxicity of lapatinib in patients with breast cancer and other HER2-positive cancers.

Methods

To evaluate the cardiotoxicity of lapatinib, the results of previous studies were quantitatively integrated using meta-analysis. Forty-five articles regarding cardiac adverse events, including left ventricular dysfunction, left ventricular ejection fraction (LVEF) decrease, arrhythmia, and other cardiac adverse events, were assessed. As a subgroup analysis in patients with breast cancer, 26 studies of lapatinib-induced cardiac adverse events were assessed.

Results

The overall incidence of cardiac adverse events was 2.70% (95% confidence interval [CI] 1.60–4.50%). The incidences of left ventricular dysfunction and LVEF decrease were 1.60% (95% CI 1.30–2.00%) and 2.20% (95% CI 1.30–3.60%), respectively. The overall incidence of cardiac adverse events was 3.00% (95% CI 1.50–6.10%) in patients with breast cancer, which was marginally higher than the rate in patients with all type of cancers.

Conclusion

The overall incidence of lapatinib-induced cardiac toxicity was relatively low based on an indirect comparison with trastuzumab. However, careful monitoring of cardiac toxicity is still needed when patients are treated with lapatinib because the related risk factors have not been clearly identified.

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 includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Konecny GE, Pegram MD, Venkatesan N et al (2006) Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66:1630–1639

    Article  CAS  PubMed  Google Scholar 

  2. Telli ML, Witteles RM (2011) Trastuzumab-related cardiac dysfunction. J Natl Compr Canc Netw 9:243–249

    Article  PubMed  Google Scholar 

  3. Johnston SR, Gomez H, Stemmer SM et al (2013) A randomized and open-label trial evaluating the addition of pazopanib to lapatinib as first-line therapy in patients with HER2-positive advanced breast cancer. Breast Cancer Res Treat 137:755–766

    Article  CAS  PubMed  Google Scholar 

  4. Leslie KK, Sill MW, Lankes HA et al (2012) Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. Gynecol Oncol 127:345–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    Article  CAS  PubMed  Google Scholar 

  6. Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129

    Article  Google Scholar 

  7. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective sties of diseases. J Natl Cancer Inst 22:719–748

    CAS  PubMed  Google Scholar 

  8. DerSimonian R, Larid N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  9. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  10. Egger M, Smith GD, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097

    Article  PubMed  PubMed Central  Google Scholar 

  12. Agulnik M, Cohen EW, Cohen RB (2007) Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non-adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol 25:3978–3984

    Article  CAS  PubMed  Google Scholar 

  13. Burstein HJ, Storniolo AM, Franco S et al (2008) A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann Oncol 19:1068–1074

    Article  CAS  PubMed  Google Scholar 

  14. Gomez HL, Doval DC, Chavez MA et al (2008) Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 26:2999–3005

    Article  CAS  PubMed  Google Scholar 

  15. Johnston S, Trudeau M, Kaufman B et al (2008) Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 26:1066–1072

    Article  CAS  PubMed  Google Scholar 

  16. Lin NU, Carey LA, Liu MC et al (2008) Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26:1993–1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ravaud A, Hawkins R, Gardner JP et al (2008) Lapatinib versus hormone therapy in patients with advanced renal cell carcinoma: a randomized phase III clinical trial. J Clin Oncol 26:2285–2291

    Article  CAS  PubMed  Google Scholar 

  18. Bekaii-Saab T, Markowitz J, Prescott N et al (2009) A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 5:5895–5901

    Article  Google Scholar 

  19. Blackwell KL, Pegram MD, Tan-Chiu E et al (2009) Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol 20:1026–1031

    Article  CAS  PubMed  Google Scholar 

  20. Ramanathan RK, Belani CP, Singh DA et al (2009) A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 64:777–783

    Article  CAS  PubMed  Google Scholar 

  21. Toi M, Iwata H, Fujiwara Y et al (2009) Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer 101:1676–1682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wülfing C, Machiels JH, Richel DJ et al (2009) A single–arm, multicenter, open–label phase 2 study of lapatinib as the second–line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer 115:2881–2890

    Article  PubMed  Google Scholar 

  23. Blackwell KL, Burstein HJ, Storniolo AM et al (2009) Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2–positive, trastuzumab–refractory metastatic breast cancer. J Clin Oncol 28:1124–1130

    Article  Google Scholar 

  24. Monk BJ, Mas Lopez L, Zarba JJ et al (2010) Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol 28:3562–3569

    Article  CAS  PubMed  Google Scholar 

  25. Ross HJ, Blumenschein GR Jr, Aisner J et al (2010) Randomized phase II multicenter trial of two schedules of lapatinib as first- or second-line monotherapy in patients with advanced or metastatic non-small cell lung cancer. Clin Cancer Res 16:1938–1949

    Article  CAS  PubMed  Google Scholar 

  26. Sridhar SS, Hotte SJ, Chin JL et al (2010) A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer. Am J Clin Oncol 33:609–613

    Article  CAS  PubMed  Google Scholar 

  27. Thiessen B, Stewart C, Tsao M et al (2010) A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol 65:353–361

    Article  CAS  PubMed  Google Scholar 

  28. DeCensi A, Puntoni M, Pruneri G et al (2011) Lapatinib activity in premalignant lesions and HER2-positive cancer of the breast in a randomized, placebo-controlled presurgical trial. Cancer Prev Res (Phila) 4:1181–1189

    Article  CAS  Google Scholar 

  29. del Campo JM, Hitt R, Sebastian P et al (2011) Effects of lapatinib monotherapy: results of a randomised phase II study in therapy–naive patients with locally advanced squamous cell carcinoma of the head and neck. Br J Cancer 105:618–627

    Article  PubMed  PubMed Central  Google Scholar 

  30. Idqbal S, Goldman B, Fenoglio-Preise CM et al (2011) Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol 22:2610–2615

    Article  Google Scholar 

  31. Galsky MD, Von Hoff DD, Neubauer M et al (2012) Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors. Invest New Drugs 30:695–701

    Article  CAS  PubMed  Google Scholar 

  32. de Souza JA, Davis DW, Zhang Y et al (2012) A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 18:2336–2343

    Article  PubMed  PubMed Central  Google Scholar 

  33. Garcia AA, Sill MW, Lankes HA et al (2012) A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study. Gynecol Oncol 124:569–574

    Article  CAS  PubMed  Google Scholar 

  34. Guarneri V, Frassoldati A, Bottini A et al (2012) Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol 30:1989–1995

    Article  CAS  PubMed  Google Scholar 

  35. Peck J, Wei L, Zalupski M et al (2012) HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib. Oncology 82:175–179

    Article  CAS  PubMed  Google Scholar 

  36. Pestrin M, Bessi S, Puglisi F et al (2012) Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res Treat 134:283–289

    Article  CAS  PubMed  Google Scholar 

  37. Iwata H, Narabayashi M, Ito Y et al (2013) A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients. Int J Clin Oncol 18:621–628

    Article  CAS  PubMed  Google Scholar 

  38. Coombes RC, Tat T, Miller ML et al (2013) An open–label study of lapatinib in women with HER–2–negative early breast cancer: the lapatinib pre–surgical study (LPS study). Ann Oncol 24:924–930

    Article  CAS  PubMed  Google Scholar 

  39. Cristofanilli M, Johnston SR, Manikhas A et al (2013) A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2 + inflammatory breast cancer. Breast Cancer Res Treat 137:471–482

    Article  CAS  PubMed  Google Scholar 

  40. Goss PE, Smith IE, O’Shaughnessy J et al (2013) Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol 14:88–96

    Article  CAS  PubMed  Google Scholar 

  41. Johnston SR, Gomez H, Stemmer SM et al (2013) A randomized and open–label trial evaluating the addition of pazopanib to lapatinib as first-line therapy in patients with HER2-positive advanced breast cancer. Breast Cancer Res Treat 137:755–766

    Article  CAS  PubMed  Google Scholar 

  42. Liu G, Chen YH, Kolesar J et al (2013) Eastern cooperative oncology group phase II trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer. Urol Oncol 31:211–218

    Article  CAS  PubMed  Google Scholar 

  43. Stacchiotti S, Tamborini E, Lo Vullo S et al (2013) Phase II study on lapatinib in advanced EGFR–positive chordoma. Ann Oncol 24:1931–1936

    Article  CAS  PubMed  Google Scholar 

  44. Fouladi M, Stewart CF, Blaney SM et al (2013) A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Neurooncol 114:173–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stebbing J, Payne R, Reise J et al (2013) The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study. PLoS ONE 8:e62543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Whang YE, Armstrong AJ, Rathmell WK et al (2013) A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration–resistant prostate cancer. Urol Oncol 31:82–86

    Article  CAS  PubMed  Google Scholar 

  47. de Azambuja E, Holmes AP, Piccart-Gebhart M et al (2014) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open–label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15(10):1137–1146

    Article  PubMed  Google Scholar 

  48. Estévez LG, Suarez-Gauthier A, Garcia E et al (2014) Molecular effects of lapatinib in patients with HER2 positive ductal carcinoma in situ. Breast Cancer Res 16:R76

    Article  PubMed  PubMed Central  Google Scholar 

  49. Holmes FA, Espina V, Liotta LA et al (2013) Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling. BMC Res Notes 6:507

    Article  PubMed  PubMed Central  Google Scholar 

  50. Agelaki S, Kalykaki A, Markomanolaki H et al (2015) Efficacy of lapatinib in therapy-resistant HER2–positive circulating tumor cells in metastatic breast cancer. PLoS ONE 10:e0123683

    Article  PubMed  PubMed Central  Google Scholar 

  51. Gelmon KA, Boyle FM, Kaufman B et al (2015) Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31. J Clin Oncol 33:1574–1583

    Article  CAS  PubMed  Google Scholar 

  52. Harrington K, Temam S, Mehanna H et al (2015) Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study. J Clin Oncol 33:4202–4209

    Article  CAS  PubMed  Google Scholar 

  53. Lorenzen S, Riera Knorrenschild J, Georg-Martin H et al (2015) Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomised phase II trial of the arbeitsgemeinschaft internistische onkologie. Eur J Cancer 51:569–576

    Article  CAS  PubMed  Google Scholar 

  54. Rimawi MF, Aleixo SB, Rozas AA et al (2015) A neoadjuvant, randomized, open-label phase II trial of afatinib versus trastuzumab versus lapatinib in patients with locally advanced HER2-positive breast cancer. Clin Breast Cancer 15:101–109

    Article  CAS  PubMed  Google Scholar 

  55. Piccart-Gebhart M, Holmes E, Baselga J et al (2016) Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol 34:1034–1042

    Article  CAS  PubMed  Google Scholar 

  56. Siegel-Lakhai WS, Beijnen JH, Vervenne WL et al (2007) Phase I pharmacokinetic study of the safety and tolerability of lapatinib (GW572016) in combination with oxaliplatin/fluorouracil/leucovorin (FOLFOX4) in patients with solid tumors. Clin Cancer Res 13:4495–4502

    Article  CAS  PubMed  Google Scholar 

  57. LoRusso PM, Jones SF, Koch KM et al (2008) Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J Clin Oncol 26:3046–3051

    Article  Google Scholar 

  58. Sendur MA, Aksoy S, Altundag K (2013) Cardiotoxicity of novel HER2–targeted therapies. Curr Med Res Opin 29:1015–1024

    Article  CAS  PubMed  Google Scholar 

  59. Lee KF, Simon H, Chen H (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398

    Article  CAS  PubMed  Google Scholar 

  60. Erickson SL, O’Shea KS, Ghaboosi N et al (1997) ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development 124:4999–5011

    CAS  PubMed  Google Scholar 

  61. Chien KR (2006) Herceptin and the heart–a molecular modifier of cardiac failure. N Engl J Med 354:789–790

    Article  CAS  PubMed  Google Scholar 

  62. Mantarro S, Rossi M, Bonifazi M et al (2016) Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer. Intern Emerg Med 11:123–140

    Article  PubMed  Google Scholar 

  63. Azim H, Azim HA Jr, Escudier B (2009) Trastuzumab versus lapatinib: the cardiac side of the story. Cancer Treat Rev 35:633–638

    Article  CAS  PubMed  Google Scholar 

  64. Jawa Z, Perez RM, Garlie L et al (2016) Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: a meta-analysis. Medicine (Baltimore) 95:e5195

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the 2016 Yeungnam University Research Grant, and by Basic Science Research Program through the National Research Foundation of Korea (NRF) founded by the Ministry of Science, ICT and Future Planning (2017R1C1B5017085). We thank Prof. Kwang-Hee Shin for the help in statistical analysis.

Author information

Authors and Affiliations

  1. College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongsangbuk-do, 38541, Republic of Korea

    Hye Duck Choi

  2. College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea

    Min Jung Chang

  3. Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, Republic of Korea

    Min Jung Chang

Authors
  1. Hye Duck Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Jung Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hye Duck Choi.

Ethics declarations

Conflicts of interest

The authors have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, H.D., Chang, M.J. Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis. Breast Cancer Res Treat 166, 927–936 (2017). https://doi.org/10.1007/s10549-017-4460-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-017-4460-9

Keywords

Search

Navigation