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Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes

The Pharmacogenomics Journal volume 18, pages 480–486 (2018)Cite this article

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Abstract

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10−26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

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Acknowledgements

This study was sponsored by GlaxoSmithKline; Tykerb is an asset of Novartis AG as of 2 March 2015.

Author information

Author notes

  1. L R Parham, L P Briley, L Warren and D J Fraser: Affiliation at the time of the study: Research & Development, GlaxoSmithKline, Research Triangle Park, NC, USA.

  2. L S Williams and N Jackson: Affiliation at the time of the study: GlaxoSmithKline, Clinical Statistics, London, UK.

  3. J Byrne, R Crescenzo and A Armour: Affiliation at the time of the study: GlaxoSmithKline, Collegeville, PA, USA.

Authors and Affiliations

  1. Target Sciences, GlaxoSmithKline, Stevenage, UK

    C F Spraggs

  2. PAREXEL International, Durham, NC, USA

    L R Parham, L P Briley, L Warren & D J Fraser

  3. Teva Pharmaceuticals, Raleigh-Durham, NC, USA

    L Warren

  4. Novartis Pharmaceuticals, Uxbridge, UK

    L S Williams & N Jackson

  5. The Hospital Affiliated to Military Medical Science, Beijing, China

    Z Jiang

  6. Hameed Latif Hospital, Lahore, Pakistan

    Z Aziz

  7. King Edward Medical College and Mayo Hospital, Lahore, Pakistan

    S Ahmed

  8. University Witwatersrand Oncology, Parktown, South Africa

    G Demetriou

  9. Central India Cancer Research Institute, Nagpur, India

    A Mehta

  10. Adaptimmune LLC, Philadelphia, PA, USA

    J Byrne

  11. Rigshospitalet, Copenhagen, Denmark

    M Andersson

  12. Kyoto University, Kyoto, Japan

    M Toi

  13. Case Western Reserve University, Cleveland, OH, USA

    L Harris

  14. University of Washington, Seattle, WA, USA

    J Gralow

  15. National Cancer Institute, Bethesda, MD, USA

    J A Zujewski

  16. Pfizer Oncology, Collegeville, PA, USA

    R Crescenzo

  17. Endocyte, Indianapolis, IN, USA

    A Armour

  18. Mayo Clinic Cancer Center, Jacksonville, FL, USA

    E Perez

  19. Université Libre de Bruxelles, Brussels, Belgium

    M Piccart

Authors
  1. C F Spraggs
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  2. L R Parham
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  3. L P Briley
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  4. L Warren
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  5. L S Williams
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  9. S Ahmed
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  12. N Jackson
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  13. J Byrne
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  14. M Andersson
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  15. M Toi
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  16. L Harris
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  17. J Gralow
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  21. E Perez
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  22. M Piccart
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Corresponding author

Correspondence to C F Spraggs.

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Spraggs, C., Parham, L., Briley, L. et al. Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes. Pharmacogenomics J 18, 480–486 (2018). https://doi.org/10.1038/tpj.2017.39

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  • DOI: https://doi.org/10.1038/tpj.2017.39

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