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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

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  • C F Spraggs
  • L R Parham
  • L P Briley
  • Mark L Warren
  • Valerie S L Williams
  • D J Fraser
  • Zhu-Ming Jiang
  • Tipu Z Aziz
  • S. Ahmed
  • G Demetriou
  • Mitul A Mehta
  • N Jackson
  • J Byrne
  • M Andersson
  • M Toi
  • Adrian L Harris
  • J Gralow
  • J A Zujewski
  • R Crescenzo
  • A Armour
  • Edith A Perez
  • Martine Piccart
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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.The Pharmacogenomics Journal advance online publication, 8 August 2017; doi:10.1038/tpj.2017.39.

Original languageEnglish
JournalThe pharmacogenomics journal
Volume18
Issue number3
Pages (from-to)480-486
ISSN1470-269X
DOIs
Publication statusPublished - 2018

    Research areas

  • Journal Article

ID: 51782746