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Pharmacogenomics J. 2018 May 22;18(3):480-486. doi: 10.1038/tpj.2017.39. Epub 2017 Aug 8.

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.

Author information

1
Target Sciences, GlaxoSmithKline, Stevenage, UK.
2
PAREXEL International, Durham, NC, USA.
3
Teva Pharmaceuticals, Raleigh-Durham, NC, USA.
4
Novartis Pharmaceuticals, Uxbridge, UK.
5
The Hospital Affiliated to Military Medical Science, Beijing, China.
6
Hameed Latif Hospital, Lahore, Pakistan.
7
King Edward Medical College and Mayo Hospital, Lahore, Pakistan.
8
University Witwatersrand Oncology, Parktown, South Africa.
9
Central India Cancer Research Institute, Nagpur, India.
10
Adaptimmune LLC, Philadelphia, PA, USA.
11
Rigshospitalet, Copenhagen, Denmark.
12
Kyoto University, Kyoto, Japan.
13
Case Western Reserve University, Cleveland, OH, USA.
14
University of Washington, Seattle, WA, USA.
15
National Cancer Institute, Bethesda, MD, USA.
16
Pfizer Oncology, Collegeville, PA, USA.
17
Endocyte, Indianapolis, IN, USA.
18
Mayo Clinic Cancer Center, Jacksonville, FL, USA.
19
Université Libre de Bruxelles, Brussels, Belgium.

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.

PMID:
28786423
DOI:
10.1038/tpj.2017.39
[Indexed for MEDLINE]

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