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Background
Lapatinib (Tykerb/Tyverb® , GlaxoSmithKline) is an EGFR/HER2 tyrosine kinase inhibitor (TKI) approved in combination with capecitabine, letrozole, paclitaxel or trastuzumab for the treatment of HER2 overexpressing metastatic breast cancer. Skin rash is an adverse event (AE) which is a class effect of TKIs and has been observed during treatment with lapatinib [1] and a range of other drugs [2]. Rash is a common side effect in lapatinib-treated patients and may cause dose interruption and treatment discontinuation. Identifying risk factors may support rash management during lapatinib use.
HLA alleles have been implicated in drug-induced hypersensitivities [2], including cutaneous reactions that range from moderate to severe [3]. Furthermore, we have previously identified and validated HLA-DRB1*07:01 allele carriage as a risk marker for hepatotoxicity observed during lapatinib treatment [4] raising the possibility that lapatinib-induced rash might also be influenced by the same, or some other HLA allele. This study investigated the association of HLA alleles with rash during lapatinib treatment, using HLA genotype and clinical phenotype data from a lapatinib monotherapy clinical trial in women with HER2 overexpressing breast cancer (Tykerb Evaluation after Chemotherapy [TEACH], EGF105485, NCT00374322). Rash was a common AE in lapatinib-treated subjects in TEACH (59 vs 15% in placebo-treated subjects), with a median time to onset of approximately 14 days in the lapatinib treatment arm. Most rash events were low grade (National Cancer Institute Common Terminology Criteria for Adverse Events v3 grade 1 [n = 557, 35%] or 2 [n = 293, 19%]), however, some lapatinib-treated subjects experienced more severe rash (grade 3 (n = 71, 5%) or 4 (n = 1, <1%).
Patients & methods
A blood DNA sample was collected prospectively from subjects who provided informed consent, resulting in 1191 subjects, comprising 76% of the TEACH safety population, who were randomized to lapatinib treatment. Classical HLA genotyping was performed for seven HLA genes: HLA-A,...