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Characterisation of the HLA-DRB107:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes

par Spraggs, Colin C.F.;Parham, Laura L.R.;Briley, Linda L.P.;Warren, Liling;Williams, Laura L.S.;Fraser, Dana D.J.;Jiang, Zefei;Aziz, Zeba;Ahmed, Shahjehan;Demetriou, Georgia;Mehta, Ajay A.O.;Jackson, Nigel;Byrne, Julie;Andersson, Michael;Toi, Masakazu;Harris, Lyndsay;Gralow, Julie;Zujewski, Jo Anne;Crescenzo, R.;Armour, Alison;Perez, Enrique;Piccart-Gebhart, Martine
Référence Pharmacogenomics journal, 18, 3, page (480-486)
Publication Publié, 2018-05

Article révisé par les pairs

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Résumé :

HLA-DRB107:01 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-DRB107:01 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-DRB107:01 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-DRB107:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB107:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB107:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.