HLA-DRB1*07:01 biomarker characterization of hepatotoxicity during lapatinib combination therapies in ALTTO.

617 Background: ALTTO (NCT00490139) is a large adjuvant breast cancer (ABC) study evaluating lapatinib, alone and in combinations with trastuzumab and taxanes. Characterization of hepatic abnormalities during lapatinib treatment in ALTTO was conducted using the lapatinib hepatotoxicity risk biomarker HLA-DRB1*07:01. Methods: Germline DNA collection for HLA-DRB1 genotype determination was achieved for 76% (6323/8270) of ALTTO subjects. Association of HLA-DRB1*07:01 allele carriage with ALT elevation during study treatments was evaluated by case-control analysis of NCI CTC AE grade 3 ALT elevation ( > 5x ULN, ALT). Results: A higher incidence of ALT elevation (2-5%, n = 6194) was observed in the three lapatinib-containing treatment arms compared with the trastuzumab monotherapy arm (1%, n = 2076; p < 0.01). Also, ALT was higher when lapatinib and taxane were administered concurrently. HLA-DRB1*07:01 carriage frequency was enriched in lapatinib-treated ALT cases compared with controls (OR 6.5, 95% CI 4.6-9.3...