HLA-B 57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer

• Published in: Clinical cancer research Vol. 22; no. 6; pp. 1371 - 1377
• Main Authors: Xu, Chun-Fang, Johnson, Toby, Wang, Xiaojing, Carpenter, Chris, Graves, Alan P., Warren, Liling, Xue, Zhengyu, King, Karen S., Fraser, Dana J., Stinnett, Sandy, Briley, Linda P., Mitrica, Ionel, Spraggs, Colin F., Nelson, Matthew R., Tada, Hiroomi, du Bois, Andreas, Powles, Thomas, Kaplowitz, Neil, Pandite, Lini N.
• Format: Journal Article
• Language: English
• Published: 15.03.2016
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-2044

Abstract Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury. Experimental Design: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted. Results: The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10−5 for maximum on-treatment ALT (MaxALT); P = 4.8 × 10−4 for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10−5 for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10−4 for ALT > 3× ULN, P = 9.8 × 10−3 for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10−5 for MaxALT, P = 5.1 × 10−6 for time to ALT > 3×ULN event, P = 5.8 × 10−6 for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation. Conclusions: These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients. Clin Cancer Res; 22(6); 1371–7. ©2015 AACR.