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

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.

• Authors: Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Chris Carpenter, Alan P Graves, Liling Warren, Zhengyu Xue, Karen S King, Dana J Fraser, Sandy Stinnett, Linda P Briley, Ionel Mitrica, Colin F Spraggs, Matthew R Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz, Lini N Pandite
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 6 Pg. 1371-7 (Mar 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26546620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• HLA-B Antigens
• HLA-B57 antigen
• Indazoles
• Pyrimidines
• Sulfonamides
• pazopanib

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Alleles
• Antineoplastic Agents (adverse effects, chemistry, therapeutic use)
• Chemical and Drug Induced Liver Injury (diagnosis, etiology, metabolism)
• Female
• Genetic Predisposition to Disease
• HLA-B Antigens (chemistry, genetics)
• Heterozygote
• Humans
• Indazoles
• Liver Function Tests
• Male
• Middle Aged
• Models, Molecular
• Molecular Conformation
• Neoplasms (complications, drug therapy)
• Pyrimidines (adverse effects, chemistry, therapeutic use)
• Structure-Activity Relationship
• Sulfonamides (adverse effects, chemistry, therapeutic use)
• Young Adult