Chun-Fang Xu 1 , Toby Johnson 2 , Xiaojing Wang 2 , Chris Carpenter 2 , Alan P Graves 2 , Liling Warren 2 , Zhengyu Xue 2 , Karen S King 2 , Dana J Fraser 2 , Sandy Stinnett 2 , Linda P Briley 2 , Ionel Mitrica 2 , Colin F Spraggs 2 , Matthew R Nelson 2 , Hiroomi Tada 2 , Andreas du Bois 3 , Thomas Powles 4 , Neil Kaplowitz 5 , Lini N Pandite 2 Show Affiliations »
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. ©2015 American Association for Cancer Research.
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 . ©2015 American Association for Cancer Research.
Entities: CellLine
Chemical
Disease
Gene
Mutation
Species
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Year: 2015
PMID： 26546620 DOI： 10.1158/1078-0432.CCR-15-2044
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531