Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma

Xu, Chunfang; Reck, Brian H.; Goodman, Vicki; Xue, Zhengyu; Huang, Lingkang; Barnes, Michael R.; Koshy, Beena; Spraggs, Colin F.; Mooser, Vincent; Cardon, Lon R.; Pandite, Lini

doi:10.1016/j.jhep.2010.09.028

Cited by 47 publications

(38 citation statements)

References 24 publications

(29 reference statements)

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“…Previous meta-analyses of pazopanib clinical trials showed older age and concomitant use of simvastatin were associated with increased risk of transaminase elevations (5,30). In a previous study using data from n ¼ 243 patients (a subset of $10% of the patients analyzed here), we reported that two SNPs in the HFE gene were associated with ALT elevation, with an estimated 12% probability that this observation occurred by chance (9). We tested the association between these two HFE SNPs and ALT elevation in the full dataset now available (n ¼ 2,190) and were unable to validate this previous finding.…”

Section: à5mentioning

confidence: 64%

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

Johnson

Wang

et al. 2016

Clinical Cancer Research

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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 ¼ 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N ¼ 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.Results: The discovery study identified an association between HLA-B Ã 57:01 carriage and ALT elevation [P ¼ 5.0 Â 10 À5 for maximum on-treatment ALT (MaxALT); P ¼ 4.8 Â 10 À4 for time to ALT > 3Â upper limit of normal (ULN) event; P ¼ 4.1 Â 10 À5 for time to ALT > 5Â ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P ¼ 8.1 Â 10 À4 for ALT > 3Â ULN, P ¼ 9.8 Â 10 À3 for ALT > 5Â ULN) in an independent dataset. In the combined data, HLA-B Ã 57:01 carriage was associated with ALT elevation (P ¼ 4.3 Â 10 À5 for MaxALT, P ¼ 5.1 Â 10 À6 for time to ALT > 3ÂULN event, P ¼ 5.8 Â 10 À6 for time to ALT > 5Â ULN event). In HLA-B Ã 57:01 carriers and noncarriers, frequency of ALT > 3Â ULN was 31% and 19%, respectively, and frequency of ALT > 5Â ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.Conclusions: These data indicate that HLA-B Ã 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.

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Section: à5mentioning

confidence: 64%

“…Previous pharmacogenetic analyses in pazopanib-treated patients identified that Gilbert syndrome UGT1A1 variants were associated with bilirubin elevation (7,8). A suggestive association between HFE polymorphisms and ALT was also reported (9).…”

Section: Introductionmentioning

confidence: 90%

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

Johnson

Wang

et al. 2016

Clinical Cancer Research

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“…However, in this case, a meta-analysis would be misjudging because of the large heterogeneity in study design, sample sizes, ethnicities, study endpoints, tested SNPs, evaluated treatments, and statistical approach. Sample sizes range from 1 to 451, in which the number of tested SNPs varied between 1 and 6852 SNPs [22,39]. Furthermore, publication bias has very likely occurred and obscures a clear conclusion from a meta-analysis.…”

Section: Discussionmentioning

confidence: 99%

“…In roughly the same patient cohorts (n = 115 explorative and n = 128 for replication), Xu et al studied 9308 SNPs in 282 candidate genes. For rs2858996 and rs707889 in HFE, which are in strong linkage disequilibrium, the TT genotypes were associated with increased ALT levels [39].…”

Section: Pharmacogenetics To Predict Pazopanib Toxicitymentioning

confidence: 93%

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

Diekstra

Swen

Gelderblom

et al. 2016

Expert Review of Molecular Diagnostics

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“…Although an expected event for pazopanib, efforts were made to explore potential underlying causes of the hepatotoxicity events observed in the 4 patients who experienced grade 3 or 4 transaminase elevations. Pharmacogenetic analyses included an evaluation of genetic markers in the HFE and UGT1A1 genes, which have been associated with ALT and bilirubin elevation, respectively, in patients with RCC treated with pazopanib (34,35); functional polymorphisms for enzymes involved in the metabolism of pazopanib and paclitaxel (CYP3A4 and CYP2C8); and transport proteins for which pazopanib and/or paclitaxel are substrates or inhibitors (ABCB1, ABCG2, and OATP1B1). In all 3 patients who provided a sample for pharmacokinetic and pharmacogenetic analysis, plasma concentrations of pazopanib were in the expected range, and in 2 patients, functional polymorphisms were detected that may have contributed to the observed liver event; one patient did not have pharmacogenetic testing performed.…”

Section: Discussionmentioning

confidence: 99%

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

Kendra

Plummer

Salgia

et al. 2015

Molecular Cancer Therapeutics

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This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3þ3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8 Ã 3 Ã 3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m 2 plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of !12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m 2 every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non-small cell lung cancer that suggest further evaluation of this combination is warranted.

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Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma

Cited by 47 publications

References 24 publications

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

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

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

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Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma

Cited by 47 publications

References 24 publications

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

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

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

A Multicenter Phase I Study of Pazopanib in Combination with Paclitaxel in First-Line Treatment of Patients with Advanced Solid Tumors

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Resources

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

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