PMID- 21245432
OWN - NLM
STAT- MEDLINE
DCOM- 20110401
LR  - 20181201
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 29
IP  - 6
DP  - 2011 Feb 20
TI  - HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in 
      women with advanced breast cancer.
PG  - 667-73
LID - 10.1200/JCO.2010.31.3197 [doi]
AB  - PURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small 
      proportion of patients with metastatic breast cancer (MBC) treated with 
      lapatinib. This study sought to identify gene variants associated with 
      lapatinib-induced ALT elevation and hepatobiliary AEs. PATIENTS AND METHODS: A 
      two-stage pharmacogenetic investigation of ALT elevation was conducted in 
      lapatinib-treated patients with MBC. Exploratory marker identification evaluated 
      classical HLA alleles, candidate genes, and genome-wide screening in 37 cases 
      with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls 
      with ALT </= 1x ULN, selected from 901 lapatinib-treated patients in 12 trials. 
      Markers achieving prespecified association thresholds were progressed to an 
      independent confirmatory data set of 24 ALT cases and 155 controls selected from 
      a subsequent trial of 374 lapatinib-treated patients. RESULTS: Of 58 variants 
      associated with ALT elevation in the exploratory data set, four exceeded the 
      prespecified significance threshold in the confirmatory analysis. These variants 
      reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the 
      confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases 
      and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a 
      predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had 
      negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 
      (95% CI 0.10 to 0.26), respectively. CONCLUSION: These results support a role for 
      immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required 
      to determine whether testing for DQA1*02:01 allele carriage is clinically useful 
      in managing liver safety risk during lapatinib treatment.
FAU - Spraggs, Colin F
AU  - Spraggs CF
AD  - GlaxoSmithKline Research and Development, Genetics Division, Medicines 
      Development Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NF, United 
      Kingdom. colin.f.spraggs@gsk.com
FAU - Budde, Laura R
AU  - Budde LR
FAU - Briley, Linda P
AU  - Briley LP
FAU - Bing, Nan
AU  - Bing N
FAU - Cox, Charles J
AU  - Cox CJ
FAU - King, Karen S
AU  - King KS
FAU - Whittaker, John C
AU  - Whittaker JC
FAU - Mooser, Vincent E
AU  - Mooser VE
FAU - Preston, Alaknanda J
AU  - Preston AJ
FAU - Stein, Steven H
AU  - Stein SH
FAU - Cardon, Lon R
AU  - Cardon LR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110118
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DQ alpha-Chains)
RN  - 0 (HLA-DQA1 antigen)
RN  - 0 (Quinazolines)
RN  - 0VUA21238F (Lapatinib)
RN  - EC 2.6.1.2 (Alanine Transaminase)
SB  - IM
MH  - Aged
MH  - Alanine Transaminase/blood
MH  - Antineoplastic Agents/*adverse effects
MH  - Breast Neoplasms/drug therapy/*genetics/pathology
MH  - Case-Control Studies
MH  - Female
MH  - Genetic Predisposition to Disease/*genetics
MH  - Genotype
MH  - HLA-DQ Antigens/*genetics
MH  - HLA-DQ alpha-Chains
MH  - Humans
MH  - Lapatinib
MH  - Liver/drug effects
MH  - Liver Diseases/*etiology
MH  - Liver Function Tests
MH  - Middle Aged
MH  - Quinazolines/*adverse effects
MH  - Randomized Controlled Trials as Topic
MH  - Risk Factors
EDAT- 2011/01/20 06:00
MHDA- 2011/04/02 06:00
CRDT- 2011/01/20 06:00
PHST- 2011/01/20 06:00 [entrez]
PHST- 2011/01/20 06:00 [pubmed]
PHST- 2011/04/02 06:00 [medline]
AID - JCO.2010.31.3197 [pii]
AID - 10.1200/JCO.2010.31.3197 [doi]
PST - ppublish
SO  - J Clin Oncol. 2011 Feb 20;29(6):667-73. doi: 10.1200/JCO.2010.31.3197. Epub 2011 
      Jan 18.