HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer.
OBJECTIVE
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.


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 ≤ 1× 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.


CONCLUSIONS
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.
GlaxoSmithKline Research and Development, Genetics Division, Medicines Development Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NF, United Kingdom. colin.f.spraggs@gsk.com
Colin F
CF
Spraggs
Laura R
LR
Budde
Linda P
LP
Briley
Nan
N
Bing
Charles J
CJ
Cox
Karen S
KS
King
John C
JC
Whittaker
Vincent E
VE
Mooser
Alaknanda J
AJ
Preston
Steven H
SH
Stein
Lon R
LR
Cardon
D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D006801:Humans; D000077341:Lapatinib; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000209:etiology*; D008111:Liver Function Tests; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
D000970:Antineoplastic Agents; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D011799:Quinazolines; D000077341:Lapatinib; D000410:Alanine Transaminase