title: Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury.
abstract: OBJECTIVE
  Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2-positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer).
  
  
  METHODS
  The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants.
  
  
  RESULTS
  In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment.
  
  
  CONCLUSIONS
  These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA. colin.f.spraggs@gsk.com.
authors.forename: Colin F
authors.initials: CF
authors.lastname: Spraggs
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Parham
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Cox
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Finkelstein
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Erica
authors.initials: E
authors.lastname: Rappold
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Joan
authors.initials: J
authors.lastname: Curran
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.affiliation: Daniel J. Schaid and Shannon K. McDonnell, Mayo Clinic, Rochester, MN; Colin F. Spraggs and Charles J. Cox, GlaxoSmithKline Research and Development, Stevenage, Hertfordshire; Joan Curran, GlaxoSmithKline Research and Development, London, United Kingdom; Laura R. Parham, GlaxoSmithKline Research and Development, Research Triangle Park, NC; Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; Dianne M. Finkelstein and Paul E. Goss, Massachusetts General Hospital, Boston, MA; and Erica Rappold and Lon R. Cardon, GlaxoSmithKline Research and Development, Philadelphia, PA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011446:Prospective Studies; D011799:Quinazolines / Q000009:adverse effects* / Q000627:therapeutic use; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D059811:HLA-DRB1 Chains; C456920:HLA-DRB1*07 antigen; D011799:Quinazolines; D000077341:Lapatinib