title: Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer.
abstract: OBJECTIVE
  A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC).
  
  
  METHODS
  Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced.
  
  
  RESULTS
  Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months.
  
  
  CONCLUSIONS
  While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.
authors.affiliation: The University of Iowa, Iowa City, IA 52242, USA. kimberly-leslie@uiowa.edu
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.forename: Heather A
authors.initials: HA
authors.lastname: Lankes
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Fischer
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Heidi
authors.initials: H
authors.lastname: Gray
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: Joan L
authors.initials: JL
authors.lastname: Walker
authors.forename: Krishnansu
authors.initials: K
authors.lastname: Tewari
authors.forename: Parviz
authors.initials: P
authors.lastname: Hanjani
authors.forename: Ovadia
authors.initials: O
authors.lastname: Abulafia
authors.forename: Peter G
authors.initials: PG
authors.lastname: Rose
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D004252:DNA Mutational Analysis; D004334:Drug Administration Schedule; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D018773:Genes, erbB-1; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D000077341:Lapatinib; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005819:Genetic Markers; D011799:Quinazolines; D000077341:Lapatinib