title: Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
abstract: OBJECTIVE
  Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 inhibitor, remains unproven in non-HER2-amplified metastatic breast cancer (MBC). EGF30008, a phase III trial of letrozole and lapatinib versus letrozole and placebo, demonstrated that lapatinib significantly improves outcome for postmenopausal women with HER2-amplified, but not HER2-negative, MBC. The hypothesis that low hormone receptor status is associated with benefit in this HER2-negative cohort was tested.
  
  
  METHODS
  A blinded retrospective biomarker evaluation used immunohistochemistry (IHC) to semiquantify estrogen receptor (ER) and progesterone receptor (PgR) expression (n = 821/952). HER2 status was determined by IHC and confirmed by FISH (n = 326). Effects of these biomarkers on progression-free survival (PFS) were examined in patients with available tissue.
  
  
  RESULTS
  In HER2-negative, ER-positive MBC, median PFS was analyzed by ER and PgR expression (H-score) by quartile (Q). There was significant improvement in patients with low ER expression (Q1, H-score <160) with lapatinib and letrozole (13.6 vs. 6.7 months; P = 0.01). No benefit was associated with stronger ER expression (Q2/3, H-score ≥ 160 and <250; 13.6 vs. 14.2 months; Q4, H-score ≥ 250; 11.2 vs. 14.2 months). There was no association between PgR H-score and benefit from lapatinib.
  
  
  CONCLUSIONS
  In postmenopausal patients with advanced hormone receptor-positive disease, weak ER expression is associated with worse outcome with letrozole treatment compared with the combination. The addition of lapatinib significantly improved PFS for this patient subgroup and augments data supporting interaction between steroid hormone and peptide hormone signaling. A prospective study validating this hypothesis is required.
authors.affiliation: Authors' Affiliations: Geffen School of Medicine at UCLA; Norris Cancer Center, University of Southern California, Los Angeles, California; GlaxoSmithKline, Collegeville, Pennsylvania; GlaxoSmithKline, Durham, North Carolina; and Royal Marsden Hospital, London, United Kingdom.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Rourke
authors.forename: Allison
authors.initials: A
authors.lastname: Florance
authors.forename: Catherine
authors.initials: C
authors.lastname: Ellis
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Martin
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D000077289:Letrozole; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000008:administration & dosage; D017698:Postmenopause; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000235:genetics; D012189:Retrospective Studies; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D000077289:Letrozole; D009570:Nitriles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; C508053:ERBB2 protein, human