title: Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study.
abstract: OBJECTIVE
  Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)-positive metastatic breast cancer.
  
  
  METHODS
  Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor.
  
  
  RESULTS
  In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59-1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy-naïve subset (n = 158) the HR was 0.78 (95% CI, 0.52-1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63-3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein.
  
  
  CONCLUSIONS
  In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients.
authors.affiliation: Lester and Sue Smith Breast Center and Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA. kosborne@bcm.edu
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.forename: Luc Y
authors.initials: LY
authors.lastname: Dirix
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Jean
authors.initials: J
authors.lastname: Robert
authors.forename: Craig
authors.initials: C
authors.lastname: Underhill
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutierrez
authors.forename: Ilenia
authors.initials: I
authors.lastname: Migliaccio
authors.forename: Valsamo K
authors.initials: VK
authors.lastname: Anagnostou
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Patrick
authors.initials: P
authors.lastname: Magill
authors.forename: Mark
authors.initials: M
authors.lastname: Sellers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D010919:Placebos; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077156:Gefitinib; D010919:Placebos; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; C508053:ERBB2 protein, human