title: HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer.
abstract: OBJECTIVE
  Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy.
  
  
  METHODS
  In available breast cancer tissue from EGF30001 (paclitaxel +/- lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine +/- lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory.
  
  
  RESULTS
  The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among "HER-2-negative" breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory.
  
  
  CONCLUSIONS
  Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033-0800, USA. press@usc.edu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
authors.forename: Ivonne E
authors.initials: IE
authors.lastname: Villalobos
authors.forename: Angela
authors.initials: A
authors.lastname: Santiago
authors.forename: Roberta
authors.initials: R
authors.lastname: Guzman
authors.forename: Armen
authors.initials: A
authors.lastname: Gasparyan
authors.forename: Yanling
authors.initials: Y
authors.lastname: Ma
authors.forename: Kathy
authors.initials: K
authors.lastname: Danenberg
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Martin
authors.forename: Lisa
authors.initials: L
authors.lastname: Williams
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: Steven
authors.initials: S
authors.lastname: Stein
authors.forename: Robert
authors.initials: R
authors.lastname: Gagnon
authors.forename: Michael
authors.initials: M
authors.lastname: Arbushites
authors.forename: Maria T
authors.initials: MT
authors.lastname: Koehler
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence / Q000592:standards; D053208:Kaplan-Meier Estimate; D007755:Laboratories, Hospital / Q000592:standards; D000077341:Lapatinib; D017056:Medical Laboratory Personnel; D010338:Pathology, Clinical / Q000592:standards; D010820:Physicians; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases