title: Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab.
abstract: OBJECTIVE
  Previous studies have highlighted the importance of an appropriate human epidermal growth factor receptor 2 (HER2) evaluation for the proper identification of patients eligible for treatment with anti-HER2 targeted therapies. Today, the relationship remains unclear between the level of HER2 amplification and the outcome of HER2-positive gastric cancer treated with first-line chemotherapy with trastuzumab. The aim of this study was to determine whether the level of HER2 gene amplification determined by the HER2/CEP17 ratio and HER2 gene copy number could significantly predict some benefit in overall survival and response to therapy in advanced gastric cancer treated with trastuzumab-based chemotherapy.
  
  
  METHODS
  Ninety patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy were studied. The optimal cutoff values for HER2/CEP17 ratio and HER2 gene copy number (GCN) for discriminating positive results in terms of response and prolonged survival were determined using receiver operating characteristic curves analyses.
  
  
  RESULTS
  In this study, a median HER2/CEP17 ratio of 6.11 (95% CI, 2.27 to 21.90) and a median HER2 gene copy number of 11.90 (95% CI, 3.30 to 43.80) were found. A mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating sensitive and refractory patients (P = .005). Similarly, the optimal cutoff for predicting survival longer than 12 months was 4.45 (P = .005), and for survival longer than 16 months was 5.15 (P = .004). For HER2 GCN, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively (P = .02).
  
  
  CONCLUSIONS
  The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.
authors.affiliation: Carlos Gomez-Martin, Elena Garralda, and Manuel Hidalgo, Spanish National Cancer Research Centre; Carlos Gomez-Martin, Jose Carlos Plaza, Fernando Lopez-Rios, and Manuel Hidalgo, Laboratorio Dianas Terapeuticas, Cenro Integral Oncologico Clara Campal, Hospital Universitario Sanchinarro; Federico Rojo and Ana Leon, Fundacion Jimenez Diaz, Madrid; Pilar Sanz-Moncasi, Hospital Royo-Villanova; Roberto Pazo-Cid and Elena del Valle, Hospital Universitario Miguel Servet, Zaragoza; Antonieta Salud and Felipe Vilardell, Hospital Universitario Arnau de Vilanova, Lérida; Francesc Pons, Mar Iglesias, and Clara Montagut, Hospital de Mar; Maria Alsina and Stefania Landolfi, Hospital Universitari Vall d'Hebrón; M. Carmen Galan and M. Jose Paulés, Instituto Catalan de Oncologia; Miriam Cuatrecasas and Laura Visa, Hospital Clinic Universitari, Barcelona; Paula Fonseca and Soledad Fernandez, Hospital Universitario Central de Asturias, Oviedo; Fernando Rivera and Marta Mayorga, Hospital Universitario Marques de Valdecilla, Santander, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomez-Martin
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Plaza
authors.forename: Roberto
authors.initials: R
authors.lastname: Pazo-Cid
authors.forename: Antonieta
authors.initials: A
authors.lastname: Salud
authors.forename: Francesc
authors.initials: F
authors.lastname: Pons
authors.forename: Paula
authors.initials: P
authors.lastname: Fonseca
authors.forename: Ana
authors.initials: A
authors.lastname: Leon
authors.forename: Maria
authors.initials: M
authors.lastname: Alsina
authors.forename: Laura
authors.initials: L
authors.lastname: Visa
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Galan
authors.forename: Elena
authors.initials: E
authors.lastname: Del Valle
authors.forename: Felipe
authors.initials: F
authors.lastname: Vilardell
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Stefania
authors.initials: S
authors.lastname: Landolfi
authors.forename: Miriam
authors.initials: M
authors.lastname: Cuatrecasas
authors.forename: Marta
authors.initials: M
authors.lastname: Mayorga
authors.forename: M
authors.initials: M
authors.lastname: Jose Paulés
authors.forename: Pilar
authors.initials: P
authors.lastname: Sanz-Moncasi
authors.forename: Clara
authors.initials: C
authors.lastname: Montagut
authors.forename: Elena
authors.initials: E
authors.lastname: Garralda
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopez-Rios
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002503:Centromere / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human