title: Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials.
abstract: BACKGROUND
  The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy.
  
  
  METHODS
  Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >2.2 and ≥2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated.
  
  
  RESULTS
  HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death.
  
  
  CONCLUSIONS
  HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant chemotherapy.
  
  
  BACKGROUND
  Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998 and ACTRN12609001036202.
authors.affiliation: Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. fountzil@auth.gr
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.forename: Urania
authors.initials: U
authors.lastname: Dafni
authors.forename: Mattheos
authors.initials: M
authors.lastname: Bobos
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.forename: Anna
authors.initials: A
authors.lastname: Batistatou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xanthakis
authors.forename: Christos
authors.initials: C
authors.lastname: Papadimitriou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kostopoulos
authors.forename: Triantafillia
authors.initials: T
authors.lastname: Koletsa
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsolaki
authors.forename: Despina
authors.initials: D
authors.lastname: Televantou
authors.forename: Eleni
authors.initials: E
authors.lastname: Timotheadou
authors.forename: Angelos
authors.initials: A
authors.lastname: Koutras
authors.forename: George
authors.initials: G
authors.lastname: Klouvas
authors.forename: Epaminontas
authors.initials: E
authors.lastname: Samantas
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Pisanidis
authors.forename: Charisios
authors.initials: C
authors.lastname: Karanikiotis
authors.forename: Ioanna
authors.initials: I
authors.lastname: Sfakianaki
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pavlidis
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.forename: Helena
authors.initials: H
authors.lastname: Linardou
authors.forename: Konstantine T
authors.initials: KT
authors.lastname: Kalogeras
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002503:Centromere; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17; D017326:Clinical Trials, Phase III as Topic; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016017:Odds Ratio; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C000618811:TOP2A protein, human
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