title: HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data.
abstract: BACKGROUND
  Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer.
  
  
  METHODS
  We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours).
  
  
  RESULTS
  We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0·89 (95% CI 0·79-1·01) for HER2 non-amplified patients and 0·71 (0·58-0·86) for HER2-amplified patients (p(interaction)=0·0485); for overall survival, HRs were 0·91 (95% CI 0·79-1·05) for HER2 non-amplified patients and 0·73 (0·59-0·89) for HER2-amplified patients (p(interaction)=0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78-1·00) for normal, 0·63 (0·46-0·87) for deleted, and 0·62 (0·43-0·90) for amplified (p(interaction)=0·0513); HRs for overall survival were 0·89 (0·78-1·03) for normal, 0·68 (0·49-0·95) for deleted, and 0·67 (0·46-0·98) for amplified (p(interaction)=0·1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50-0·81) for altered and 0·88 (0·78-1·00) for normal (p(interaction)=0·0183); HRs for overall survival were 0·67 (0·52-0·86) for altered and 0·89 (0·78-1·03) for normal (p(interaction)=0·0455).
  
  
  CONCLUSIONS
  Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours.
  
  
  BACKGROUND
  Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.
authors.affiliation: Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy. adileo@usl4.toscana.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Fanny
authors.initials: F
authors.lastname: Piette
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.forename: Christopher
authors.initials: C
authors.lastname: Poole
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Helena
authors.initials: H
authors.lastname: Earl
authors.forename: Henning
authors.initials: H
authors.lastname: Mouridsen
authors.forename: Frances P
authors.initials: FP
authors.lastname: O'Malley
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
authors.forename: Minna
authors.initials: M
authors.lastname: Tanner
authors.forename: Alison
authors.initials: A
authors.lastname: Munro
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Twelves
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.forename: Lois
authors.initials: L
authors.lastname: Shepherd
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D017326:Clinical Trials, Phase III as Topic; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D019317:Evidence-Based Medicine; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D018579:Patient Selection; D000075223:Poly-ADP-Ribose Binding Proteins; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
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; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human