title: Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial.
abstract: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC).
  
  
  
  In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459).
  
  
  
  Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients.
  
  
  
  In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone.
  
  
  
  The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.
authors.affiliation: West German Study Group, Moenchengladbach; Breast Center Niederrhein, Ev. Bethesda Hospital, Moenchengladbach. Electronic address: oleg.gluz@wsg-online.com.
authors.forename: O
authors.initials: O
authors.lastname: Gluz
authors.affiliation: West German Study Group, Moenchengladbach; Women's Clinic, University Clinics Schleswig-Holstein, Luebeck.
authors.forename: C
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen; Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Huober
authors.affiliation: Sample & Assay Technologies, QIAGEN, Marseille, France.
authors.forename: H
authors.initials: H
authors.lastname: Peyro-Saint-Paul
authors.affiliation: West German Study Group, Moenchengladbach.
authors.forename: R E
authors.initials: RE
authors.lastname: Kates
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover.
authors.forename: H H
authors.initials: HH
authors.lastname: Kreipe
authors.affiliation: Institute of Pathology, University Clinics Erlangen, Erlangen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology Viersen, Viersen.
authors.forename: E
authors.initials: E
authors.lastname: Pelz
authors.affiliation: Institute of Pathology, University Clinics Erlangen, Erlangen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Erber
authors.affiliation: Department of Obstetrics and Gynecology, Heinrich-Heine-University Duesseldorf, Duesseldorf.
authors.forename: S
authors.initials: S
authors.lastname: Mohrmann
authors.affiliation: Department of Obstetrics and Gynecology, Staedtisches Klinikum, Frankfurt.
authors.forename: V
authors.initials: V
authors.lastname: Möbus
authors.affiliation: Clinics Deggendorf Mammacenter Ostbayern, Deggendorf.
authors.forename: D
authors.initials: D
authors.lastname: Augustin
authors.affiliation: Department of Gynecology and Obstetrics, St Josephs-Hospital, Wiesbaden.
authors.forename: G
authors.initials: G
authors.lastname: Hoffmann
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg; Department of Gynecology, University Hospital Halle/Saale, Halle.
authors.forename: C
authors.initials: C
authors.lastname: Thomssen
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg.
authors.forename: F
authors.initials: F
authors.lastname: Jänicke
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum Rechts der Isar der Technischen Universität Muenchen (TUM), Munich.
authors.forename: M
authors.initials: M
authors.lastname: Kiechle
authors.affiliation: Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen.
authors.forename: D
authors.initials: D
authors.lastname: Wallwiener
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Bonn, Bonn.
authors.forename: W
authors.initials: W
authors.lastname: Kuhn
authors.affiliation: West German Study Group, Moenchengladbach; Breast Center Niederrhein, Ev. Bethesda Hospital, Moenchengladbach.
authors.forename: U
authors.initials: U
authors.lastname: Nitz
authors.affiliation: West German Study Group, Moenchengladbach; Breast Center, University of Munich and CCC of LMU, Munich, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Harbeck
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D018572:Disease-Free Survival; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005820:Genetic Testing; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D014408:Biomarkers, Tumor; D000077143:Docetaxel; D015251:Epirubicin; D047628:Estrogen Receptor alpha; D005472:Fluorouracil; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D043823:Taxoids; C506487:ESR1 protein, human; C508053:ERBB2 protein, human
keywords: breast cancer subtypes; central grade; genomic grade index; prognosis