title: Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.
abstract: BACKGROUND
  Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1.
  
  
  METHODS
  HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF).
  
  
  RESULTS
  In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable).
  
  
  CONCLUSIONS
  Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1.
  
  
  BACKGROUND
  NCT01565200.
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium geraldine.gebhart@bordet.be.
authors.forename: G
authors.initials: G
authors.lastname: Gebhart
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: L E
authors.initials: LE
authors.lastname: Lamberts
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Z
authors.initials: Z
authors.lastname: Wimana
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Garcia
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Emonts
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Ameye
authors.affiliation: Antwerp University Hospital, Antwerpen, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Antwerp University Hospital, Antwerpen, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Huizing
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Aftimos
authors.affiliation: Radboud University Medical Center Nijmegen, Nijmegen.
authors.forename: J
authors.initials: J
authors.lastname: Tol
authors.affiliation: Radboud University Medical Center Nijmegen, Nijmegen.
authors.forename: W J G
authors.initials: WJ
authors.lastname: Oyen
authors.affiliation: VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Vugts
authors.affiliation: VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: O S
authors.initials: OS
authors.lastname: Hoekstra
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: C P
authors.initials: CP
authors.lastname: Schröder
authors.affiliation: VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: C W
authors.initials: CW
authors.lastname: Menke-van der Houven van Oordt
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Guiot
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Brouwers
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Awada
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Flamen
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000008:administration & dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008875:Middle Aged; D049268:Positron-Emission Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D019788:Fluorodeoxyglucose F18; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: HER2 imaging; HER2-positive breast cancer; prediction of T-DM1 efficacy