title: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.
abstract: BACKGROUND
  Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer.
  
  
  METHODS
  Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880.
  
  
  RESULTS
  296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5.
  
  
  CONCLUSIONS
  The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer.
  
  
  BACKGROUND
  GlaxoSmithKline, Roche, and Teva.
authors.affiliation: German Breast Group, Neu-Isenburg, Germany; Universität Frankfurt, Frauenklinik, Frankfurt, Germany. Electronic address: gunter.vonminckwitz@germanbreastgroup.de.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
authors.affiliation: Universität Heidelberg, Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: German Breast Group, Neu-Isenburg, Germany; Sana Kliniken Offenbach, Brustzentrum, Offenbach, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Hämatoonkologische Schwerpunktpraxis, München, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Salat
authors.affiliation: Charité Berlin, Institute of Pathology, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Luisenkrankenhaus Düsseldorf, Brustzentrum, Düsseldorf, Germany.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Rezai
authors.affiliation: St Gertrauden Krankenhaus, Brustzentrum St Getrauden, Germany.
authors.forename: Jens U
authors.initials: JU
authors.lastname: Blohmer
authors.affiliation: Sana Kliniken Offenbach, Brustzentrum, Offenbach, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.affiliation: Klinikum rechts der Isar der Technischen Universität München, Frauenklinik, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Paepke
authors.affiliation: Universität Rostock, Frauenklinik, Rostock, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.affiliation: SRH Waldklinikum, Gera, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zahm
authors.affiliation: Kliniken Essen-Mitte, Frauenklinik, Essen, Germany.
authors.forename: Sherko
authors.initials: S
authors.lastname: Kümmel
authors.affiliation: Universität Kiel, Frauenklinik, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: Praxisklinik, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Klare
authors.affiliation: Universität Ulm, Frauenklinik, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Universität Magdeburg, Frauenklinik, Magdeburg, Germany.
authors.forename: Serban
authors.initials: S
authors.lastname: Costa
authors.affiliation: Onkologie Bethanien, Frankfurt, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Tesch
authors.affiliation: Klinikum zum Roten Kreuz, Frauenklinik, München, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hanusch
authors.affiliation: Eilenriede-Klinik, Hannover, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Hilfrich
authors.affiliation: Agaplesion Markus Krankenhaus, Frankfurt, Germany.
authors.forename: Fariba
authors.initials: F
authors.lastname: Khandan
authors.affiliation: Universität Erlangen, Frauenklinik, Erlangen, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Charité Berlin, Institute of Pathology, Berlin, Germany.
authors.forename: Bruno V
authors.initials: BV
authors.lastname: Sinn
authors.affiliation: Zentrum für Pathologie, Zytologie und Molekularpathologie Neuss, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Engels
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: Keyur
authors.initials: K
authors.lastname: Mehta
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nekljudova
authors.affiliation: Helios-Klinikum, Berlin-Buch, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human