title: Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane-Anthracycline Containing Chemotherapy-DAFNE (GBG-70).
abstract: OBJECTIVE
  Dual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane-based chemotherapy can reach pathologic complete response (pCR) rates of up to 60% in HER2-positive breast cancer. The DAFNE (Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment) phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting.
  
  
  METHODS
  Participants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20 mg/d) and trastuzumab [(8) 6 mg/kg/3 weeks] alone; followed by 12-week treatment with paclitaxel (80 mg/m(2)/1 week), trastuzumab, and afatinib; followed by 12 weeks with epirubicin (90 mg/m(2)/3 weeks), cyclophosphamide (600 mg/m(2)/3 weeks), and trastuzumab before surgery. Primary objective was pCR rate, defined as ypT0/is ypN0. We expected a pCR rate of 70%; 65 patients were needed to exclude a rate of ≤55%.
  
  
  RESULTS
  pCR rate was 49.2% [90% confidence interval (CI), 38.5-60.1] in 65 treated patients. Patients with hormone receptor-negative (N = 19) or hormone receptor-positive (N = 46) tumors showed pCR rates of 63.2% and 43.5%, respectively (P = 0.153). Patients with (N = 9) or without (N = 56) lymphocyte predominant breast cancer (LPBC) showed pCR rates of 100% and 41.1%, respectively (P < 0.001). PCR rate was not different in patients with or without PIK3CA tumor mutations (P = 0.363). Clinical responses were seen in 96.3% of 54 evaluable patients, and breast conserving surgery was possible in 59.4% of 62 assessable patients. Most frequent nonhematologic grade 3-4 toxicities were diarrhea (7.7%), increased creatinine (4.6%), and infection (4.6%). One patient developed symptomatic congestive heart failure.
  
  
  CONCLUSIONS
  Neoadjuvant treatment with afatinib, trastuzumab, and chemotherapy showed acceptable tolerability, and a pCR rate comparable with that of other anti-HER2 doublets but below challenging expectations.
authors.affiliation: Klinikum zum Roten Kreuz, Frauenklinik, München, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hanusch
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: Helios-Klinikum, Berlin-Buch, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.affiliation: Klinikum rechts der Isar der Technischen Universität München, Frauenklinik, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Paepke
authors.affiliation: Kliniken Essen-Mitte, Frauenklinik, Essen, Germany.
authors.forename: Sherko
authors.initials: S
authors.lastname: Kümmel
authors.affiliation: Sana Kliniken Offenbach, Brustzentrum, Offenbach, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.affiliation: Universität Ulm, Frauenklinik, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Eilenriede-Klinik, Hannover, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Hilfrich
authors.affiliation: Universität Rostock, Frauenklinik, Rostock, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.affiliation: Universität Kiel, Frauenklinik, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: Charité Berlin, Institute of Pathology, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Universität Magdeburg, Frauenklinik, Magdeburg, Germany.
authors.forename: Serban
authors.initials: S
authors.lastname: Costa
authors.affiliation: St. Gertrauden Krankenhaus, Brustzentrum, St. Getrauden, Germany.
authors.forename: Jens Uwe
authors.initials: JU
authors.lastname: Blohmer
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: Nicole
authors.initials: N
authors.lastname: Burchardi
authors.affiliation: German Breast Group, Neu-Isenburg, Germany. Oncologic Senology Centre, Düsseldorf, Germany. gunter.vonminckwitz@germanbreastgroup.de.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011799:Quinazolines / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D011799:Quinazolines; D043823:Taxoids; D000077716:Afatinib; D000068878:Trastuzumab