title: Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer.
abstract: OBJECTIVE
  Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC).
  
  
  METHODS
  Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety.
  
  
  RESULTS
  Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days.
  
  
  CONCLUSIONS
  Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA. ian_krop@dfci.harvard.edu.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Suter
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Chau T
authors.initials: CT
authors.lastname: Dang
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamagni
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Citron
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Smitt
authors.affiliation: Ian E. Krop, Dana-Farber Cancer Institute, Boston, MA; Thomas M. Suter, Bern University Hospital, Bern, Switzerland; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York; Marc L. Citron, Hofstra North Shore-Long Island Jewish School of Medicine, New Hyde Park, NY; Luc Dirix, Sint-Augustinus Hospital, Antwerp, Belgium; Gilles Romieu, Institut du Cancer de Montpellier Val d'Aurelle, Montpellier; Mario Campone, Institut de Cancérologie de l'Ouest/René Gauducheau, Nantes Saint-Herblain, France; Claudio Zamagni, Policlinico Sant'Orsola-Malpighi Hospital, Bologna; Luca Gianni, San Raffaele Hospital, Milan, Italy; and Na Xu and Melanie Smitt, Genentech, South San Francisco, CA.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage; D005240:Feasibility Studies; D005472:Fluorouracil / Q000008:administration & dosage; D006261:Headache / Q000139:chemically induced; D006333:Heart Failure / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology; D006801:Humans; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D015251:Epirubicin; D005472:Fluorouracil; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human