title: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort.
abstract: BACKGROUND
  In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy.
  
  
  METHODS
  We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495.
  
  
  RESULTS
  Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5.4 years (IQR 3.1-6.8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0.64 (95% CI 0.44-0.93; two-sided log-rank p=0.016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0.29 (95% CI 0.11-0.78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group).
  
  
  CONCLUSIONS
  These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.
authors.affiliation: San Raffaele Hospital, Milan, Italy. Electronic address: gianni.luca@hsr.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Interdisziplinäres Onkologisches Zentrum München, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.affiliation: NN Petrov Research Institute of Oncology, St Petersburg, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Semiglazov
authors.affiliation: Hospital Clínico Universitario de Valencia-INCLIVA Health Research Institute, University of Valencia, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: NN Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Tjulandin
authors.affiliation: San Raffaele Hospital, Milan, Italy.
authors.forename: Milvia
authors.initials: M
authors.lastname: Zambetti
authors.affiliation: IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Moliterni
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Central Clinical Hospital NA Semashko, Moscow, Russia.
authors.forename: Mikhail J
authors.initials: MJ
authors.lastname: Byakhov
authors.affiliation: NN Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lichinitser
authors.affiliation: Instituto Valenciano de Oncologia, Valencia, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Climent
authors.affiliation: Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.affiliation: Hospital de la Santa Creu i Sant Pau, Department of Medical Oncology, Barcelona, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Ojeda
authors.affiliation: Department of Oncology, University Hospital of Udine, Udine, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Mansutti
authors.affiliation: NN Petrov Research Institute of Oncology, St Petersburg, Russia.
authors.forename: Alla
authors.initials: A
authors.lastname: Bozhok
authors.affiliation: Fondazione Michelangelo, Milan, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Magazzù
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Heinzmann
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Jutta
authors.initials: J
authors.lastname: Steinseifer
authors.affiliation: Fondazione Michelangelo, Milan, Italy.
authors.forename: Pinuccia
authors.initials: P
authors.lastname: Valagussa
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018734:Genes, erbB-2; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016016:Proportional Hazards Models; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab