title: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
abstract: BACKGROUND
  Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.
  
  
  METHODS
  In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688.
  
  
  RESULTS
  Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients).
  
  
  CONCLUSIONS
  Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Oncologia Medica, San Raffaele Cancer Centre, Milan, Italy. gianni.luca@hsr.it
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.forename: Young-Hyuck
authors.initials: YH
authors.lastname: Im
authors.forename: Laslo
authors.initials: L
authors.lastname: Roman
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Mei-Ching
authors.initials: MC
authors.lastname: Liu
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Staroslawska
authors.forename: Juan
authors.initials: J
authors.lastname: de la Haba-Rodriguez
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Jose Luiz
authors.initials: JL
authors.lastname: Pedrini
authors.forename: Brigitte
authors.initials: B
authors.lastname: Poirier
authors.forename: Paolo
authors.initials: P
authors.lastname: Morandi
authors.forename: Vladimir
authors.initials: V
authors.lastname: Semiglazov
authors.forename: Vichien
authors.initials: V
authors.lastname: Srimuninnimit
authors.forename: Giulia
authors.initials: G
authors.lastname: Bianchi
authors.forename: Tania
authors.initials: T
authors.lastname: Szado
authors.forename: Jayantha
authors.initials: J
authors.lastname: Ratnayake
authors.forename: Graham
authors.initials: G
authors.lastname: Ross
authors.forename: Pinuccia
authors.initials: P
authors.lastname: Valagussa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001938:Brazil; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D002170:Canada; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D005060:Europe; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008408:Mastectomy; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000077143:Docetaxel; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab