title: Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients.
abstract: BACKGROUND
  Neoadjuvant Chemotherapy (NC) including trastuzumab induces a high rate of pathological Complete Responses (pCR) in patients with locally advanced HER2-overexpressing Breast Cancer (BC), but is penalized by a severe cardiotoxicity when combined with anthracyclines. A phase II study was designed to assess whether an anthracycline-free NC regimen based on the early addition of trastuzumab to paclitaxel may increase the pCR rate without inducing severe cardiotoxicity in patients with locally advanced HER2-overexpressing BC. Immunomonitoring was performed to assess the contribution of patients' immunological background to the induction of clinical responses.
  
  
  METHODS
  Stage II-III HER2-positive BC patients received 24 weeks paclitaxel and trastuzumab NC, followed by 1 year adjuvant trastuzumab ± hormonal and/or radio-therapy. Assessment of pCR rate was the primary endpoint. A group of HER2-negative BC patients treated with neoadjuvant taxanes and anthracyclines was included. Serum levels of 10 cytokines and the efficiency of trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC) were monitored in vitro every 3 months.
  
  
  RESULTS
  From July 2006 to February 2013, we enrolled 109 patients including 46 evaluable HER2-positive cases. A pCR rate of 50% was reached and no severe cardiotoxicity occurred. Serum cytokine profiling revealed only an IL-10 decrease (P = 0.02) in patients achieving a partial response, while HER2-negative patients disclosed marked cytokines changes. Compared to the unfavourable F/F genotype, patients carrying the V allele in the FcγRIIIa-158 polymorphism showed a higher efficacy of trastuzumab-ADCC throughout treatment (P ≤0.05).
  
  
  CONCLUSIONS
  In the absence of anthracyclines, trastuzumab and paclitaxel induced a high rate of pCR, exploiting the synergy between the immunomodulating properties of these drugs and the retained immunological proficiency of patients with HER2-overexpressing BC.
  
  
  BACKGROUND
  Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Miolo
authors.forename: Elena
authors.initials: E
authors.lastname: Muraro
authors.forename: Debora
authors.initials: D
authors.lastname: Martorelli
authors.forename: Davide
authors.initials: D
authors.lastname: Lombardi
authors.forename: Simona
authors.initials: S
authors.lastname: Scalone
authors.forename: Simon
authors.initials: S
authors.lastname: Spazzapan
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
authors.forename: Tiziana
authors.initials: T
authors.lastname: Perin
authors.forename: Elda
authors.initials: E
authors.lastname: Viel
authors.forename: Elisa
authors.initials: E
authors.lastname: Comaro
authors.forename: Renato
authors.initials: R
authors.lastname: Talamini
authors.forename: Ettore
authors.initials: E
authors.lastname: Bidoli
authors.forename: Elisa
authors.initials: E
authors.lastname: Turchet
authors.forename: Diana
authors.initials: D
authors.lastname: Crivellari
authors.affiliation: Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, C,R,O, National Cancer Institute, Via F, Gallini 2, 33081 Aviano, PN, Italy. rdolcetti@cro.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D000068878:Trastuzumab; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C496124:FCGR3A protein, human