title: A nonreplicating adenoviral vector that contains the wild-type p53 transgene combined with chemotherapy for primary breast cancer: safety, efficacy, and biologic activity of a novel gene-therapy approach.
abstract: BACKGROUND
  : Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV-p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response.
  
  
  METHODS
  : In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV-p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods.
  
  
  RESULTS
  : The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39-71 years), and the median tumor size was 8 cm (range, 5-11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21(WAF1/Cip1) mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30-41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7-100%). There was no increase in systemic toxicity.
  
  
  CONCLUSIONS
  : Ad5CMV-p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies.
authors.affiliation: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77230, USA. mcristof@mdanderson.org
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.forename: Savitri
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: Laura
authors.initials: L
authors.lastname: Guerra
authors.forename: Kristine
authors.initials: K
authors.lastname: Broglio
authors.forename: Banu
authors.initials: B
authors.lastname: Arun
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Booser
authors.forename: Kerstin
authors.initials: K
authors.lastname: Menander
authors.forename: Jill
authors.initials: J
authors.lastname: Van Wart Hood
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008875:Middle Aged; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D019076:Transgenes
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin