title: Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer.
abstract: OBJECTIVE
  We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial.
  
  
  METHODS
  Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status.
  
  
  RESULTS
  With a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17).
  
  
  CONCLUSIONS
  pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel.
authors.affiliation: National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA. xy32m@nih.gov
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Yang
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Costantino
authors.forename: Chungyeul
authors.initials: C
authors.lastname: Kim
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Mamounas
authors.forename: Dat
authors.initials: D
authors.lastname: Nguyen
authors.forename: Jong-Hyeon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: Kelley
authors.initials: K
authors.lastname: Kidwell
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D003520:Cyclophosphamide; D004317:Doxorubicin; D017239:Paclitaxel; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012694:Serine