title: Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.
abstract: BACKGROUND
  Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel.
  
  
  METHODS
  The prognostic and predictive values of TP53 were analyzed in tumor samples by gene sequencing within exons 5 to 8. Patients were classified according to p53 protein status predicted from TP53 gene sequence, as wild-type (no TP53 variation or TP53 variations which are predicted not to modify p53 protein sequence) or mutant (p53 nonsynonymous mutations). Mutations were subcategorized according to missense or truncating mutations. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome.
  
  
  RESULTS
  TP53 gene status was determined for 18% (520 of 2887) of the women enrolled in BIG 02-98. TP53 gene variations were found in 17% (90 of 520). Nonsynonymous p53 mutations, found in 16.3% (85 of 520), were associated with older age, ductal morphology, higher grade and hormone-receptor negativity. Of the nonsynonymous mutations, 12.3% (64 of 520) were missense and 3.6% were truncating (19 of 520). Only truncating mutations showed significant independent prognostic value, with an increased recurrence risk compared to patients with non-modified p53 protein (hazard ratio = 3.21, 95% confidence interval = 1.740 to 5.935, P = 0.0002). p53 status had no significant predictive value for response to docetaxel.
  
  
  CONCLUSIONS
  p53 truncating mutations were uncommon but associated with poor prognosis. No significant predictive role for p53 status was detected.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00174655.
authors.affiliation: Molecular Carcinogenesis Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 8, France.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernández-Cuesta
authors.forename: Catherine
authors.initials: C
authors.lastname: Oakman
authors.forename: Priscila
authors.initials: P
authors.lastname: Falagan-Lotsch
authors.forename: Ke-Seay
authors.initials: KS
authors.lastname: Smoth
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Quinaux
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: M Stella
authors.initials: MS
authors.lastname: Dolci
authors.forename: Evandro De
authors.initials: ED
authors.lastname: Azambuja
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dell'orto
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.forename: Prudence A
authors.initials: PA
authors.lastname: Francis
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Angelo Di
authors.initials: AD
authors.lastname: Leo
authors.forename: Magali
authors.initials: M
authors.lastname: Olivier
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000077143:Docetaxel; D004317:Doxorubicin; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C508053:ERBB2 protein, human