title: p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.
abstract: BACKGROUND
  Abnormal expression of the cell cycle regulatory proteins p27(Kip1) (p27) and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome.
  
  
  METHODS
  We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group-Intergroup Trial S9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) or sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1-7, and the median value was used as the cut point. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence or death. All P values were from two-sided statistical tests.
  
  
  RESULTS
  Lower p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor-positive patients, lower p27 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 expression and survival was found in hormone receptor-negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29).
  
  
  CONCLUSIONS
  Low p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor-positive tumors.
authors.affiliation: Division of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA. pporter@fhcrc.org
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Porter
authors.forename: William E
authors.initials: WE
authors.lastname: Barlow
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Ming Gang
authors.initials: MG
authors.lastname: Lin
authors.forename: Xiaopu P
authors.initials: XP
authors.lastname: Yuan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Donato
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Charles M
authors.initials: CM
authors.lastname: Haskell
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: James M
authors.initials: JM
authors.lastname: Roberts
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D019927:Cyclin E / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016019:Survival Analysis
chemical_list: D019927:Cyclin E; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; D003520:Cyclophosphamide