title: Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V.
abstract: BACKGROUND
  The objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin-dependent kinase inhibitor p27(Kip1) in patients with early-stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers.
  
  
  METHODS
  Immunoreactivity for p27 protein was analyzed on tumor slides from 461 patients who were enrolled in the International Breast Cancer Study Group (IBCSG) Trial V (median follow-up, 13 years), including 198 patients with lymph node negative disease and 263 patients with lymph node positive disease. Tumors with < 50% immunoreactive neoplastic cells were considered low expressors. Immunoreactivity for p27 was correlated with several clinicopathologic characteristics. Disease free survival (DFS) and overall survival were analyzed according to p27 immunoreactivity and treatment group.
  
  
  RESULTS
  In the lymph node negative population, decreased p27 immunoreactivity was associated with higher tumor grade (P = 0.001) and HER-2/neu overexpression (P = 0.04). In the lymph node positive population, low p27 expression was associated with higher tumor grade (P = 0.01), low expression of thymidylate synthase (P = 0.001), and higher Ki-67 expression (P = 0.007). DFS was not significantly different according to p27 status in either lymph node negative patients (10-year DFS: low p27 expression, 53% +/- 5%; high p27 expression, 55% +/- 5%) or in lymph node positive patients (10 year DFS: low p27 expression, 33% +/- 4%; high p27 expression, 32% +/- 4%). However, in the lymph node negative population, the benefit of one course of perioperative chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil was confined exclusively to patients with tumors that showed reduced p27 immunoreactivity (P = 0.03; test for interaction).
  
  
  CONCLUSIONS
  This analysis indicates that p27 immunoreactivity has little if any prognostic value in patients with early-stage breast carcinoma. However, these findings suggest that, in patients with breast carcinoma who have negative lymph node status, reduced p27 immunoreactivity is associated with HER-2/neu overexpression and may be predictive of a benefit from the early administration of adjuvant chemotherapy.
authors.affiliation: Department of Medical Oncology, Ospedale San Giovanni, Bellinzona, Switzerland. vito.spataro@blue.ch
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Spataro
authors.forename: Heather
authors.initials: H
authors.lastname: Litman
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Fausto
authors.initials: F
authors.lastname: Maffini
authors.forename: Michele
authors.initials: M
authors.lastname: Masullo
authors.forename: Rastko
authors.initials: R
authors.lastname: Golouh
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Martinez-Tello
authors.forename: Piergioranni
authors.initials: P
authors.lastname: Grigolato
authors.forename: Keith B
authors.initials: KB
authors.lastname: Shilkin
authors.forename: Barry A
authors.initials: BA
authors.lastname: Gusterson
authors.forename: Monica
authors.initials: M
authors.lastname: Castiglione-Gertsch
authors.forename: Karen
authors.initials: K
authors.lastname: Price
authors.forename: Jurii
authors.initials: J
authors.lastname: Lindtner
authors.forename: Hernan
authors.initials: H
authors.lastname: Cortés-Funes
authors.forename: Edda
authors.initials: E
authors.lastname: Simoncini
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Byrne
authors.forename: John
authors.initials: J
authors.lastname: Collins
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000276:immunology; D017024:Chemotherapy, Adjuvant; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D025521:Tumor Suppressor Proteins