title: Re-evaluating adjuvant breast cancer trials: assessing hormone receptor status by immunohistochemical versus extraction assays.
abstract: BACKGROUND
  Tumor levels of steroid hormone receptors, a factor used to select adjuvant treatment for early-stage breast cancer, are currently determined with immunohistochemical assays. These assays have a discordance of 10%-30% with previously used extraction assays. We assessed the concordance and predictive value of hormone receptor status as determined by immunohistochemical and extraction assays on specimens from International Breast Cancer Study Group Trials VIII and IX. These trials predominantly used extraction assays and compared adjuvant chemoendocrine therapy with endocrine therapy alone among pre- and postmenopausal patients with lymph node-negative breast cancer. Trial conclusions were that combination therapy provided a benefit to pre- and postmenopausal patients with estrogen receptor (ER)-negative tumors but not to ER-positive postmenopausal patients. ER-positive premenopausal patients required further study.
  
  
  METHODS
  Tumor specimens from 571 premenopausal and 976 postmenopausal patients on which extraction assays had determined ER and progesterone receptor (PgR) levels before randomization from October 1, 1988, through October 1, 1999, were re-evaluated with an immunohistochemical assay in a central pathology laboratory. The endpoint was disease-free survival. Hazard ratios of recurrence or death for treatment comparisons were estimated with Cox proportional hazards regression models, and discriminatory ability was evaluated with the c index. All statistical tests were two-sided.
  
  
  RESULTS
  Concordance of hormone receptor status determined by both assays ranged from 74% (kappa = 0.48) for PgR among postmenopausal patients to 88% (kappa = 0.66) for ER in postmenopausal patients. Hazard ratio estimates were similar for the association between disease-free survival and ER status (among all patients) or PgR status (among postmenopausal patients) as determined by the two methods. However, among premenopausal patients treated with endocrine therapy alone, the discriminatory ability of PgR status as determined by immunohistochemical assay was statistically significantly better (c index = 0.60 versus 0.51; P = .003) than that determined by extraction assay, and so immunohistochemically determined PgR status could predict disease-free survival.
  
  
  CONCLUSIONS
  Trial conclusions in which ER status (for all patients) or PgR status (for postmenopausal patients) was determined by immunohistochemical assay supported those determined by extraction assays. However, among premenopausal patients, trial conclusions drawn from PgR status differed--immunohistochemically determined PgR status could predict response to endocrine therapy, unlike that determined by the extraction assay.
authors.affiliation: IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA. mregan@jimmy.harvard.edu
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Mauro G
authors.initials: MG
authors.lastname: Mastropasqua
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.forename: Rastko
authors.initials: R
authors.lastname: Golouh
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Bob
authors.initials: B
authors.lastname: Brown
authors.forename: Mart
authors.initials: M
authors.lastname: Suurküla
authors.forename: Gerald
authors.initials: G
authors.lastname: Langman
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.forename: Stephen
authors.initials: S
authors.lastname: Braye
authors.forename: Piergiovanni
authors.initials: P
authors.lastname: Grigolato
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Monica
authors.initials: M
authors.lastname: Castiglione-Gertsch
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Barry
authors.initials: B
authors.lastname: Gusterson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001681:Biological Assay; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D017698:Postmenopause; D011237:Predictive Value of Tests; D017697:Premenopause; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone