title: Cyclooxygenase-2 inhibition does not improve the reduction in ductal carcinoma in situ proliferation with aromatase inhibitor therapy: results of the ERISAC randomized placebo-controlled trial.
abstract: OBJECTIVE
  Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)-positive DCIS.
  
  
  METHODS
  Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 x 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision.
  
  
  RESULTS
  Ninety women were randomized: all were ER positive, 49 (54%) had grade III tumors, and 29 (32%) were HER2 positive (3+). Exemestane reduced proliferation compared with placebo with a median reduction of 9% (95% confidence interval, 6-14; P < 0.001). Progesterone receptor was reduced by exemestane (mean decrease, 19%; 95% confidence interval, 9-28; P = 0.011). The effect of exemestane on proliferation was seen regardless of grade, HER2, or PR expression. Celecoxib had no effect on proliferation or apoptosis alone, or in combination with exemestane.
  
  
  CONCLUSIONS
  Exemestane reduces proliferation in ER-positive DCIS. Aromatase inhibition is a potential alternative to tamoxifen in patients who have undergone breast conservation for ER-positive DCIS.
authors.affiliation: Department of Academic Surgery, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Bundred
authors.forename: Angela
authors.initials: A
authors.lastname: Cramer
authors.forename: Julie
authors.initials: J
authors.lastname: Morris
authors.forename: Lorna
authors.initials: L
authors.lastname: Renshaw
authors.forename: Kwok-Leung
authors.initials: KL
authors.lastname: Cheung
authors.forename: Pamela
authors.initials: P
authors.lastname: Flint
authors.forename: Rachael
authors.initials: R
authors.lastname: Johnson
authors.forename: Oliver
authors.initials: O
authors.lastname: Young
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: Sue
authors.initials: S
authors.lastname: Grassby
authors.forename: Lorraine
authors.initials: L
authors.lastname: Turner
authors.forename: Andrew
authors.initials: A
authors.lastname: Baildam
authors.forename: Lester
authors.initials: L
authors.lastname: Barr
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D010919:Placebos; D011720:Pyrazoles / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D019394:Ki-67 Antigen; D010919:Placebos; D011720:Pyrazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013449:Sulfonamides; C056516:exemestane