title: COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast, and is a target for treatment.
abstract: BACKGROUND
  Stratification of patients for treatment of ductal carcinoma in situ (DCIS) is suboptimal, with high systemic overtreatment rates.
  
  
  METHODS
  A training set of 95 tumours from women with pure DCIS were immunostained for proteins involved in cell survival, hypoxia, growth factor and hormone signalling. A generalised linear regression with regularisation and variable selection was applied to a multiple covariate Cox survival analysis with recurrence-free survival 10-fold cross-validation and leave-one-out iterative approach were used to build and test the model that was validated using an independent cohort of 58 patients with pure DCIS. The clinical role of a COX-2-targeting agent was then tested in a proof-of-concept neoadjuvant randomised trial in ER-positive DCIS treated with exemestane 25 mg day(-1)± celecoxib 800 mg day(-1).
  
  
  RESULTS
  The COX-2 expression was an independent prognostic factor for early relapse in the training (HR 37.47 (95% CI: 5.56-252.74) P=0.0001) and independent validation cohort (HR 3.9 (95% CI: 1.8-8.3) P=0.002). There was no significant interaction with other clinicopathological variables. A statistically significant reduction of Ki-67 expression after treatment with exemestane ± celecoxib was observed (P<0.02) with greater reduction in the combination arm (P<0.004). Concomitant reduction in COX-2 expression was statistically significant in the exemestane and celecoxib arm (P<0.03) only.
  
  
  CONCLUSIONS
  In patients with DCIS, COX-2 may predict recurrence, aiding clinical decision making. A combination of an aromatase inhibitor and celecoxib has significant biological effect and may be integrated into treatment of COX2-positive DCIS at high risk of recurrence.
authors.affiliation: US Terapia Molecolare e Farmacogenomica/UO Chirurgia Generale Senologica, AO Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Generali
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: F M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: 1] Department of Anatomical Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Victorian Cancer Biobank, Rathdowne Street, Carlton, Victoria 3053, Australia [3] Department of Pathology, Melbourne University, Parkville, Victoria 3052, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Deb
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, School of Medicine and Anatomical Pathology, Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Cummings
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, School of Medicine and Anatomical Pathology, Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
authors.forename: L E
authors.initials: LE
authors.lastname: Reid
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: M
authors.initials: M
authors.lastname: Taylor
authors.affiliation: US Terapia Molecolare e Farmacogenomica/UO Chirurgia Generale Senologica, AO Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Andreis
authors.affiliation: US Terapia Molecolare e Farmacogenomica/UO Chirurgia Generale Senologica, AO Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Allevi
authors.affiliation: U.O. Anatomia Patologica, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ferrero
authors.affiliation: Department of Anatomical Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Byrne
authors.affiliation: Chirurgia Generale, Dipartimento di Chirurgia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Martinotti
authors.affiliation: US Terapia Molecolare e Farmacogenomica/UO Chirurgia Generale Senologica, AO Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bottini
authors.affiliation: 1] Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK [2] NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, School of Medicine and Anatomical Pathology, Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
authors.forename: S R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: 1] Department of Anatomical Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, Melbourne University, Parkville, Victoria 3052, Australia.
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000068579:Celecoxib; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D016019:Survival Analysis
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; C056516:exemestane