title: Preoperative chemoradiotherapy in rectal cancer induces changes in the expression of nuclear β-catenin: prognostic significance.
abstract: BACKGROUND
  Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/β-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of β-catenin/E-cadherin, and to determine whether these changes are associated with survival.
  
  
  METHODS
  The Immunohistochemical expression of nuclear β-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46-50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis.
  
  
  RESULTS
  CRT induced significant changes in the expression of nuclear β-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear β-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear β-catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear β-catenin expression after CRT almost reached the cut-off for significance (p = 0.06).
  
  
  CONCLUSIONS
  In our study, preoperative CRT for LARC induced significant changes in nuclear β-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival.
authors.affiliation: Department of Radiation Oncology, University Hospital Virgen de la Victoria, Campus Teatinos s/n, Málaga, 29010, Spain. jaimegomezmillan@gmail.com.
authors.forename: Jaime
authors.initials: J
authors.lastname: Gomez-Millan
authors.forename: Lydia
authors.initials: L
authors.lastname: Perez
authors.forename: Ines
authors.initials: I
authors.lastname: Aroca
authors.forename: Maria
authors.initials: M
authors.lastname: Del Mar Delgado
authors.forename: Vanessa
authors.initials: V
authors.lastname: De Luque
authors.forename: Alicia
authors.initials: A
authors.lastname: Román
authors.forename: Esperanza
authors.initials: E
authors.lastname: Torres
authors.forename: Soraya
authors.initials: S
authors.lastname: Ramos
authors.forename: Sofia
authors.initials: S
authors.lastname: Perez
authors.forename: Eloisa
authors.initials: E
authors.lastname: Bayo
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Medina
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D015820:Cadherins / Q000378:metabolism*; D000069287:Capecitabine; D059248:Chemoradiotherapy / Q000379:methods*; D003107:Colorectal Surgery / Q000379:methods*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000628:therapy*; D011300:Preoperative Care / Q000379:methods*; D011446:Prospective Studies; D012004:Rectal Neoplasms / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil