title: Microsatellite status and cell cycle associated markers in rectal cancer patients undergoing a combined regimen of 5-FU and CPT-11 chemotherapy and radiotherapy.
abstract: BACKGROUND
  Microsatellite instability (MSI) and expression of cell cycle-related markers may predict a favorable outcome in colorectal cancer patients. The aim of this study was to elucidate the molecular profiles of patients with rectal cancers treated with neoadjuvant chemotherapy (5-Fluorouracil and CPT-11), radiotherapy and surgery that correlate with response to therapy.
  
  
  METHODS
  Fifty-seven patients with rectal cancer were treated with the same preoperative chemotherapy regimen, radiotherapy (45 to 54 Gy) followed by surgery. The microsatellite status, the expression of the mismatch repair proteins MLH1 and MSH2 and p21WAF1/C1PI, p27, bcl-2, topoisomerase II (topo II) and Ki-67 were assessed in the pretreatment biopsies. The response to adjuvant therapy was categorized in the resected specimens as complete response (CR, no microscopic residual tumor present) and partial response (PR, tumor present).
  
  
  RESULTS
  p21WAF1/C1PI, expression characterized the CR with 12 out of 30 tumors (40%) positive for this marker. None of the patients whose tumors did not express p21WAFI/C1PI (10 patients) was a CR (p=0.011). Overall, the tumors with CR also showed higher expression of bcl-2, Ki-67, topo II and p27. However, p53 was more frequently expressed in the PR tumors. Tumors with high microsatellite instability showed CR (3/5, 60%) more often than PR, whereas tumors with stable microsatellites showed PR (26/36, 80%) more often than CR (p=0.099).
  
  
  CONCLUSIONS
  We conclude that a molecular profile characterized by high microsatellite instability with loss of mismatch repair protein expression and p21WAF1/C1PI is predictive of an improved response to neoadjuvant treatment with 5-FU, CPT-11 and radiation therapy.
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Charara
authors.forename: Tina Bocker
authors.initials: TB
authors.lastname: Edmonston
authors.forename: Susan
authors.initials: S
authors.lastname: Burkholder
authors.forename: Rhonda
authors.initials: R
authors.lastname: Walters
authors.forename: Pramila
authors.initials: P
authors.lastname: Anne
authors.forename: Edith
authors.initials: E
authors.lastname: Mitchell
authors.forename: Robert
authors.initials: R
authors.lastname: Fry
authors.forename: Bruce
authors.initials: B
authors.lastname: Boman
authors.forename: Deborah
authors.initials: D
authors.lastname: Rose
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
authors.forename: Walter
authors.initials: W
authors.lastname: Curran
authors.forename: Juan
authors.initials: J
authors.lastname: Palazzo
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D017024:Chemotherapy, Adjuvant; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin