title: Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas.
abstract: Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR).
  
  
  METHODS
  We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics.
  
  
  RESULTS
  Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS.
  
  
  CONCLUSIONS
  In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.
authors.affiliation: Department of Gastrointestinal Medical Oncology.
authors.forename: Kanwal P S
authors.initials: KP
authors.lastname: Raghav
authors.forename: Aditya V
authors.initials: AV
authors.lastname: Shetty
authors.forename: Syed M A
authors.initials: SM
authors.lastname: Kazmi
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Morris
authors.forename: Melissa
authors.initials: M
authors.lastname: Taggart
authors.forename: Keith
authors.initials: K
authors.lastname: Fournier
authors.forename: Richard
authors.initials: R
authors.lastname: Royal
authors.forename: Paul
authors.initials: P
authors.lastname: Mansfield
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001063:Appendiceal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000068579:Celecoxib; D000068818:Cetuximab; D051546:Cyclooxygenase 2 / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000627:therapeutic use; D012189:Retrospective Studies; D013449:Sulfonamides / Q000627:therapeutic use; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D000077544:Panitumumab; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068579:Celecoxib; D000068818:Cetuximab
keywords: Appendix adenocarcinoma; COX-2; Celecoxib; Cetuximab; KRAS; MSI