title: Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer.
abstract: OBJECTIVE
  Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non-small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers. Abnormalities of EGFR and related pathways may have an effect on responsiveness of advanced colorectal cancer to combination chemotherapy with gefitinib.
  
  
  METHODS
  We examined patients with previously untreated metastatic colorectal cancer, who were enrolled into two phase I/II trials of combination chemotherapy (irinotecan, leucovorin, and 5-fluorouracil) and daily oral gefitinib. We obtained paraffin tissue blocks of primary tumors from 31 patients, sequenced the EGFR, KRAS, and BRAF genes, and did immunohistochemistry for EGFR, phosphorylated AKT1, p53, p21, and p27.
  
  
  RESULTS
  Twelve (39%) of the 31 patients experienced a partial objective response to the therapy. A novel EGFR mutation in exon 18 (c.2170G>A, p.Gly724Ser) was identified in only one patient who did not experience an objective tumor response. EGFR immunohistochemistry was not predictive of responsiveness. In contrast, loss of p21 was associated with a higher response rate to therapy (P = 0.05). Moreover, the response rate among patients whose tumors maintained p21 expression and possessed a mutation in p53 was only 9% (1 of 11, P = 0.005). Overexpression of phosphorylated AKT1 also seemed to predict a trend towards resistance to the therapy.
  
  
  CONCLUSIONS
  p21 expression in colorectal cancer, especially in combination with p53 mutation, is a predictor of resistance to the combination chemotherapy with gefitinib. Activating EGFR mutations are rare in colorectal cancer and do not seem to confer sensitivity to gefitinib and chemotherapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Mami
authors.initials: M
authors.lastname: Cantor
authors.forename: Mohan
authors.initials: M
authors.lastname: Brahmandam
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Chungdak
authors.initials: C
authors.lastname: Namgyal
authors.forename: Takako
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Kate
authors.initials: K
authors.lastname: Kinsella
authors.forename: Ann L
authors.initials: AL
authors.lastname: Michelini
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D018797:Cell Cycle Proteins / Q000032:analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis; D018631:ras Proteins / Q000032:analysis / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077146:Irinotecan; D066246:ErbB Receptors; C494918:AKT1 protein, human; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; D002955:Leucovorin; D000077156:Gefitinib; D005472:Fluorouracil; D002166:Camptothecin