Title | Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Ogino S, Meyerhardt JA, Cantor M, Brahmandam M, Clark JW, Namgyal C, Kawasaki T, Kinsella K, Michelini AL, Enzinger PC, Kulke MH, Ryan DP, Loda M, Fuchs CS |
Journal | Clin Cancer Res |
Volume | 11 |
Issue | 18 |
Pagination | 6650-6 |
Date Published | 2005 Sep 15 |
ISSN | 1078-0432 |
Keywords | Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Base Sequence, Camptothecin, Cell Cycle Proteins, Colorectal Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, DNA Mutational Analysis, ErbB Receptors, Female, Fluorouracil, Gefitinib, Humans, Immunohistochemistry, Irinotecan, Leucovorin, Male, Middle Aged, Mutation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Quinazolines, ras Proteins, Treatment Outcome, Tumor Suppressor Protein p53, Tumor Suppressor Proteins |
Abstract | PURPOSE: 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. EXPERIMENTAL DESIGN: 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. |
DOI | 10.1158/1078-0432.CCR-05-0738 |
Alternate Journal | Clin Cancer Res |
PubMed ID | 16166444 |
Grant List | P01 CA55075-13 / CA / NCI NIH HHS / United States P01 CA87969-03 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.