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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , ErbB Receptors/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cell Cycle Proteins/analysis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Cyclin-Dependent Kinase Inhibitor p27 , DNA Mutational Analysis , ErbB Receptors/analysis , Female , Fluorouracil/administration & dosage , Gefitinib , Humans , Immunohistochemistry , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Mutation/drug effects , Protein Serine-Threonine Kinases/analysis , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins B-raf/analysis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-akt , Quinazolines/administration & dosage , Treatment Outcome , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Proteins/analysis , ras Proteins/analysis , ras Proteins/geneticsABSTRACT
Chemotherapy options for esophagogastric adenocarcinoma remain limited. Irinotecan has demonstrated broad activity in a variety of epithelial malignancies. Forty-six patients with previously untreated, measurable, unresectable, or metastatic esophagogastric adenocarcinoma were enrolled. Patients received irinotecan (125 mg/m2 intravenously over 90 min weekly) for 4 consecutive weeks followed by a 2-week rest. Forty-three patients received at least one treatment and were evaluable for response and toxicity. One complete and five partial responses were observed, for an overall response rate of 14% (95% CI, 4-24%). Median survival for all 43 patients was 6.4 months (95% CI, 4.6-8.2 months). Grade 3 to 4 toxicity included 10 patients (23%) with neutropenia, 13 patients (30%) with late diarrhea, 6 patients (14%) with vomiting, and 6 patients (14%) with fatigue. We conclude that although single-agent irinotecan is an active agent for esophagogastric adenocarcinoma, the schedule utilized in this trial is associated with moderate toxicity. When used as a single-agent, a tri-weekly schedule may be preferable for this patient population.
