Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer

Purpose: Recently, activating mutations of the epidermal, growth factor- receptor (EGFR) gene 9 I e discovered in, non -small cell lung- cancers sensitive to gefftinib, (ZD1839, an EGFR tyro-. sine kinase inhibitor) but I 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, phosphohorylated AKT1- p53, p21, and p27. Results: Twelve (39%) of the 31 patients experienced. a partial objective response to the therpy ) was identified in only one apy. A novel EGFR -mutation in exon 18 (c. 21760G>A, p,Gly724Ser) 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). Overexpresssion 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 to confer sensitivity to gefitinib and mutations are, rare. in colorectal cancer and do not seem chemotherapy.