The new england journal of medicine 1260 n engl j med 351;12 www.nejm.org september 16, 2004 by Schnyder et al. did not include subjects with homocysteine levels higher than 13.5 µmol per liter. Studies are needed that will test the efficacy of homocysteine-lowering vitamin regimens containing betaine instead of folate. EGFR Mutations and Sensitivity to Gefitinibto the editor: The important study by Dr. Lynch and colleagues (May 20 issue) 1 suggests that specific mutations in the epidermal growth factor receptor (EGFR) characterize a subgroup of non-smallcell lung cancers that may be highly responsive to gefitinib therapy. Do these mutations predict a greater sensitivity to chemotherapy as well? The overall objective response rate to first-line combination chemotherapy for metastatic non-small-cell lung cancer is about 20 percent. 2 Only tumors from a small cohort of patients who had a response to gefitinib were studied for the specific mutations, but all patients except one had also received prior chemotherapy. Although the authors describe Patient 6 as "representative" of the cohort, the percentage of other patients who previously had a response to chemotherapy is not reported. If the rate of response to first-line chemotherapy was high for the other patients in the cohort who had a response to gefitinib, the specific mutations may be predictive of either chemotherapy or gefitinib sensitivity, thus identifying a distinct subgroup of patients with non-smallcell lung cancer. to the editor: Lynch et al. and Paez et al. 1 report that mutations in the EGFR kinase domain in lung cancers are associated with responsiveness to gefitinib. We performed a mutational analysis of the EGFR kinase region on tumor tissue from nine patients with an event-free survival of more than 24 weeks in our phase 2 trial of gefitinib in patients with glioblastoma. 2 No mutations affecting the amino acid sequence in the kinase region were detected. However, our experience with EGFR immunolocalization in brain and lung tumors indicates that the cytoplasmic and membranous localization of wild-type EGFR and the constitutively active mutant EGFRvIII in brain tumors as compared with only membranous localization in lung tumors supports additional differences in the biology of EGFR between these tumor systems (McLendon R: personal communication). In summary, EGFR in glioblastoma did not have mutations in the kinase region, and any activity of gefitinib in glioblastoma would occur through an alternative mechanism reflective of important pathophysiological differences between glioblastomas and lung carcinomas.

EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

Our data indicate that unlike NSCLC, EGFR kinase mutations are rare in unselected cases of SCCHN within the United States and are not linked to gefitinib or erlotinib responses in SCCHN. Alternative mechanisms, including ERBB2 mutations, may underlie responsiveness in this tumor type.

Purpose: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non^small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. Experimental Design: We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. Results: Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non^small cell lung cancer. We also identified the TKI drug resistance^associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. Conclusion: The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.