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.

Among patients with metastatic non-small-cell lung cancer, early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival. (Funded by an American Society of Clinical Oncology Career Development Award and philanthropic gifts; ClinicalTrials.gov number, NCT01038271.)

BACKGROUND-Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.

Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non–small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.