{"entity":{"id":"paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004","kind":"paper","name":"Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib","aka":[],"tldr":"A drug that worked spectacularly in about one patient in ten and did nothing in the rest. Sequencing the tumours of nine responders found the answer: eight of them had a mutation in the gene the drug targets.","summary":"Lynch, Bell, Sordella and colleagues at Massachusetts General Hospital, with Haber as senior author, searched for mutations in EGFR in primary tumours from patients who had responded to gefitinib, patients who had not, and patients never exposed to it, then expressed the mutant proteins in cultured cells to test their function.\n\nIt appeared on the same day as Paez and colleagues' independent report in Science (paper-paez-egfr-mutations-gefitinib-science-2004). Together they are the founding papers of precision oncology in solid tumours: not a new drug, but an explanation of why an existing drug worked in a minority, which converted a failure into a triumph by changing who received it.","asOf":"2026-09-25","links":[{"label":"N Engl J Med 2004","url":"https://doi.org/10.1056/NEJMoa040938"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/15118073/"}],"tags":["lung-evidence"],"related":["paper-paez-egfr-mutations-gefitinib-science-2004","paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009","paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","targeted-therapy-roadmap"],"cancers":["lung-cancer","nsclc","egfr-mutant-nsclc","lung-adenocarcinoma"],"sections":["targeted-therapy","diagnostics"],"technologies":["ngs"],"targets":["egfr"],"drugs":["gefitinib","erlotinib"],"companies":[],"institutions":["mgh"],"pathways":["ras-mapk","pi3k-akt-mtor"],"terms":["driver-mutation","oncogene-addiction"],"trials":[],"people":["thomas-lynch","lecia-sequist"],"bottlenecks":["b-biomarker-validation","b-undruggable-targets","b-translational-valley"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2004,"doi":"10.1056/NEJMoa040938","pmid":"15118073","authors":"Lynch TJ, Bell DW, Sordella R, et al.","paperType":"translational","findings":["Somatic mutations in the tyrosine kinase domain of EGFR were identified in eight of nine patients with gefitinib-responsive lung cancer and in none of the seven patients with no response.","The mutations led to increased growth factor signalling and conferred susceptibility to the inhibitor when the mutant proteins were expressed in cultured cells.","The authors conclude that screening for such mutations may identify the patients who will respond."],"whatItMeans":"The template for every driver mutation since: find the responders, sequence them, and give the drug only to people whose tumour carries the lesion it was built for. Gefitinib had been close to abandonment on the strength of unselected trials.","caveats":["Sixteen patients in the response comparison; the effect size was obvious but the sample was tiny.","It predicts response, not survival: the randomised evidence that selecting by mutation improves outcomes came five years later with IPASS.","The same mutations that confer sensitivity set up the T790M resistance mutation described the following year."],"changedPractice":true},"route":"/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/","neighbours":{"paper":[{"id":"paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005","kind":"paper","name":"EGFR mutation and resistance of non-small-cell lung cancer to gefitinib","route":"/key-papers/paper-kobayashi-egfr-t790m-gefitinib-resistance-nejm-2005/"},{"id":"paper-paez-egfr-mutations-gefitinib-science-2004","kind":"paper","name":"EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy","route":"/key-papers/paper-paez-egfr-mutations-gefitinib-science-2004/"},{"id":"paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009","kind":"paper","name":"Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma","route":"/key-papers/paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}],"cancer":[{"id":"lung-adenocarcinoma","kind":"cancer","name":"Adenocarcinoma of the lung","route":"/cancers/lung-adenocarcinoma/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"oncogene-addiction","kind":"term","name":"Oncogene addiction","route":"/terms/oncogene-addiction/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"drug":[{"id":"erlotinib","kind":"drug","name":"Erlotinib","route":"/drugs/erlotinib/"},{"id":"gefitinib","kind":"drug","name":"Gefitinib","route":"/drugs/gefitinib/"}],"institution":[{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"}],"pathway":[{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"person":[{"id":"lecia-sequist","kind":"person","name":"Lecia V. Sequist","route":"/people/lecia-sequist/"},{"id":"thomas-lynch","kind":"person","name":"Thomas J. Lynch Jr.","route":"/people/thomas-lynch/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-translational-valley","kind":"bottleneck","name":"The valley of death between lab and product","route":"/bottlenecks/b-translational-valley/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}]}}