# EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy

Source: https://onco.cc/key-papers/paper-paez-egfr-mutations-gefitinib-science-2004/  
OnCo record `paper-paez-egfr-mutations-gefitinib-science-2004` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The second of the two 2004 papers that found EGFR mutations. It also explained why Japanese patients responded to gefitinib far more often than American ones: the mutation was simply much more common in Japan.

## Summary

Paez, Jänne, Lee and colleagues at the Dana-Farber Cancer Institute and the Broad Institute, with Meyerson as senior author, sequenced receptor tyrosine kinase genes in non-small-cell lung cancer and matched normal tissue, then looked for the same mutations in responders to gefitinib and in a hypersensitive cell line.

The geographic difference it documented is the paper's second contribution. A response rate that varied by country had been read as a difference in practice or reporting; it turned out to be a difference in the prevalence of a mutation, which is the first demonstration in lung cancer that tumour genotype, not population, explains a drug's performance.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: Science
- Year: 2004
- DOI: 10.1126/science.1099314
- Authors: Paez JG, Jänne PA, Lee JC, et al.
- Findings: Somatic EGFR mutations were found in 15 of 58 unselected tumours from Japan and in 1 of 61 from the United States.; EGFR mutations were found in additional samples from United States patients who responded to gefitinib, and in a lung adenocarcinoma cell line hypersensitive to gefitinib.; No EGFR mutations were found in gefitinib-insensitive tumours or cell lines.
- What it means: Why a drug can look useless in one trial and transformative in another: the trials had different proportions of the patients the drug was for. It is the argument for genotyping before drawing conclusions from a response rate.
- Caveats: Small, unbalanced cohorts (58 Japanese and 61 United States tumours) and a retrospective response comparison.; Sequencing of selected receptor tyrosine kinase genes, not the genome; other drivers in the same tumours were not looked for.; Prevalence estimates from tumour series of that era are not population estimates.

## Sources

- Science 2004: https://doi.org/10.1126/science.1099314
- PubMed: https://pubmed.ncbi.nlm.nih.gov/15118125/

## Connected records

- key papers: [Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/), [Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma](https://onco.cc/key-papers/paper-mok-ipass-gefitinib-pulmonary-adenocarcinoma-nejm-2009/)
- roadmaps: [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](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- cancers: [Adenocarcinoma of the lung](https://onco.cc/cancers/lung-adenocarcinoma/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/)
- targets: [EGFR](https://onco.cc/targets/egfr/)
- drugs: [Gefitinib](https://onco.cc/drugs/gefitinib/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/), [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- people: [Matthew Meyerson](https://onco.cc/people/matthew-meyerson/), [Pasi A. Jänne](https://onco.cc/people/pasi-janne/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Trials do not represent the people who get cancer](https://onco.cc/bottlenecks/b-trial-diversity/)
- journals: [Science](https://onco.cc/journals/science/)

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