As if there weren't already enough reasons to give up smoking, a new study has revealed yet another: smokers not only develop lung cancer more often than non-smokers, but differences in the genetic make-up of tumours from the two groups mean that those that arise in smokers are less likely to respond to existing targeted therapies.

Gefitinib selectively inhibits the activity of the epidermal growth factor receptor (EGFR) tyrosine kinase and brings about tumour regression in 10–28% of patients with lung cancer. Pao et al. analysed the EGFR sequence in tumours from 10 patients with non-small-cell lung cancer (NSCLC) who showed this response, and a further 7 patients who had shown a similar response to a related drug, erlotinib. Of the 17 tumours, 12 (∼71%) had mutations in EGFR, consistent with the results of previous studies that alterations in this gene are associated with a good response to gefitinib, and indicating that the same holds for erlotinib.

Importantly, 75% of the tumours with EGFR mutations were taken from patients classified as 'never smokers' — that is, people who have smoked fewer than 100 cigarettes in their lifetime — and showed an adenocarcinoma histology that is typical of NSCLCs from these patients.

To extend these results, the authors carried out a prospective study of EGFR mutations in adenocarcinomas resected from never smokers. They found that 7 out of 15 of these tumours (∼47%) carried mutations in the EGFR tyrosine kinase domain. By contrast, for tumours selected at random from current or former smokers, just 5% carried this type of mutation, three-quarters of which were tumours from patients who had given up smoking at least 30 years before surgery. These patterns of EGFR mutation indicate that tumours in never smokers are far more likely to respond to gefitinib and erlotinib than those that arise in smokers.

These results provide a molecular basis for previous findings that never smokers show better responses to treatment with gefitinib. However, as only ∼10% of lung cancers arise in this group, the most important challenge for the future will be to develop new therapeutic strategies that are effective against the vast majority of lung tumours, which develop in smokers and do not carry EGFR mutations.