Lung cancer has always been viewed as a smoker’s disease as smoking is undoubtedly the most important known risk factor. Thus, not much attention has been paid to the never-smokers afflicted with this disease.

However, the truth is that the number of never-smokers with lung cancer is not insignificant, especially in Asia. There have been various reports that a high proportion of lung cancer patients among the Asians, especially Chinese women, are never-smokers. About 10-15% of lung cancers occur in lifetime never-smokers in the West while about 30-40% of lung cancer patients are never-smokers among the Asian countries.

In a review of 883 patients with non-small-cell lung cancer (NSCLC) seen at the Outram Institute, 269 (30.5%) were females and among the females, 196 (68.5%) were never-smokers. Table 1. Thus, female never-smokers DO get lung cancer and the point to note is that the problem is not small.

	Smoking status			p -value
	Current	Former	Never
Gender (n = 883) Male Female	397 (88.0) 54 (12.0)	127 (87.0) 19 (13.0)	90 (31.5) 196 (68.5)	< 0.001

Table 1. Sex distribution of 883 NSCLC patients seen at Outram Institute from 1999 to 2002

Are there differences between never-smokers and smokers with lung cancer?

Many epidemiological studies have found that the characteristics of lung cancer among never-smokers are different from that of smokers. Consistent findings include higher proportion of women, adenocarcinoma, as well as an earlier age at diagnosis among the never-smokers.

In our review, we also found that never-smokers with lung cancer had better survival compared to smokers, after adjusting for sex, performance status, stage, co-morbidities, significant weight loss and treatment. Fig. 1.

Fig 1. Kaplan-Meier survival curves based on smoking status

All these differences suggest that lung cancer in never-smokers may be biologically different and inherently more indolent when compared to the smokers. Furthermore, the underlying genetic alterations in the lung tumour tissues are also different between the two groups, with a higher incidence of epidermal growth factor receptor (EGFR) mutations among the never-smokers and more K-ras mutations among the smokers.

Preliminary work at our centre performing gene expression profiling of newly diagnosed lung cancer patients demonstrate a clear delineation between smokers and non-smokers that is independent of histology. Hopefully, our work may be able to provide more information about the molecular differences between the two groups of patients in the not-so-distant future.

Is it the passive smoke or are there other risk factors for female never-smokers getting lung cancer?

There is definite evidence that passive smoking can increase the risk of lung cancer. More than 50 studies have found an association between passive smoking and lung cancer. The pooled excess risk of lung cancer from exposure to spousal smoking was about 20% for women and 30% for men while exposure to environmental tobacco smoke at the workplace increases the risk to about 12-19%.

However, passive smoking cannot explain all the lung cancer cases among never-smokers as only an estimated 3000 lung cancer deaths in USA were attributable to secondhand smoke, which leaves the majority of cases unaccounted for. Furthermore, molecular differences in tumours between smokers and never-smokers suggest that the causative factor(s) is unlikely tobacco smoke as the same etiological agent should result in similar genomic profiles.

Never-smokers with NSCLC have a median age of diagnosis of lung cancer that is 7 years earlier than smokers. Most early onset cancers have some genetic predisposition and it is conceivable that there may be a genetic component involved in lung cancer carcinogenesis among female non-smokers. Environmental risk factors for lung cancer, other than smoking, include indoor exposure to asbestos, radon, arsenic, chromium, nickel, tar and soot.

However, only a few of these have been studied specifically in never-smokers and furthermore, these are not common in our present environment and the contribution to lung cancer in our population is likely minimal. Other postulated environmental risk factors include the human papillomavirus that was suggested by a Taiwanese study. However, our own study did not support this hypothesis.

Another debatable risk factor is the exposure to cooking oil fumes, which was suggested by a Chinese study. However, this was not duplicated in a study among Singapore Chinese women.

CONCLUSION

Lung cancer can affect both smokers and never-smokers. Whether there are important factors other than smoking contributing to lung cancer among the never-smokers is presently unknown.

The important thing is not to dismiss never-smokers with persistent respiratory symptoms that are suggestive of lung cancer. Lung cancer should not be regarded as just a smoker’s disease.

 

Toh Chee Keong, Consultant
Department of Medical Oncology
National Cancer Centre, Singapore