When Non-Smokers Get Lung Cancer

Introduction

Lung cancer can occur in non-smokers. The population trend in lung cancer is changing and this is increasingly recognized worldwide.   In Asia, up to a third of lung cancer patients diagnosed are never smokers while the figures in West are lower.  Intriguingly, there are differences between gender too.  In one of the studies reported, approximately 15% of men compared with 60 to 80 percent of women with lung cancer were never-smokers!

With the regional haze affecting countries like Singapore, Malaysia, Indonesia and Brunei, some patients have asked about the effect of haze on lung cancer. Haze is known to carry small PM 2.5 particles that can penetrate deeper into the bronchi (or lung airways). Fine particulate matter less than 2.5 microns (PM2.5) is an air pollutant that affects people’s health and reduces visibility outdoors. Besides causing a host of health problems affecting the respiratory tract and eyes, studies suggest that long term exposure may be associated with increased mortality from lung cancer and heart disease. People with chronic lung and heart problems, children and the elderly may be particularly sensitive to PM2.5.

Risk factors for non-smoker lung cancer

• Passive smoking

• Environmental exposure to carcinogens such as radon, asbestos, chromium, arsenic etc

• Lung disease with lung damage

• Genetic susceptibility – not conclusive

Our oncology specialist, Dr Leong Swan Swan, is one of the co-authors of a publication in 2006 (Journal of Clinical Oncology) of never smokers with non-small cell lung cancer (NSCLC) in Singapore. Out of 883patients, 68.5% of the never smokers in their study with non-small cell lung cancer were females. The median age at diagnosis for lung cancer in patients who have never smoked was younger than that for current / ex-smokers.

The question of whether genetic susceptibility plays a part is suggested mainly by population-based studies, where some studies have shown an association between lung cancer in non-smokers and a family history of lung cancer. The difficulty is teasing out environmental exposures in these studies with an appropriate control group. With modern DNA technology using genome wide association studies (GWAS), results have been mixed.

The epidermal growth factor receptor (EGFR) is an important gene belonging to the tyrosine kinase family. In non-small cell lung cancer, EGFR mutation is known to be more common in the tumours of never-smokers compared to smokers. Interestingly, some of these mentioned families have germline mutation in the epidermal growth factor receptor which increases their risk for lung cancer. There have been other genes including HER2, reported in these families. There was also reported mutation in EGFR in T790M, a mutation which confers drug resistance.

Different biological types of lung cancer

Many people might consider lung cancer as a single disease but increasingly this is changing. The predominant cell type in non-smokers with lung cancer is adenocarcinoma. In contrast, lung cancer which develop in smokers, although frequently is also of adenocarcinoma cell type, has a higher proportion of squamous cell and small cell subtype.

More importantly, on a molecular basis, there are now clear differences in these lung cancers. These differences are not appreciated by just examining the tumour under a microscope or immunohistochemistry. Molecular analysis with techniques for mutation in specific genes, probes for fusion genes are needed. At OncoCare Cancer Centre, Singapore, we have access to these good quality laboratories that perform these tests with a reasonable turnaround time.

Some of these molecular mutations tested are:

• EGFR  – Epidermal Growth Factor Receptor

• ALK Rearrangement – A fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene

• ROS-1 Gene

Treatment of lung cancer in non-smokers

Can we cure lung cancer in non-smokers? Yes if detected early! Unfortunately, fewer patients with early stage I and stage II lung cancer are diagnosed. Unlike locally advanced and disseminated (stage IV) lung cancer, early lung cancer can be treated with curative intent with aggressive management. In some of these patients with early stage lung cancer, adjuvant chemotherapy or chemo-radiotherapy may further improve survival as well.

The advantage for never smokers in contrast to smokers is that generally, their lung condition is healthier (better pulmonary function).  This allows them to tolerate aggressive treatment like resection of part of the lung (eg, lobectomy, pneumonectomy) better. On the other hand, non-smokers may not suspect that they will ever get lung cancer and diagnosis of lung cancer may be delayed and detected at a more advanced stage, if the suspicion is not high for example, for a persistent cough.

Specific drug or medication used in never-smokers compared with smokers has been best studied in tumours with EGFR mutations. Higher response rates have been reported for EGFR tyrosine kinase inhibiors (TKI) as compared to chemotherapy if the patients have an EGFR mutation. These oral drugs like Erlotinib (Tarceva), Gefitinib (Iressa), Afatanib (Giotrif) have transformed lung cancer treatment, improving outcome and tolerability with good quality of life.  Similar advances have been made with targeted agents against ALK and ROS-1, like Crizotinib and Ceritinib.

“Expert knowledge means better care for cancer”

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