Risk factors of non-smoking lung cancer

Po-Yin Chang

Lung cancer in US• The leading cause of cancer, estimated in

2009: – Estimated 219,440 new cases– Mortality: 1st rank in both men and women– 2nd rank in incidence (15%) in both genders

Lung & bronchus 30%

Prostate 9%

Colon & rectum 9%

Pancreas 6%

Leukemia 4%

Liver & intrahepatic bile duct 4%

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin lymphoma 3%

Kidney & renal pelvis 3%

All other sites 25%

26% Lung & bronchus

15% Breast

9% Colon & rectum

6% Pancreas

5% Ovary

4% Non-Hodgkin lymphoma

3% Leukemia

3% Uterine corpus

2% Liver & intrahepatic bile duct

2% Brain/ONS

25% All other sites

Men292,540

Women269,800

Estimated Cancer Mortality, 2009

ONS: Other nervous system

American Cancer Society, 2009.

Lung cancer worldwide

• The proportion of lung cancer patients in developing nations increased from 31% to 49.9% in the last two decades

• 15% of men and 53% of women with lung cancer worldwide are never smokers

• Geographic differences: the proportion of lung cancer of never smoking women:– 83% in Asian countries, 15% in US

Pathological features among non-smoking lung cancer patients

• Adenocarcinoma, especially bronchioloalveolar carcinoma

• Asian ethnicity• Female• Better response to Epithelium Growth Factor

Receptor (EGFR) Tyrosine Kinase (TK) inhibitors, such as erlotinib and gefitinib

Etiologic factors and molecular features

• Several etiologic factors have been proposed:– Occupational and environmental factors:

exposure to radon, asbestos, heavy metals– Cooking fumes– Environmental tobacco smoke – Human papilloma virus (HPV) infection– Inherited genetic susceptibility

• Molecular features– EGFR mutations, p53 mutations, K-ras mutations

Environmental tobacco smoke (ETS)

• ETS exposure from spouses and workplace resulted in an excess risk of 20% for developing lung cancer in never smokers

• 2 meta-analyses: never smokers with smoking spouses had greater risks of lung cancer than those with non-smokers spouses– ETS ↑35% lung cancer risk in men, 25% in women

Environmental tobacco smoke (ETS)

• Population-based prospective study, including 28,414 lifelong non-smoking Japanese women – Hazard ratio for LC incidence in women with a

smoking husband was 1.34 [.81 – 2.21]– Lung adenocarcinoma:

• Current smoking husband: ↑risk of lung adenocarcinoma, current v.s. never: 2.03 [1.07–3.86]

• Dose-response relationships: both the intensity and the amount of the husband’s smoking are related to the increased risk

Exposure to cooking fumes

• A meta-analysis reported an increased risk of lung cancer in China– Exposure to domestic coal for heating and cooking – Indoor exposure to coal dust and chronic exposure to

cooking oil vapor, though publication bias might affect these two factors

• More cooking dish-years, higher the OR of lung cancer– Different frying methods: deep-frying have the highest

risk

EGFR mutations

• Somatic EGFR mutations: – Predictors of response to EGFR tyrosine kinase

inhibitors, such as gefitinib and erlotinib, especially among non-smokers than smokers with NSCLC

– Researchers found more activating mutations in the EGFR-TK domain in never smokers than smokers lung cancer patients

J Clin Oncol 2007;25:561

The EGFR-signaling pathway and potential sites for inhibitor activity

Hodkinson P S et al. Chest 2008;133:1209-1216

©2008 by American College of Chest Physicians

Site 1: CetuximabSite 2: ErlotinibSite 3: Downstream signaling inhibitors

Molecular features

• K-ras mutations:– More frequently seen in lung adenocarcinoma– More frequently detected among smokers– Less common in Asian patients– Never smokers: G to A transition; smokers: G to T

or G to C transversion

• p53 mutations:– 40 to 60% of NSCLC, more frequently reported in

smokers than never smokers

Inherited genetic susceptibility

• Family history of lung cancer was associated with higher risk for female non-smoking lung cancer, OR=5.7[1.9-16.9]– Higher risk was seen if the relative was a woman,

younger than 60 yrs old, adenocarcinoma patients

• A Major susceptibility locus on chromosome 6q23-25– Chromosome 6 includes more than 100 genes, and

some of them are potential candidates for the role of a lung cancer susceptibility gene

Inherited genetic susceptibility

• White, non-smoking lung cancer: – Cytochrome P450 1A1 polymorphism Ile463Val: ↑3

folds of risk– The effect of 1A1 polymorphism is strong especially

among adenocarcinoma patients and patients with glutathione-S-transferase M1 (GSTM1) null genotype

• Japan, non-smoking female lung cancer cases– GSTM1 null genotype: associated with an increased

risk of lung cancer, OR=1.37[.9-2.09]

Hormonal status

• Estrogen receptor(ER) α and β are detected in lung normal and cancer tissue in both gender – ERβ is more frequently expressed in lung tissue,

detected more commonly in never smokers than smokers, more in women than men

• Some studies show the higher intratumoral estradiol level in NSCLC, which increase the growth of ERα/β among these NSCLC patients

• Role of hormone replacement therapy (HRT)?

Hormonal status:Controversial role of HRT

• Interaction between estrogens and tobacco carcinogens– Lower median age at lung cancer diagnosis, a shorter

median survival time in women with HRT around the time of diagnosis

– The effect was more evident in smoking than nonsmoking women

• However, inverse relationship was observed between HRT use and NSCLC risk in post-menopausal women with ER positive lung tumor

HPV infection

• HPV 16/18 DNA was detected in 77(54.6%) of 141 lung cancer patients

• Higher prevalence of HPV DNA in lung cancer patients of Asian ethnicity, not in Caucasians

• HPV is acquired through the oral cavity by prenatal or sexual transmission

Summary• Environmental tobacco smoke • Cooking fumes• Molecular features

– EGFR mutations, p53 mutations, K-ras mutations

• Inherited genetic susceptibility• Hormonal status• Human papilloma virus (HPV) infection• Occupational and environmental factors

– exposure to radon, asbestos, heavy metals

Conclusion• Lung cancer in never smokers is a distinct

disease with unique molecular and biologic characteristics

• Incidences are different across the globe• The unique genetic and epigenetic markers

suggest a separate but overlapping carcinogenesis pathway

• Tobacco smoking should be discouraged for sure

References

• Subramanian J, and Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007; 25: 561-70

• Scagliotti GV, Longo M, and Novello S. Nonsmall cell lung cancer in never smokers. Curr Opin Oncol 2009; 21: 99-104

Thank you

2009 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2009.

Men766,130

Women713,220

27% Breast

14% Lung & bronchus

10% Colon & rectum

6% Uterine corpus

4% Non-Hodgkin lymphoma

4% Melanoma of skin

4% Thyroid

3% Kidney & renal pelvis

3% Ovary

3% Pancreas

22% All Other Sites

Prostate 25%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Melanoma of skin 5%

Non-Hodgkin5% lymphoma

Kidney & renal pelvis 5%

Leukemia 3%

Oral cavity 3%

Pancreas 3%

All Other Sites 19%