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
Estimated Cancer Mortality, 2009
26%
Men
Women
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%
American Cancer All other sites
Society, 2009.
25%
292,540
Lung & bronchus
269,800
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
ONS: Other
nervous system
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 nonsmoking 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
Site 1: Cetuximab
Site 2: Erlotinib
Site 3:
Downstream
signaling inhibitors
Hodkinson P S et al. Chest 2008;133:1209-1216
©2008
by American College of Chest Physicians
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 postmenopausal 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*
Men
766,130
Women
713,220
Prostate
25%
27%
Breast
Lung & bronchus
15%
14%
Lung & bronchus
Colon & rectum
10%
10%
Colon & rectum
Urinary bladder
7%
6%
Uterine corpus
Melanoma of skin
5%
4%
Non-Hodgkin
lymphoma
5%
Non-Hodgkin
lymphoma
4%
Melanoma of skin
Kidney & renal pelvis
5%
4%
Thyroid
Leukemia
3%
3%
Kidney & renal pelvis
Oral cavity
3%
3%
Ovary
Pancreas
3%
3%
Pancreas
19%
22%
All Other Sites
All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2009.