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Epidemiology and Global Trend of Adenocarcinoma
Professor Tony Mok
Dept of Clinical Oncology
The Chinese University of Hong Kong
Age Adjusted Incidence Rate of Adenocarcinoma in USA (per 100,000)
Wu JNCI 1986, Dodds JNCI 1986, Travis Cancer 1995
More so in patients<65 year old
More so in patients<65 year old
Age Adjusted Incidence Rate of Squamous Cell Carcinoma in USA (per 100,000)
0
5
10
15
20
25
30
Male 70' Male 80' Female 70' Female 80'
Wu
Dodd
Travis
Wu JNCI 1986, Dodds JNCI 1986, Travis Cancer 1995
Change in Percentage of Squamous Cell Carcinoma Subtype in Asia
0
10
20
30
40
50
60
Watababe Ikeda Chan Lam
Male 70
Male 80
Female 70
Female 80
Japan Hong Kong
Cigarette Filters
• Invented in 1935• Popularized in the 60’• In the 50’, filters were manufactured from
crocidolite asbestosis. Banned since the association with lung cancer and mesothelioma
• Now made from acetalated cellulose• Claims to reduce larger particles including
tars and nicotine
Cancer Cell Type and Lung Airway Compartments
Modified from Sun, Schiller, and Gazdar, Nat Rev Cancer, 7:778, 2007
Squamous Ca
SCLC
Adenocarcinoma
© 2007 Nature Publishing Group
Less large particle may Imply less exposure ofCarcinogen in larger
airways
Less large particle may Imply less exposure ofCarcinogen in larger
airways
Smoking-Related Lung Cancer Cell Type (Female)
At a history of 40 pack-years relative to lifelong nonsmoking, the odds ratio for women was 27.9 (95% confidence interval (CI) 14.9-52.0) and that for men was 9.60 (95% CI 5.64-16.3).
Morabia A Cancer 68:2074, 1991
Increase in tobacco consumption with filtered cigarette
• At a history of 40 pack-years relative to lifelong nonsmoking, the odds ratio for women was 27.9 (95% confidence interval (CI) 14.9-52.0) and that for men was 9.60 (95% CI 5.64-16.3).
• Higher consumption of tobacco in female who switched from non-filtered to filtered cigarette.
Risch H Am J Epidermiol 138:281, 1993
Changes in nature of cigarette
• High nitrate content– Enhances combustion– Increase N-nitrosamines
• Favor– Impact of combusted flavorants is unknown
• Larger puffs with low-yield cigarettes– Inhale more deeply– Puff volume at 55ml at 5 times per minutes
Summary on smoking-related adenocarcinoma
• A trend toward increase in adenocarcinoma of lung in smoker
• Cigarette filter and modified tobacco contributed to the higher incidence– Exposure of carcinogens to lower airway– Deeper and larger puffs
Lung Cancer in Never Smokers
Squamous Cell Ca (~35%)
Adenocarcinoma (~45%)
Predominance of Adenocarcinoma Histology
SCLC (~20%)
Per
cent
age
0
20
40
60
80
Smokers(n = 21,853)
Never Smokers(n = 5,144)
Adenocarcinoma
Squamous Cell Ca
Modified from Sun, Schiller and Gazdar, Nat Rev Cancer, 7:778, 2007
0.4:1 3.4:1
Change in cigarette consumption in USA
Rise in incidence of adenocarcinoma despite the
decline in tobacco consumption
Rise in incidence of adenocarcinoma despite the
decline in tobacco consumption
Adenocarcinoma in non-smoker
• USA– Rising incidence in non-smoker but histologic subtype were not
available– Detection bias not clear from older studies
• Asia– Denial of smoking history in female population– Only two small studies suggested a rise in incidence of
adenocarcinoma
Wu JNCI 74:747, 1985; Kabat G Cancer 755, 1984; Koo Int J Epidermiol S14, 1990
Smoker Non-smoker
Male (USA) 25-33% 31-54%
Female (USA) 33-43% 49-73%
Female (Asia) 29% 64-80%
Impact of rising incidence of adenocarcinoma in China: 2000–2005
No. of new cases % of change
Age-standardised mortality rates (per
100,000)
2000 2005 2000 2005
Male 261,839 332,286 26.9 43.0 49.0
Female 119,648 165,622 38.4 19.1 22.9
64-80% non-smoker
Yang et al Can Epi Bio Prv 14(1):243<2005 Parkin et al CA Cancer 55:74, 2005
Lung Cancer not related to smoking in China
25% of male lung cancer were not smoking related
25% of male lung cancer were not smoking related
72% of female lung cancer were not smoking related
72% of female lung cancer were not smoking related
Wang et al Cancer Causes and Control 21:959, 2010
Majority of lung cancer in non-smokers are adenocarcinoma and total number of lung cancer is increasing, but there is no
definite evidence of increase in proportion of adenocarcinoma
Carcinogenesis of adenocarcinoma in non-smoker:Atypical adenomatous hyperplasia (AAH)
Modified from Gazdar et al, in press Lancet Oncology 2009
• AAH in 23-35% of adenocarcinomas vs. 3-7% of squamous cell ca (Nakanishi et al Br J Cancer, 1990; Chapman et al, Br J Cancer, 2000)
BAC Adenocarcinoma
Atypical AdenomatousHyperplasia (AAH)
Lung Cancer in Never SmokersDifferent Molecular Pathways
0
10
20
30
40
50
60
70
80
TP53(n=137)
KRAS(n=846)
Mutations1
Per
cent
age
SmokersNon Smokers
71%
48%
21%
4%
1 Modified from Sun et al, Nat Rev 7:778, 20072 Modified from Riely et al, Clin Cancer Res 14:5731, 2008
0
5
10
15
20
25
30
35
40
45
50
G-T and A-G at CpG sites
G-A Transition
Pe
rce
nta
ge
TP53 Mutations (n=137)1
0
10
20
30
40
50
60
70
80
90
100
G-A Transition
G-T / G-C Transversion
Pe
rce
nta
ge
KRAS Mutations (n=482)2
EGFR versus KRAS Driven Lung Cancer
Sun et al Nat Rev Cancer, 7:778, 2007
Never SmokerEGFR Signaling Pathway
SmokerKRAS Signaling Pathway
Meta-analysis of Risk Factors in Never Smokers
Risk Factor Risk (Hazard Ratio with 95% CI)
Meta-analysis
Cooking Fume 2.12 (1.81 to 2.47) 7 studies from China/Taiwan
Environmental Tobacco Smoking
1.21 (1.13-1.30) 44 case-control studies
Coal burning 2.66 (1.39 to 5.07) 7 studies from China/Taiwan
Family History 1.51 (1.11 to 2.06) 28 case control studies
Report of US Surgeon General 2006, Zhao Total Environ 366:500, 2006Matakidou et al Br J Can 93:825, 2006
What is the genetic factor that predispose non-smokers to develop
adenocarcinoma of lung??
What is the genetic factor that predispose non-smokers to develop
adenocarcinoma of lung??
Change in Environmental Tobacco Smoking
• Increase in tobacco consumption from 60’ to 80’ may indirectly increase spousal exposure to environmental tobacco smoking
• Non-smoking female spouse of male smoker had about 30% increase in risk of lung cancer (OR 1.30)
• No difference between adenocarcinoma (OR 1.29) and non-adenocarcinoma (OR 1.37)
Fontham JAMA 271:1752, 1997
Change in diagnostic procedure
• Adenocarcinoma is previously under-diagnosis – 43 of 153 lung cancer only diagnosed post mortem (30% in non-smoker vs 8% in
smoker)
• Advances in fibro-optic bronchoscopy and needle aspiration– 53-75% of adenocarcinoma present a peripheral
nodule, and routine needle biopsy started only in 1980
1961 Rigid Bronchoscopy
Surgery Autopsy
Adenocarcinoma 2% 10% 28%
Squamous cell carcinoma
42% 54% 35%
Theros AM Roentgen 128:893, 1983; Whitewell BJC 15:440, 1961
Summary
• Global trend in increase in incidence of adenocarcinoma• Increase in adenocarcinoma in smokers
– Cigarette filter and higher consumption contribute to the increase
• Increase in adenocarcinoma in non-smokers– Major of non-smoker lung cancer is adenocarcinoma but no
definite evidence on rising proportion– Etiology and carcinogenesis of adenocarcinoma involve
distinguish molecular change– Environmental factors contribute the increase but real reason is
not known– Diagnostic bias exists
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