Epidemiology and Global Trend of Adenocarcinoma

Professor Tony Mok

Dept of Clinical Oncology

The Chinese University of Hong Kong

Rising incidence in adenocarcinoma?

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 ratio of adenocarcinoma vs SCC

Change in Percentage of Adenocarcinoma Subtype in Asia

Japan Hong Kong

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

Percentage of Adenocarcinoma in Female European (80’)

A global trend towards an increase in both the total number and proportion

of adenocarcinoma. WHY?

Adenocarcinoma in smoker

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

Filtered cigarette in USA Market

95%

Smoking-Related Lung Cancer Cell Type (Male)

Morabia A Cancer 68:2074, 1991

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

Adenocarcinoma in non-smoker

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

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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

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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

Oncogene in Chinese Patients with NSCLC

An SJ,…Wu YL Plos ONE 7(6):e40109

Genome profile of smoker vs non-smoker adenocarcinoma in China

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??

What are other potential explanations for change in incidence of adenocarcinoma in

non-smoker?

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 classification and pathological technique

Charloux et al Int J Epidemiology 26:14, 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