Lung CancerMolecular Pathology of Cancer Boot CampJanuary 4, 2012Jennifer Rider, ScD

Learning objectives

•Basic descriptive epidemiology•Major risk factors•Historical perspective on establishing

smoking as a causal agent •Key differences in disease among smokers

and non-smokers

Five-year survival rates

ACS Cancer Facts & Figures 2011

Lung Cancer Epidemiology: Risk factors1. Cigarette smoking 2. Environmental tobacco smoke3. Radon4. Occupational exposures

a. Asbestos b. Asbestos x smoking interactionc. Cooking oil vapors and indoor coal burning

5. Ambient air pollution6. Genetic factors

Smoking▫Lung cancer risk depends on:

▫Years smoked▫Age smoking initiated▫Number of cigarettes smoked per day▫Tar/Nicotine

▫Risk roughly proportional to yield (down to one-half risk)

▫BUT negated by compensation in numbers smoked

▫Risk elevated in cigar/pipe smokers▫Amount smoked and inhaling contribute

Constituents of the cigarette

•7000 chemicals▫Carbon monoxide/vapor phase components▫Nicotine▫“Tar” = particulate – (nicotine + water)▫60 carcinogens▫Additives

Selected carcinogens in cigarette smoke•Policyclic aromatic hydrocarbons (PAH):

benzo[a]pyrene•Tobacco-specific nitrosamines (TSNA)•Aromatic amines: 4-aminobiphenyl•Benzene•Arsenic, Nickel, Chromium•Polonium-210

Smoking Cessation• Among individuals who have smoked less

than 20 years• Lung cancer risk reverts to non-smoker level

after about 15 years of cessation.• Among individuals who have already

developed lung cancer• Quitting reduces risks of developing a second

cancer

Lung cancer incidence and trends, and smoking behavior among men – United States

Tobacco Use in the US, 1900-1999

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

Year

Per

Cap

ita C

igar

ette

Con

sum

ptio

n

0

10

20

30

40

50

60

70

80

90

100

Age

-Adj

uste

d Lu

ng C

ance

r D

eath

R

ates

*

*Age-adjusted to 2000 US standard population.

Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

Per capita cigarette consumption

Male lung cancer death rate

Female lung cancer death rate

0%5%

10%15%20%25%30%35%40%45%

% s

mo

kers

Current smoking prevalence in US, 1965-1998

Smoking prevalence by sex

0%

10%

20%

30%

40%

50%

60%

70%

World East Asia/Pacific

U.S.

Men

Women

1933: JAMA begins to accept advertising for cigarettes

“Just as pure as the water you drink…and practically untouched by human hands.”

--Chesterfield advertisement, NY State

Journal of Medicine, 1933

“The following hints may prove helpful. In combination they are nearly perfect and 99 44/100% of the nicotine will go into the filter or your friends’ faces.” Consumer Reports, 1938

Barriers to acceptance of smoking-lung cancer relationship•Ecologic data - other plausible

alternatives•Smoking common in scientific community•Influence of tobacco companies•Novelty of epidemiological techniques•Strength of infectious disease model

▫Necessary and sufficient causes▫Isolate and identify agent▫Laboratory/animal evidence key▫Smoking associated with multiple diseases

A new model of causality

•Bradford Hill’s guidelines▫Strength of association▫Consistency▫Specificity▫Temporal sequence▫Dose-response/biologic gradient▫Biological plausibility▫Coherence▫Experimental evidence▫Analogy

•Active smoking accounts for 90% of lung cancer deaths, but only 10% smokers develop lung cancer

SmokingGenetic

Polymorphisms

Lung cancer risk

Lung Cancer Subtypes

•Squamous cell carcinoma•Adenocarcinoma•Large-cell carcinoma•Small-cell undifferentiated carcinoma

>90% of Lung

Cancers in US

Primarily adenocarcinoma

Primarily SCLC and squamous cell carcinoma

Sun et al., Nature Reviews Cancer 2007

Lung Cancer in Never Smokers

•Estimated 25% of lung cancers not attributable to smoking▫15% among men▫53% among women

•7th leading cause of cancer death worldwide

•Only relatively weak risk factors identified•Distinct histological, geographical and

gender distribution

Sun et al., Nature Reviews Cancer 2007

Proportion of Lung Cancer in Never Smokers

Sun et al., Nature Reviews Cancer 2007

Mutation profile among smokers vs. nonsmokers

Sun et al., Nature Reviews Cancer 2007

Gefitinib (Iressa) effectiveness among Asian patients with NSCLC

Lim et al., Br J Cancer 2005