The Lung Cancer Epidemic: is there anything we can do?

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The Lung Cancer Epidemicis there anything we
can do?
Diana C. Márquez-Garbán
University of California, Los
Angeles Division of Hematology-Oncology
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Acknowledgements
National Program Excellent University EU/Slovakia
Dr. Martina Nebohácová
National Program Excellent University EU/Slovakia
UCLA Richard J. Pietras Hermes J.
Garbán Hsiao-Wang Chen Olga Weinberg Edward
Garon Eugene Tsai Jeison Recinos
UCLA Lung Cancer SPORE Program Dr. Steven Dubinett
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Global Incidence

• 1.3 million deaths/year worldwide.
  
• Lung cancer kills more people than any other
  cancer
• Number one killer in men and second in women
• 5 year survival still at 14
• Risk factors radon, asbestos, air pollution

Tobacco smoke responsible for 87 of cases of
Lung Cancer
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Smoking and Lung Cancer History

Phenomenal increase in the number of deaths
attributed to cancer of the lung (1922-1947)
Cigarette smoking is related to Lung Cancer
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Death rate from lung cancer and consumption of
tobacco (1900-1950)
Lung Cancer
Tobacco
Cigarettes
Doll et al. British Medical Journal (1950)
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Death rates from lung cancer and consumption of
tobacco (1880-2000)
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Smoking prevalence for men in Slovakia
The Tobacco Atlas, WHO, 2002
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Smoking prevalence for women in Slovakia
The Tobacco Atlas, WHO, 2002
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Toxic chemicals in tobacco smoke
Nicotine the addictive agent in tobacco
smoke Formaldehyde used in preservation
of laboratory specimens Ammonia used in
toilet cleaner Hydrogen Cyanide used in
rat poison Acetone used in nail polish
remover Carbon monoxide - found in car
exhaust Tar - particulate matter in
cigarette smoke Toluene - found in paint
thinners Phenol used in fertilisers.1,2
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Smoking Damages Virtually Every Part of the Body
Smoking
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Second-hand smoke also does
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Normal and Smokers lung
Normal
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Tobacco Is a Risk Factor for 6 of the Worlds 8
Leading Causes of Death
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Lung Cancer Facts
Myth Lung cancer is a mans disease. Fact
The incidence of lung cancer in men has been
leveling off in recent years. In women, however,
the incidence is rising rapidly.
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Lung cancer among women at epidemic proportions
Age-adjusted death rates for lung cancer and
breast cancer among women, US, 1930-1997.
600 increase in death rate in 50 years
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1960 First brand specifically manufactured for
women
Virginia Slims You've come a long way, baby"
"It's a woman thing "Find Your Voice
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Virginia Slims remembers when a woman carried
more weight than a man
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Marketing campaigns targeted women with the
social pressures they face


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Women who smoke like men, die like men
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Classification

• Non-Small Cell (85)
• Adenocarcinoma 40 of all cases
• Most common among women
• Squamous
• Large Cell

• Small Cell
• Related to Smoking
• More Aggressive than NSCLC

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Lung Cancer
Symptoms Persistent cough Hoarseness Change in
color (blood) or amount of sputum Recurrent
pneumonia, bronchitis Diagnosis Radiology Chest
X-ray, CT scan, MRI scan, PET scan Biopsy
Needle, bronchoscope-directed, open surgical
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Lung Cancer
X-ray
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Staging and Treatment of Lung Cancer
Stage I Early Surgery Stage II
/- Radiation Stage III /-
Chemotherapy
Stage IV Advanced Chemotherapy
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Non-small Cell Lung Cancer

• Staging
• Estimate prognosis
• Guide treatment decisions
• 70 present with advanced locoregional or
  metastatic involvement
• Stage IIIA, IIIB, or IV
• 5 year survival 1-25

Ginsberg RJ, et al. Cancer Principles and
Practices of Oncology. 5th ed. 1997858-911.
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Lung Cancer One Name, Many Diseases

• Heterogenous disease
• Smokers vs. non-smokers
• Women vs men
• Epidemiologic findings suggest women more
  susceptible than men to the effects of tobacco
  smoke (Henschke C, JAMA 2006)
• Women develop the disease at an earlier age and
  with less reported tobacco exposure than men
• Among non-smokers, women are particularly
  vulnerable to lung cancer (80 of cases) ?
• Women increasing incidence

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Do Hormones Influence Lung Cancer Progression?

• Estrogen contributes to normal lung development
• Association of estrogen levels and lung cancer
  survival
• Serum estrogen elevated in women with lung cancer
  compared to similar age without lung cancer
  (Tiuriunova et al, 1986)
• Hormone replacement therapy and lung cancer
  survival
• Lung epithelium express ER-? and ER-?
• Receptors are active
• Lung epithelium produce estrogen (via aromatase)
• Estrogen stimulates proliferation in vitro and in
  vivo

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Cell functions and alterations
In vitro cell models
In vivo tumor xenografts in mice
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Estrogen Receptor Membrane and Nuclear Actions
in Tumor Growth Regulation
Gruber et al. New Engl J Med (2002)
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Antibodies to ERa and ERb React with Nuclei and
Membrane-Cytoplasmic Sites in NSCLC Cells in
vitro
ERa ERb
Non-Permeabilized
FITC-conjugated secondary antibody to primary
C-terminal or N-terminal ER antibodies
Permeabilized
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Estrogens stimulate growth of non-small cell
lung cancer
Estrogen enhances NSCLC proliferation
several-fold
(Stabile et al. 2002, 2004 Pietras et al. 2005)
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Estrogen Receptor a and Estrogen Receptor b
Expression in NSCLC from the Clinic
Extra-nuclear localization
Nuclear localization
ER-alpha
ER-beta
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Estrogen signaling interacts with EGFR/HER
pathways
EGFR/HER
estrogen
shc
Faslodex (ICI 182,780)
ER
TKI (Erlotinib/Gefitinib)
MNAR
ER
ARO
cytoplasm
MAPK/AKT
ER
ER
Ligand-independent
Ligand-dependent
P
ER
SRC-3
Growth Survival Angiogenesis
TF
ER
ER
nucleus
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Activated Estrogen Receptor Alpha is present in
NSCLC tumor specimens
S167
S118
A/B
C
E
D
F
C
N
Estrogen receptor alpha serine phosphorylation
ER-phospho S118
ER-phospho S167
88 (15/17 adeno)
80 (16/20 adeno)
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Antiestrogen Faslodex blocks estrogen-induced
growth
tumor xenograft nude mice
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NSCLC Tissue Microarray
Standard Histologic Block
Tissue Cores
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Lung tumor microarray tumor aromatase and
survival
Low Aromatase
Low Aromatase (blue curve)
High Aromatase
High Aromatase (red curve)
Survival probability in postmenopausal women with
Stage I/II NSCLC and tumor aromatase expression
(Plt0.038)
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What can we do?
Tobacco is the worlds single most avoidable
cause of death
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Most Countries Have Not Implemented Effective
Tobacco Control Policies
WHO Report on the Global Tobacco Epidemic, 2008
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In the 20th century the tobacco epidemic killed
100 million people worldwide
During the 21st century, it could kill 1,000
million
WHO Report on the Global Tobacco Epidemic, 2008
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We must become the change we want to see Mahatma
Gandhi (1869-1948)
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Lung Cancer Facts
90 of new smokers begin as teenagers one third
of these new smokers will eventually die of
tobacco related diseases.
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1970-today advertising with so-called light
and low-tart
Tobacco companies use lies cigarettes with
reduced risk
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Risks men are not exposed to

• Birth Control Pill- Increased risk of heart
  attack and stroke
• Mother to be- baby likely to be under weight
• Smoking reduces fertility
• Reach menopause earlier than non smokers
• Higher risk of osteoporosis
• Increased risk of cervical cancer

Stopping - Improves weight of baby - After 2y
risk of HA and stroke decrease
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Myths about smoking

• It won't happen to me.
• Its not like I am hurting anyone but myself.
• I'm not hooked. I can stop anytime I want.
• 4 Sure I smoke, but at least I don't do drugs,
  have unsafe sex, or get drunk.
• 5 Its better to smoke because if I quit, Im
  going to get fat.
• 6 I smoke "light" cigarettes, so I won't get
  hurt as much.
• 7 I've tried to quit, but I can't.

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Second Hand Smoke

• It causes heart disease and lung cancer
• Exposed at home or work- Increased risk of lung
  cancer and heart disease
• People with heart disease at increased risk of HA
• Even brief exposure can be dangerous

• In children
• Respiratory symptoms in children and slows the
  growth of their lungs
• Sudent infant death syndrome, acute respiratory
  infections, ear problems and worsens asthma

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Advertisement from Australian campaign to prevent
smoking in teenagers Every cigarette is doing
you damage