Lung Cancer.pdf

288 W.N. Hittelman, J.M. Kurie, and S.G. Swisher
but might not become physiologically important (or be selected for) until
other cellular changes have occurred (e.g., the ability to grow outside the
normal lung environment). This notion could explain why some genetic
changes are found more frequently in lesions thought to be early in the tumorigenesis
process whereas other genetic changes are not usually detected
until later in the tumorigenesis process.
Implications of Molecular Changes
for Risk Estimation, Monitoring of Response
to Chemopreventive Interventions, Early Detection,
and Characterization of Newly Diagnosed Lesions
The burden of lung cancer on the human population could be reduced
through measures that interfere with factors that initiate and drive the
lung tumorigenesis process (e.g., smoking cessation and chemoprevention).
Another method proposed for reducing the burden of lung cancer is
early detection of tumors, when the likelihood of definitive treatment may
be greater. However, clinical studies to examine the impact of chemopreventive
or early detection measures are hampered because of the difficulty
of identifying individuals with a high lung cancer risk. For example, while
chronic smoking significantly increases lung cancer risk, only approximately
10% of long-term smokers will develop lung cancer in their lifetime.
As a result, chemoprevention trials using cancer incidence as a primary
end point require tens of thousands of study participants and tens of
years of follow-up for adequate statistical analysis. Similarly, even if physical
tests such as spiral computed tomography (spiral CT) are one day
proven effective in detecting early-stage lung lesions, tens of thousands of
individuals would have to be screened to identify sufficient numbers of
individuals with detectable (and relevant) lung lesions to permit examination
of the value of early detection in decreasing the morbidity of lung
cancer. Strategies are therefore needed to identify individuals at high risk
for lung cancer, to evaluate the response of the lung to chemopreventive
intervention, to improve the physical detection of early lesions, and to
characterize the lung lesions identified by sensitive imaging techniques.
Risk Estimation
Since lung tumorigenesis is a multistep genetic process, one approach to
estimating lung cancer risk is to examine lung tissue for molecular changes
commonly associated with lung cancers. Theoretically, individuals with
the highest number of molecular changes in their lung tissue would be at
the highest risk for lung cancer development. Indeed, when normal and
premalignant lesions in resected lung tumor specimens are molecularly
characterized, clonal molecular changes are detected involving genes com-