Overview of lung cancer etiology, incidence, and treatment

Pathologists have described various different his-
tologies of lung cancer. There are two major sub-
types: small cell lung cancer (SCLC), and nonsmall
cell lung cancer (NSCLC). SCLC accounts for 25%of
lung cancer cases in the United States, and NSCLC
accounts for the remaining 75%. NSCLCs can be
further subdivided into several subtypes: adenocar-
cinoma (Ad), squamous cell carcinoma (SCC), large
cell carcinoma (LCC), bronchioalveolar carcinoma
(BAC), and variousmixed subtypes.While this clas-
sification system is based on histology, there are sig-
nificant molecular differences between SCLC and
NSCLC. Thus, there is an ongoing effort to describe
these differences in terms of mRNA expression pro-
files as well as the acquired genetic and epigenetic
changes between the different subtypes. There are
significant clinical differences in terms of prognosis
and treatment strategies for the different subtypes.
Therefore, another effort is directed at determin-
ing if specific molecular abnormalities predict stage
and prognosis as well as the different responses to
chemotherapy and radiation therapy well described
in patients.
We need to understand the molecular differences
between tumors arising in current smokers, for-
mer smokers, and lifetime never smokers. Are there
different acquired molecular abnormalities in lung
cancers arising in women and men or in persons of
different ethnicity or age? Can we use the molec-
ular abnormalities found in lung tissue, sputum,or those shed into the blood as aids for very early
diagnosis or learning who is at the highest risk for
developing cancer? These patients would be can-
didates for extensive screening and early detection
efforts. Could some of the changes be targets for de-
veloping tumor-specific vaccines or targeting drugs
to specific molecular abnormalities for therapeutic
purposes? A molecular diagnostic platform was re-
cently approved for use in breast cancer, and similar
designsmust be developed for use in suspected lung
cancer cases. Possible targets for these platforms in-
clude altered gene expression patterns, serum pro-
tein profiles, and aberrantly methylated DNA.
Although it seems intuitive that the large mass
of tumor cells that make up the bulk of the tu-
mor should be the target of cancer drugs, recent
evidence suggests that this bulk tumor cell popu-
lation may be less important to tumor progression
than a rare cancer stem cell that can self-renew,
initiate invasion, and propagate metastases. These
cancer stem cells are often less sensitive to cytotoxic
chemotherapy than the bulk primary tumor, and
evade first-line therapy as a result. The key to tar-
geting these rare cells is the development of molec-
ularly targeted therapies based on the profile of the
individual tumors.
Individual tumors exhibit significant phenotypic
and epigenetic variation, yet they are normally
clonal with respect to crucial genetic alterations.
This means that the evolution of a particular tumor
is driven, at least in part, by the oncogenic changes it
has acquired, and suggests that the continued prop-
agation of the tumor also depends on the activ-
ity of the oncogenes it contains. Bernard Weinstein
likened this effect of oncogene dependence to an
Achilles “heal” for the tumor: he proposed that be-
cause tumors are “addicted” to the presence of a par-
ticular oncogene, they might be uniquely sensitive
to compounds or natural products (antibodies) that
specifically target the function of the activated onco-
gene [10]. Similarly, a given tumor with a mutation
in a “gatekeeper” tumor suppressor gene whose loss
of function is absolutely required for a particular tu-
mor to develop may be hypersensitive to replacing
the activity of that tumor suppressor gene (TSG).
These concepts are the basis for rational, or molec-
ularly targeted, therapeutic approaches. Severalexamples of this new therapeutic approach are now
available and are having a significant impact in the
clinic (Table 4.1).
To fully exploit the potential targets in human
cancer cells for rational drug design, an understand-
ing of the mutational repertoire of human cancer
is necessary. Recently there have been several re-
ports on large-scale sequencing of candidate genes
in cancer cells (such as all tyrosine kinases) that
have identifiedmutations in several genes that drug
targets such as PI3 kinases [12]. Following this, the
NIH, in collaborationwith the Broad Institute atMIT
and Johns Hopkins University among others, has
begun to collect data for The Cancer Genome At-
las (TCGA). Over the next decade, this project will
produce a wealth of information that will need to
be analyzed and put into biological context to be
exploited for pharmaceutical development [13].