Nej MR A 0802714

The n e w e ng l a n d j o u r na l of m e dic i n e
review article
Molecular Origins of Cancer
Lung Cancer
Roy S. Herbst, M.D., Ph.D., John V. Heymach, M.D., Ph.D.,
and Scott M. Lippman, M.D.
L
ung cancer is the leading cause of cancer deaths in the united From the Departments of Thoracic/Head
States1 and worldwide. The two major forms of lung cancer are nonsmall- and Neck Medical Oncology (R.S.H.,
J.V.H., S.M.L.), Cancer Biology (R.S.H.,
cell lung cancer (about 85% of all lung cancers) and small-cell lung cancer J.V.H.), and Clinical Cancer Prevention
(about 15%). Despite advances in early detection and standard treatment, non (S.M.L.), University of Texas M.D. Ander-
small-cell lung cancer is often diagnosed at an advanced stage and has a poor son Cancer Center, Houston. Address re-
print requests to Dr. Lippman at the De-
prognosis. The treatment and prevention of lung cancer are major unmet needs that partment of Thoracic/Head and Neck
can probably be improved by a better understanding of the molecular origins and Medical Oncology, Unit 432, M.D. Ander-
evolution of the disease. son Cancer Center, 1515 Holcombe Blvd.,
Houston, TX 77030, or at slippman@
Nonsmall-cell lung cancer can be divided into three major histologic subtypes: mdanderson.org.
squamous-cell carcinoma, adenocarcinoma, and large-cell lung cancer. Smoking
causes all types of lung cancer but is most strongly linked with small-cell lung Drs. Herbst and Heymach contributed
equally to this article.
cancer and squamous-cell carcinoma; adenocarcinoma is the most common type
in patients who have never smoked (Fig. 12-8). This review will focus on major N Engl J Med 2008;359:1367-80.
recent advances in the molecular study of the origins and biology of squamous-cell Copyright 2008 Massachusetts Medical Society.
carcinoma and adenocarcinoma, since they constitute the vast majority of diagnosed
lung cancers (Table 15,8-14). These advances have been facilitated by the development
of molecular techniques and biomarkers for defining cancer risk, prognosis, and
optimal therapy aimed at personalized prevention and treatment of lung cancer.
Mol ecul a r Or igins
Host Susceptibility
Epidemiologic studies showing an association between family history and an in-
creased risk of lung cancer provided the first evidence of host susceptibility (Fig. 1).
Lung-cancer susceptibility and risk also are increased in inherited cancer syndromes
caused by rare germ-line mutations in p53,15 retinoblastoma,16 and other genes,17
as well as a germ-line mutation in the epidermal growth factor receptor (EGFR)
gene.18 More recently, three large genomewide association studies identified an as-
sociation between single-nucleotide polymorphism (SNP) variation at 15q2415q25.1
and susceptibility to lung cancer. The region of the SNP variation was recently
linked to lung carcinogenesis and includes two genes encoding subunits of the
nicotinic acetylcholine receptor alpha, which is regulated by nicotine exposure.19-22
Lung-cancer susceptibility and risk also increase with reduced DNA repair ca-
pacity (particularly when accompanied by exposure to tobacco smoke)23 that re-
sults, for example, from germ-line alterations in nucleotide excision repair genes
such as ERCC1.24 Increased expression of DNA synthesis and repair genes, includ-
ing RRM1 (the regulatory subunit of ribonucleotide reductase) and ERCC1, in non
small-cell lung cancer correlates with a better prognosis overall but no benefit
from platinum-based chemotherapy.25,26 Table 1 presents gene abnormalities in-
volved in the development of different histologic types of lung cancer.
n engl j med 359;13 www.nejm.org september 25, 2008 1367

The New England Journal of Medicine
Downloaded from nejm.org on September 30, 2014. For personal use only. No other uses without permission.
Copyright 2008 Massachusetts Medical Society. All rights reserved.
Normal Precancer Early-stage cancer Advanced cancer
Smoking-related
Clonal patch
Tobacco smoke
Host susceptibility
Unknown factors
Not smoking-related
Tissue injury Clonal patches Invasion, angiogenesis Metastatic spread

Common Genetic, Dysregulated
Molecular
germ-line epigenetic pathways,
cellular
genetic changes proliferation,
features
variations apoptosis
Treatment Definitive local therapy with or Systemic therapy with or

Prevention
approaches without adjuvant therapy without radiation therapy
Roles for
molecular Cancer risk Prognostic, predictive Predictive
markers
Figure 1. Molecular Evolution of Lung Cancer.

Environmental factors, such as tobacco smoke, and genetic susceptibility interact to influence carcinogenesis. Factors that are unrelated
COLOR FIGURE
2 Tissue
to smoking including genetic, hormonal, and viral (e.g., human papillomavirus) factors have been suggested.Draft 11 injury9/4/08 (e.g.,
from tobacco smoke, reflected in the discolored smoking-related lungs) initially occurs in the form of genetic and Author
epigenetic Herbst
changes (e.g.,
Fig # 1
mutations, loss of heterozygosity, and promoter methylation) and global transcriptome changes (e.g., inflammation and apoptosis path-
Title
3,4 and eventually lead to aberrant pathway activation and cellular function Molecular evolution of lung
ways). These changes can persist long term (e.g.,
cancer dysregulated
proliferation and apoptosis) to produce premalignant changes, including dysplasia and clonal patches. Additional ME changes can result in
angiogenesis, invasion and early-stage cancer, and advanced cancer and metastasis.5 Many molecular changes DE in earliest-stage
Schwartz cancer
Artist Knoper
also occur in advanced disease.6,7 Premalignant patches contain clones and subclones (inset), which can involve lossAUTHOR of heterozygosity,
PLEASE NOTE:
microsatellite instability, and mutations (e.g., in p53 and epidermal growth factor receptor [EGFR]). Lung cancers unrelated and related
Figure has been redrawn to reset
and type has been
Please check carefully
smoking have strikingly different molecular profiles, including those of mutations in p53, KRAS, EGFR, and HER2. Smoking-related patches
Issue date 9/25/08
and primary cancers (usually squamous-cell carcinoma and small-cell lung cancer) most often develop in the central airway.4,8 Most tumors
that are not related to smoking are adenocarcinomas and develop in the peripheral airways. Molecular markers can signify risk (in people with-
out cancer), prognosis (outcome independent of treatment), and sensitivity to treatment through predictive markers. Such stage-specific mark-
ers can span the course of disease from its early stages through its late stages. They also can help define mechanisms of resistance to therapy.
1368 n engl j med 359;13 www.nejm.org september 25, 2008

Table 1. Genetic Abnormalities Specific in the Lung to NonSmall-Cell Lung Cancer and Small-Cell Lung Cancer.*
Abnormality NonSmall-Cell Lung Cancer Small-Cell Lung Cancer

Squamous-Cell
Carcinoma Adenocarcinoma
Precursor
Lesion Known (dysplasia) Probable (atypical adenomatous hyperplasia) Possible (neuroendocrine field)
Genetic change p53 mutation KRAS mutation (atypical adenomatous hyperplasia Overexpression of c-MET
in smokers), EGFR kinase domain mutation
(in nonsmokers)
Cancer
KRAS mutation Very rare 10 to 30% Very rare
BRAF mutation 3% 2% Very rare
EGFR
Kinase domain mutation Very rare 10 to 40% Very rare
Amplification 30% 15% Very rare
Variant III mutation 5% Very rare Very rare
HER2
Kinase domain mutation Very rare 4% Very rare
Amplification 2% 6% Not known
ALK fusion Very rare 7% Not known
MET
Mutation 12% 14% 13%
Amplification 21% 20% Not known
TITF-1 amplification 15% 15% Very rare
p53 mutation 60 to 70% 50 to 70% 75%
LKB1 mutation 19% 34% Very rare
PIK3CA
Mutation 2% 2% Very rare
Amplification 33% 6% 4%
* Nonsmall-cell lung cancer includes squamous-cell carcinoma and adenocarcinoma.

Neuroendocrine fields have been detected only in tissue surrounding tumors and have been characterized by extremely high rates of allelic
loss and by c-MET overexpression (Salgia R: personal communication).
Variations are based in part on smoking profiles.
The percentages include increased gene copy numbers from amplification or polysomy and represent percentages from resected cancers.
The percentages are higher in primary tumors from patients with metastatic disease. Increased copy numbers have been reported in
squamous dysplastic lesions but not in adenocarcinoma precursors.
Genomic EGFR variant III mutations have been detected only in lung squamous-cell carcinoma, and these tumors are sensitive preclinically
to irreversible EGFR tyrosine kinase inhibitors. The incidence of 5% is substantially lower than that of 30 to 40% for the detection in
squamous-cell carcinoma or adenocarcinoma by immunohistochemical analysis or other techniques.
The anaplastic lymphoma kinase (ALK) fusion gene (involving chromosome 2p), consisting of parts of EML4 and ALK, is transforming in
fibroblasts and occurs in adenocarcinoma but not in other types of nonsmall-cell lung cancer or other nonlung cancers.
Clonal Evolution ally related cells, or clonal patches containing

Changes in certain genes (e.g., proinflammatory 40,000 to 360,000 cells, have been mapped in the
interleukin-8 [IL8] and some DNA-repair genes) lung.30 The size and number of subclones in a
occur in nonmalignant lung tissue of smokers clonal patch may contribute to the cancer risk.31
and patients with lung cancer, a finding consis- Early events in the development of nonsmall-
tent with diffuse tissue injury.3,27-29 These chang- cell lung cancer include loss of heterozygosity at
es probably precede epithelial clonal evolution, an chromosomal region 3p21.3 (site of RASSF1A, a
important element of the molecular origins of member of the Ras association domain family,
lung and other cancers (Fig. 1). Patches of clon- and FUS1), 3p14.2 (FHIT, a fragile histidine triad

Ligand binding
and dimerization Other receptor tyrosine
kinases (e.g., IGF-1R, c-Met)
Hypoxia EGFR VEGF
LKB1
AMPK
PI3K Ras
TSC2
Akt Raf
HIF-1 mTOR Mek
Gene transcription, cellular effects
Proliferation Invasion Metastasis Resistance to apoptosis Angiogenesis
Figure 2. Epidermal Growth Factor Receptor (EGFR) Cell-Signaling Pathways. COLOR FIGURE
Draft 8 9/4/08
EGFR activates several major downstream signaling pathways, including RasRafMek and the pathway consisting
Author Herbst
of phosphoinositide 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), which Fig # in turn 2 may have an
effect on proliferation, survival, invasiveness, metastatic spread, and tumor angiogenesisTitle
throughEpidermalpathways growth that
factor are
either dependent on or independent of the hypoxia inducible factor (HIF). These pathways also may be
receptor modulated
cell signaling pathways
drive lung cancer development,
by other receptor tyrosine kinases, such as insulin-like growth factor 1 receptor (IGF-1R) and cMET, and
growth and by the
progression
LKB1amp-activated protein kinase (AMPK) pathway, which is involved in energy sensing and cellular stress. Most
ME
DE
of these functions depend on signaling through the kinase domain. However, kinase-independent functions, such
Schwartz
46 Artist Knoper
as maintaining glucose transport, have been reported. TSC2 denotes tuberous sclerosis complex 2, and VEGF vas-
AUTHOR PLEASE NOTE:
cular endothelial growth factor. Figure has been redrawn and type has been reset
Issue date 9/25/08
gene), 9p21 (p16), and 17p13 (p53).32 All these greater risk of recurrence and second primary
genes are tumor-suppressor genes. Loss-of-hetero tumors. These findings suggest that in the future
zygosity patterns in squamous-cell carcinoma molecular analyses of surgical margins may help
and adenocarcinoma differ (e.g., chromosome 3p identify patients most likely to benefit from adju-
deletions are much more extensive in squamous- vant therapy.
cell carcinoma). Mutations in the EGFR kinase Methylated genes in premalignant squamous-
domain occur early in the development of adeno- cell lung lesions (e.g., metaplasia and dysplasia) are
carcinoma that is generally unrelated to smok- p16 and FHIT (frequently and very early) and O-6-
ing, and KRAS mutations occur early in the devel- methylguanine-DNA methyltransferase (MGMT),
opment of smoking-related adenocarcinoma.33,34 death-associated protein kinase (DAPK), and
Clonal patches with methylation of promoter re- RASSF1A (less frequently or rarely and in advanced
gions of genes (epigenetic changes), p53 mutation, precancers).35-41 The early methylation of p16 in
EGFR mutation, c-Myc amplification, loss of hetero the development of squamous-cell lung cancer
zygosity, and microsatellite instability can occur (e.g., in normal lung tissue in approximately
in normal tissue surrounding nonsmall-cell lung 50% of smokers)36 exemplifies differences with
tumors5,30,32,34,35 and may be associated with a that in the development of adenocarcinoma, in

which p16 methylation occurs very rarely and

only late in precursors (e.g., high-grade atypical
Extracellular
adenomatous hyperplasia).37 Methylation markers domain
in sputum are associated with the risk of lung Ligand-binding
cancer (e.g., methylated p16)38 and the recurrence EGFR variant III del pocket
of lung cancer (methylated ASC-TMS1,39 also (del exons 27)
Squamous-cell
called PYCARD). Recent data show that promoter carcinoma
methylation of various genes, including p16 in
stage I nonsmall-cell lung cancer, is associated
with recurrence after resection.40,41 Agents that
Transmembrane
reverse epigenetic changes have shown promise domain
in a mouse model of lung carcinogenesis and are
Intracellular
being tested in humans with lung cancer.42 domain
Bronchoalveolar stem cells, which may be
precursors of lung adenocarcinoma, were identi- Exon 19 del
Adenocarcinoma
fied recently in studies in mice.43 The KRAS, Pten, ATP-binding pocket
phosphoinositide 3-kinase (PI3K), and cyclin- Catalytic
domain
dependent kinase pathways have been implicated T790M
Adenocarcinoma
in the proliferation of these stem cells.44,45 The L858R (exon 21 del)
potential role of bronchoalveolar stem cells and Adenocarcinoma
other tumorigenic stem-cell populations in the P Phosphorylation

development and prognosis of human lung can-
cer and its resistance to drugs is an important
area of future investigation.
Mol ecul a r E volu t ion Figure 3. Effect of Deletions and Mutations in the Epidermal COLORGrowth
FIGURE Factor
Receptor Gene (EGFR) on Disease Development andDraft Drug 6 Targeting. 8/28/08
EGFR Family results 3Herbst
Ligand binding to the EGFR extracellular domainAuthor in receptor ho-
Fig #
modimerization and tyrosine phosphorylation, with the phosphate derived
EGFR regulates important tumorigenic process- Title Deletions and mutations of
from ATP bound within the kinase catalytic domain. EGFR mutations
epidermal growth factorhave
es, including proliferation, apoptosis, angiogene- affecting lung cancer
transforming potential in preclinical lung models and candevelopment occur early and drugin hu-
targeting
sis, and invasion (Fig. 2), and, along with its man lung carcinogenesis. EGFR point mutationsME (e.g., L858R) and exon 19
ligands, is frequently overexpressed in the devel- deletions, which occur predominantly in adenocarcinoma
DE of the lung, are
Schwartz
Knoper
opment and progression of nonsmall-cell lung located within the catalytic domain and result in Artist
constitutive EGFR activa-
AUTHOR PLEASE NOTE:
tion. These mutations are associated with increased Figure sensitivity totypeEGFR ty-
cancer.2,5,34,46 Clinical trials of the EGFR tyrosine has been redrawn and has been reset
rosine kinase inhibitors, such as erlotinib and gefitinib. In contrast, muta-
kinase inhibitor erlotinib for second-line or third- Issue date 9/25/08
tions in T790M (an amino acid located within the ATP binding site of the
line treatment of such tumors and of the mono- EGFR kinase domain) are associated with acquired resistance to these drugs.
clonal antibody against EGFR, cetuximab (com- EGFR variant III mutant deletions occur in the extracellular domain and are
bined with chemotherapy), for treatment of associated with squamous-cell cancer.
previously untreated, advanced disease47,48 vali-
dated EGFR as a molecular target for therapy.
EGFR mutations that were discovered during clini- nonsmokers and are tightly associated with sensi-
cal trials led to extensive studies of the roles of tivity to the EGFR tyrosine kinase inhibitors gefi-
these mutations and EGFR amplification in the tinib and erlotinib and so appear to explain most
pathogenesis of the disease and its prognosis of the dramatic responses to these agents.5052
and sensitivity to treatment. More than 80% of these mutations in lung can-
Several groups of investigators independently cer involve in-frame deletions within exon 19 or
identified somatic mutations in the kinase do- the L858R mutant within exon 21. EGFR muta-
main of EGFR in lung adenocarcinoma in approxi- tions are associated with an improved prognosis
mately 10% of specimens from patients in the in nonsmall-cell lung cancer, even when treated
United States and in 30 to 50% of specimens with cytotoxic chemotherapy.53,54 EGFR amplifi-
from patients in Asia49 (Fig. 3). The mutations cation is detected in dysplasia (especially of a high
occur with increased frequency in women and grade), which is associated with lung-cancer risk

when detected in the sputum of smokers, and is of mutant EGFR expression led to regression of
associated with a poor prognosis but also with tumors, suggesting the need for persistent mu-
sensitivity to EGFR inhibitors.55,56 The epidemio- tant EGFR activity for continued tumor survival.
logic links highlight three factors whether the Lung tumors also developed in transgenic mice
patient is a nonsmoker, Asian, and female with lung-specific expression of EGFR variant III
that are associated independently and collective mutation (in-frame deletion of exons 27 from
ly with an improved response to EGFR tyrosine the extracellular domain) (Fig. 3).13 Mutations of
kinase inhibitors. However, erlotinib appears the region that encodes the tyrosine kinase do-
to prolong survival in virtually all subgroups of main of EGFR have been detected in specimens
patients with nonsmall-cell lung cancer.48 There of atypical adenomatous hyperplasia from Asian
are major differences in clinical, pathological, patients with no history of smoking.71 These mu-
sex-related, and molecular factors between smok- tations also occur in normal epithelium within
ers and lifelong nonsmokers in whom lung can- and adjacent to tumors with EGFR tyrosine kinase
cer develops (Fig. 1). mutations (a localized-field effect, possibly reflect
The vast majority of patients who have an ing stem-cell expansion) and before EGFR ampli-
initial response to erlotinib and gefitinib even- fication, a change associated with tumor progres-
tually have a relapse.49,57,58 Recent studies have sion and metastasis.72
identified EGFR T790M mutations (in exon 20) in HER2 mutations and amplification have been
tumors before drug treatment59 and in tumors identified in patients with lung adenocarcinoma.
of patients who had a relapse after therapy with The frequency of such mutations is less than 5%,
standard reversible EGFR tyrosine kinase inhibi- and the frequency of such amplification is 5 to
tors.57 The binding kinetics of the mutant EGFR 10%. HER2 kinase domain mutations (in-frame
appear to be altered by the T790M mutation insertions in exon 20) and EGFR kinase domain
(Fig. 3). Irreversible EGFR inhibitors suppress mutations have similar associations with female
T790M-mutant tumor cells in vitro and are prom- sex, nonsmoking status, and Asian background
ising treatments for T790M-mutant tumors.60 in patients with adenocarcinoma.73 HER2 amplifi-
Amplification of the met proto-oncogene (MET), cation is associated with sensitivity to inhibitors
another major mechanism of acquired resistance of the EGFR tyrosine kinase74; HER2 mutations are
to EGFR tyrosine kinase inhibitors, marks a poor associated with resistance to such inhibitors but
prognosis.61-63 Other proposed resistance mech- also with sensitivity to HER2-targeted therapy.75
anisms include activation of other receptor tyro HER3 kinase domain mutations have not been
sine kinases, such as insulin-like growth factor 1 detected in patients with nonsmall-cell lung
receptor (which can bypass EGFR to activate cancer.76 Mutations in the HER4 kinase domain
critical downstream signaling pathways [Fig. 2]), were found in 2 to 3% of Asian patients with
KRAS mutations, and the epithelial-to-mesenchy this disease, with a possible association with
mal transition.58,64,65 The epithelial-to-mesen- male sex and smoking.77
chymal transition is a program of cell develop-
ment involving loss of cell adhesion, repressed RasRafMek
E-cadherin expression, and increased cell mobility. The RasRafMek pathway is involved in signal-
Preclinical and clinical data suggest that EGFR ing downstream from EGFR and in other path-
mutations are early events in the development of ways leading to the growth of cancer cells and
nonsmall-cell lung cancer.66-70 EGFR mutations, tumor progression (Fig. 2). Activating KRAS mu-
including those involving exons 18, 19, and 20 tations are limited to nonsmall-cell lung cancer
and L858R, can transform fibroblasts and lung (predominantly adenocarcinomas), virtually mu-
epithelial cells.67 Furthermore, in transgenic mice tually exclusive of mutations in the EGFR and
with lung-specific expression of exon 19 deletion HER2 kinase domains, and associated with resis-
or the L858R mutation, atypical adenomatous tance to EGFR inhibitors (tyrosine kinase inhibi-
hyperplasia, which is considered to be a precur- tors and cetuximab) and chemotherapy.58,78,79
sor lesion of peripheral adenocarcinoma, was Most KRAS mutations in lung adenocarcinoma
followed by lesions resembling bronchioalveolar are smoking-related GT transversions (substitu-
carcinoma at 5 to 6 weeks of age and invasive tions of a purine for a pyrimidine) and affect
adenocarcinomas at 8 to 10 weeks.68 Deinduction exon 12 (in 90% of patients) or exon 13.2,79 A dis-

tinct KRAS mutational profile consisting of GA tiation, and the development of metastases.88
transition mutations was recently detected in Results in transgenic KRas-mutant mice in which
patients with adenocarcinoma who had never LKB1 was inactivated suggest that the gene plays
smoked; its functional significance is unclear.79 a role in the differentiation and invasive behavior
Transversions (smokers) and transitions (non- of such tumors.87 The presence of LKB1 mutations
smokers) also have been reported for p53 muta- alone (i.e., without KRas mutations) was not asso-
tions in lung adenocarcinoma.2 KRAS mutations ciated with the development of lung cancer in
appear to be an early event (e.g., detectable in the mice. Low levels of LKB1 protein were associated
preinvasive lesions of atypical adenomatous hy- with high grades of dysplasia in atypical adeno
perplasia and bronchoalveolar carcinoma33) that matous hyperplasia lesions, suggesting that LKB1
precedes smoking-related lung adenocarcinoma. has an early role in the development of premalig-
They generally mark a poor prognosis. Further nant lesions in the lung.89 LKB1 mutations (includ-
evidence supporting this genes role in the patho- ing point mutations and deletions) were found in
genesis of lung cancer comes from transgenic 34% of adenocarcinomas and 19% of squamous-
mice bearing a mutated KRAS and in which multi- cell carcinomas from 144 human specimens of
focal atypical adenomatous hyperplasia and ade- nonsmall-cell lung cancer.87 However, much low-
nocarcinoma develop.80 MET activation occurs er rates of LKB1 mutation (<5%) were found in
early in KRAS-induced carcinogenesis in this mod- adenocarcinomas from Asian patients.90,91 LKB1
el.81 BRAF mutations have also been detected in mutations are associated with smoking and with
nonsmall-cell lung cancer9 and may be an early KRAS mutations and are virtually exclusive of
event in lung tumorigenesis.82 EGFR mutations.91
PI3KAktmTOR TITF1
The pathway consisting of PI3K, Akt, and mam- Amplification of thyroid transcription factor 1
malian target of rapamycin (mTOR), which is (TITF1, also called NKX2-1) in the 14q13.3 region
downstream of EGFR, is activated early in lung was the most common focal event in a high-reso-
carcinogenesis.83 Akt is also overexpressed in lution analysis of gene copy numbers in human
bronchial dysplasia. Inhibition of Akt can induce lung adenocarcinoma.92 This study used an array
apoptosis of human premalignant and malignant with the capacity to genotype many SNPs. As a
lung cells and prevent lung carcinogenesis in an result, the investigators also identified amplifi-
animal model. An mTOR inhibitor can block ma- cation in regions containing KRAS, Myc, vascular
lignant progression of atypical adenomatous hyper endothelial growth factor (VEGF), and several cell-
plasia lesions in the KRas mouse model.84 Since cycle genes in the tumor specimens. TITF1 encodes
mTOR drives tumorigenesis in part through mac- a lineage-specific transcription factor that is es-
rophages, a prominent component of the tumor sential for the formation of cells lining lung al-
microenvironment, the antitumor effect of mTOR veoli (type II pneumocytes). In vitro, transfection
inhibition requires the tumor microenvironment. of immortalized normal human lung epithelial
There is mutation or amplification of PIK3CA, cells with at least two of the three genes TITF1,
which encodes the PI3K catalytic subunit, in a sub- NKX2-8, and PAX-9 in the 14q13.3 region caused
group of nonsmall-cell lung tumors, especially increased growth of the cells,93 suggesting that
squamous-cell carcinoma, in association with these three genes may work cooperatively in the
increased PI3K activity and Akt expression.85 pathogenesis of lung cancer in which there is am-
plification at 14q13.3 (detected by high-resolution
LKB1 comparative genomic hybridization array). Re-
LKB1 (also called STK11) is frequently mutated in cent data indicate that squamous-cell carcinoma
nonsmall-cell lung tumors and is thought to act also exhibits TITF1 amplification, as detected on
as a tumor-suppressor gene through interactions fluorescence in situ hybridization, but not TITF1
with p53 and CDC42, modulating the activity of protein, in contrast to adenocarcinoma.94
AMPK (a multifunctional protein kinase) and
other possible mechanisms that are just begin- Angiogenesis
ning to be studied.86,87 LKB1 is thought to func- VEGF levels in bronchial epithelial cells of smok-
tion in early tumorigenesis, subsequent differen- ers increase in association with the progression

of bronchial dysplasia from low grade to high and redundancy of tumor-cell signaling networks
grade.95 Bronchial hyperplasia, metaplasia, and involving genetic, epigenetic, and microenviron-
carcinoma in situ are associated with increased mental effects. Emerging high-throughput tech-
microvessel density, and a distinctive pattern niques for assessing genomic DNA, messenger
known as angiogenic squamous dysplasia can RNA (mRNA), microRNA, methylation, and pro-
occur.96 Factors associated with increased tumor tein or phosphoprotein signaling networks should
angiogenesis correlate with the development and help address these obstacles (Fig. 4). The Cancer
prognosis of lung cancer.97-99 Circulating VEGF Genome Atlas is a large-scale project designed
levels may predict the clinical benefit of VEGF to provide a comprehensive profile of human
inhibitors in patients with this disease. Many an- tumors according to their gene mutations, alter-
giogenic factors are regulated at least in part ations in gene copy number, and epigenetic
through the hypoxia-regulated pathways, such as changes. Squamous-cell carcinoma of the lung
hypoxia-induced factor (HIF) 1 and 2.100,101 In will be one of the first tumors profiled by this
addition to hypoxia, VEGF and other angiogenic atlas.
factors are also regulated by EGFR through HIF-
dependent and independent mechanisms102 and Gene Profiling
by oncogenes such as KRAS and p53. VEGF has Tumor molecular heterogeneity is a major reason
recently been validated as a therapeutic target on that patients with nonsmall-cell lung cancer with
the basis of the results of a phase 3 trial, which a similar clinical stage and tumor histology can
led the Food and Drug Administration (FDA) to have dramatically different clinical outcomes and
approve the VEGF monoclonal antibody bevaci- responses to treatment. Microarray techniques
zumab in combination with standard chemother- that profile the expressions of tens of thousands
apy for previously untreated, advanced nonsmall- of genes simultaneously can measure this tumor
cell lung cancer.103 heterogeneity at a global level. Gene-expression
Interactions between the VEGF and EGFR profiles that are associated with subtypes of non
pathways and an association between acquired small-cell lung cancer108,109 and with reduced
resistance to EGFR blockade and increased VEGF recurrence-free or overall survival of patients
expression in preclinical models104 led to the have been identified.110-113 Combined clinical and
hypothesis that dual blockade of VEGF and EGFR molecular information provides better indications
might be more effective than either approach of cancer risk114 and prognosis.115
alone. Randomized phase 2 trials of dual inhibi- In a recent analysis of 672 invasion-associated
tion with bevacizumab plus erlotinib105 or the genes from 125 frozen specimens of early-stage
VEGF receptorEGFR tyrosine kinase inhibitor tumors,111 microarray and reverse-transcriptase
vandetanib (combined with chemotherapy)106,107 polymerase-chain-reaction (RT-PCR) analyses iden-
had promising results. Phase 3 testing of both tified a molecular signature of five genes as an
approaches in patients with platinum-resistant independent predictor of relapse-free and overall
disease is ongoing. survival. In two validation cohorts, another re-
cently developed gene-expression profile (meta-
mol ecul a r profil ing gene) predicted clinical outcome with an accuracy
of 72% and 79% (greater than that for tumor
technical advances stage, tumor diameter, nodal status, or other
Molecular profiling, including the profiling of clinical measures) and predicted the outcome in
genes and proteins, to guide treatment may im- patients with stage IA tumors.112 Randomized,
prove the clinical outcome in patients with non controlled trials will need to validate these sig-
small-cell lung cancer (Fig. 1). Progress in the natures and establish whether the patients with
identification of markers, mutations, and genomic stage IA tumors who were identified as being at
signatures far outstrips the modest improvement high risk will benefit from adjuvant therapy. One
in treatments that are based on these molecular such phase 3 trial, coordinated by the Cancer
advances. Formidable obstacles to developing ef- and Leukemia Group B, is approved and under
fective markers include tumor heterogeneity, the final review. It will evaluate a large predictive set
highly complex interplay between the environ- of metagenes (or subgroups of gene-expression
ment and host and the complexity, multiplicity, profiles consisting of 25 to 200 genes) in patients

Host
Germ-line genetic profiling

(e.g., SNP arrays)
Blood-based profiling
Proteomics
Cytokine, angiogenic factors
Circulating DNA or RNA
Circulating cells (e.g., tumor,
endothelial, lymphocytes)
Genetic or epigenetic
Interactions involving
Mutation the host, tumor,
Deletion and therapy Personalized
Amplification
Tumor sensitivity medicine
Translocation
Methylation to therapy
Gene expression
Expression arrays
MicroRNA profiling
PCR-based approaches
Proteins
IHC
Proteomics
Tumor, local environment
Figure 4. Molecular-Profiling Approaches to the Development of Personalized Therapy.

Host profiling involves innate characteristics of the cancer patient. All markers that are involved in profiling lung cancerCOLOR canFIGURE
apply to the
Draft 6 or resistance
tumor or its local environment. Predictive markers identify groups of patients who are likely to have increased sensitivity 9/4/08 to
Author Herbst
a given therapy, a critical step in personalizing treatment. It has been traditional to assess individual genetic orFigprotein
# 4
prognostic or
predictive markers (e.g., HER2 for breast cancer), but emerging techniques permit global analyses of the genomic, Title gene-expression, epi-
Molecular profiling approaches
genetic, and protein profiles of the host (innate), including markers in blood and in tumor or nonmalignant lung tissue. These methods
for development of personalized
therapy
include single-nucleotide polymorphism (SNP) arrays to assess genomic alterations, bisulfite sequencing, andME methylation-specific poly-
merase chain reaction (PCR) to assess epigenetic changes, microarrays for assessing gene expression or microRNA DE levels,
Schwartzand proteom-
ic methods (such as mass spectroscopy, reverse-phase protein arrays, and multiplex beads) to assess intracellular Artist signalingKnoper in tumor tis-
AUTHOR PLEASE NOTE:
sue and cytokines and angiogenic factors in blood. Blood-based profiling includes markers derived from the host (e.g., lymphocytes)
Figure has been redrawn and type has been reset
and the tumor and local environment (e.g., circulating tumor cells and tumor-derived cytokines) (red arrows). IHC denotes immunohis-
Issue date 9/25/08

tochemical analysis.
with stage IA tumors who are undergoing adju- response. Recently developed in vitro profiles
vant chemotherapy. predicting the sensitivity of tumors to EGFR in-
For the majority of patients with advanced or hibitors and other therapies have yet to be as-
metastatic nonsmall-cell lung cancer, the most sessed clinically.113
important potential effect of molecular markers MicroRNA has recently emerged as an impor-
is likely to be in predicting the response to spe- tant regulator of gene expression. High-through-
cific therapies with the goal of personalizing put analyses have shown that microRNA expres-
treatment (Fig. 4). Many exciting potential pre- sion is commonly deregulated in lung and other
dictive markers have been developed in vitro and cancers.116,117 Using real-time RT-PCR, investi-
need validation in tumor samples and clinical gators recently identified a five-microRNA sig-
trials.113 For example, gene-expression signatures nature that is associated with treatment out-
have been developed for cisplatin and pemetrexed come.116 Loss of microRNA-128b, a putative
on the basis of in vitro sensitivity; the cisplatin regulator of EGFR that is located on chromo-
in vitro signature predicted the likelihood of some 3p, has been shown to correlate with the

response to EGFR inhibition in patients with nosis and predicting the response to chemother-
lung cancer.117 apy or EGFR inhibitors have been developed in
Studies suggest that information about tumor- tumors and cell lines.126,127
specific genetic and epigenetic changes also may Proteomic profiling from blood is also under
be obtained from the blood of patients with lung study, allowing repeated measurements during
cancer. Circulating DNA can be detected in the treatment without the need for tumor tissue.
plasma and serum of such patients, and levels of Serum mass spectrometry profiles can distin-
this DNA are associated with a poor progno guish patients with nonsmall-cell lung cancer
sis.118,119 Tumor-specific DNA alterations (such from normal controls124,128 and patients with bet-
as loss of heterozygosity), promoter methylation, ter outcomes from those with worse outcomes
and KRAS and EGFR mutations have also been after treatment with EGFR tyrosine kinase inhib
detected in the blood of patients with lung can itors.129 New techniques also permit the multi-
cer.120-122 New techniques for capturing circulat- plex analysis of dozens of cytokines and angio-
ing tumor cells allow the detection of EGFR- genic factors in small amounts of serum or
activating mutations and the drug-resistance plasma. This approach is being used in develop-
allele T790M. Such techniques appear to be more ing predictive markers in nonsmall-cell lung
sensitive than those for capturing circulating cancer. Although promising, blood- and tissue-
DNA. Furthermore, a decline in the number of based proteomic approaches remain investiga-
circulating tumor cells was associated with tu- tional and await prospective testing and valida-
mor response on radiography.123 These studies tion in large, randomized trials before they can
suggest that blood profiling may provide useful be applied clinically.
information about genetic changes in tumors
that could ultimately help detect lung cancer and C onclusions
guide therapy.
The molecular origins of lung cancer lie in com-
Protein Profiling plex interactions between the environment and
Profiling of genomic and mRNA expression pro- host genetic susceptibility. Lung cancer then
vides an incomplete picture of the heterogeneity evolves through genetic and epigenetic changes,
of nonsmall-cell lung cancer. Levels of mRNA including deregulated signaling pathways, which
do not always correlate with protein levels and do are potential targets for chemoprevention and
not provide information on proteinprotein inter- therapy. Emerging techniques for genomic, gene-
actions or post-translational modifications such expression, epigenetic, and proteomic profil
as phosphorylation that may be critical for regu- ing92,114,125,130,131 could revolutionize clinical ap-
lating protein activity.124 Furthermore, most tar- proaches across the spectrum of lung-cancer types
geted therapeutic agents are designed to inhibit and subtypes by identifying practical molecular
the activity of proteins such as tyrosine kinases. markers of risk (in precancer), early detection
Therefore, protein-based profiling is likely to be and prognosis (in early-stage cancer), and treat-
essential in understanding the complexity of pro- ment sensitivity (in early-stage and advanced-
tein signaling networks and developing molecu- stage cancer). Genomewide and other molecular
lar signatures that predict a response to therapy. assessments are helping elucidate germ-line vari-
Immunohistochemical analysis remains the ations that may contribute to lung cancer risk,19-21
most widely applied method for assessing indi- prognosis,132 and treatment sensitivity133,134 and
vidual proteins and may be useful for estimating somatic genetic alterations that occur in lung
prognosis and predicting the response to ther adenocarcinomas14,50-52 and in high-risk lung
apy.25,26 Emerging high-throughput proteomic tissue associated with tumors or in smokers.3,28,29
techniques, such as mass spectrometry and pro- Molecular targeted research has produced the re-
tein microarrays, have the potential to view sig- cently FDA-approved EGFR and VEGF inhibitors
nal transduction networks more globally than is erlotinib and bevacizumab, which have modestly
possible with immunohistochemical analysis. improved the outcome in patients with nonsmall-
Such techniques are feasible in small amounts of cell lung cancer.48,103 Molecular profiling of the
tumor tissue.125 Proteomic signatures for prog- type described in this review has begun in clini-

cal trials112,135-137 and promises to select patients Heymach, serving on advisory boards for and receiving research
grants from AstraZeneca, Pfizer, and GlaxoSmithKline and serv-
who are most likely to benefit from therapy and ing on an advisory board for Genentech; and Dr. Lippman, serving
to guide the development of more effective agents on advisory boards for OSI and Genentech. No other potential
that will personalize standard medicine for lung conflict of interest relevant to this article was reported.
We thank Lauren A. Byers, Balvindar S. Johal, and Ignacio I.
cancer.138 Wistuba for their careful comments and other contributions re-
Dr. Herbst reports receiving consulting fees and research garding aspects of this work; and Bich N. Tran, Suzanne E. Davis,
grants from Bristol-Myers Squibb, ImClone, Genentech, Amgen, and Kendall Morse for their contributions to the preparation of
AstraZeneca, and OSI and lecture fees from Genentech; Dr. the manuscript.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Molecular Origins of Cancer

Mol ecul a r Or igins

n engl j med 359;13 www.nejm.org september 25, 2008 1367

Normal Precancer Early-stage cancer Advanced cancer

Tissue injury Clonal patches Invasion, angiogenesis Metastatic spread

Treatment Definitive local therapy with or Systemic therapy with or

Figure 1. Molecular Evolution of Lung Cancer.

1368 n engl j med 359;13 www.nejm.org september 25, 2008

The New England Journal of Medicine

Abnormality NonSmall-Cell Lung Cancer Small-Cell Lung Cancer

* Nonsmall-cell lung cancer includes squamous-cell carcinoma and adenocarcinoma.

Clonal Evolution ally related cells, or clonal patches containing

n engl j med 359;13 www.nejm.org september 25, 2008 1369

HIF-1 mTOR Mek

Gene transcription, cellular effects

Proliferation Invasion Metastasis Resistance to apoptosis Angiogenesis

Issue date 9/25/08

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The New England Journal of Medicine

which p16 methylation occurs very rarely and

other tumorigenic stem-cell populations in the P Phosphorylation

n engl j med 359;13 www.nejm.org september 25, 2008 1371

1372 n engl j med 359;13 www.nejm.org september 25, 2008

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Germ-line genetic profiling

Figure 4. Molecular-Profiling Approaches to the Development of Personalized Therapy.

Issue date 9/25/08

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1376 n engl j med 359;13 www.nejm.org september 25, 2008

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The New England Journal of Medicine

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full text of all journal articles on the world wide web

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The New England Journal of Medicine

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