PRIMER

Non-small-cell lung cancer

Cesare Gridelli1, Antonio Rossi1, David P. Carbone2, Juliana Guarize3, Niki Karachaliou4,
Tony Mok5, Francesco Petrella3, Lorenzo Spaggiari3 and Rafael Rosell4
Abstract | Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of
cancer-related death worldwide. Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours,
represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk
factor for developing this disease, but radon exposure and air pollution also have a role. Most patients are
diagnosed with advanced-stage disease owing to inadequate screening programmes and late onset of
clinical symptoms; consequently, patients have a very poor prognosis. Several diagnostic approaches can
be used for NSCLC, including X‑ray, CT and PET imaging, and histological examination of tumour biopsies.
Accurate staging of the cancer is required to determine the optimal management strategy, which includes
surgery, radiochemotherapy, immunotherapy and targeted approaches with anti-angiogenic monoclonal
antibodies or tyrosine kinase inhibitors if tumours harbour oncogene mutations. Several of these driver
mutations have been identified (for example, in epidermal growth factor receptor (EGFR) and anaplastic
lymphoma kinase (ALK)), and therapy continues to advance to tackle acquired resistance problems. Also,
palliative care has a central role in patient management and greatly improves quality of life. For an
illustrated summary of this Primer, visit: http://go.nature.com/rWYFgg

Correspondence to C.G.
e-mail: cgridelli@libero.it
Division of Medical Oncology,
S.G. Moscati Hospital,
Contrada Amoretta, 83100
Avellino, Italy.
Article number: 15009
doi:10.1038/nrdp.2015.9
Published online 21 May 2015
Lung cancer is one of the most frequently diagnosed
cancers and is the leading cause of cancer-related death
worldwide1. Owing to the absence of clinical symp-
toms and effective screening programmes, most lung
cancers are diagnosed at an advanced stage. Accurate
staging of lung cancer is, however, vital because treat-
ment options and prognosis depend on it. The Tumour-
Node-Metastasis (TNM) classification system forms the
basis for staging, and it was updated by the International
Association for the Study of Lung Cancer staging com-
mittee after evaluation of outcomes in an extensive
worldwide database of patients. The current (seventh)
edition classifies all histotypes of lung cancer 2,3 (TABLE 1).
Non-small-cell lung cancer (NSCLC), which
includes adenocarcinoma (gland-forming), squamous
cell carcinoma and large-cell carcinoma histosubtypes
(FIG. 1), represents approximately 85% of all new lung
cancer cases. Small-cell lung cancer (SCLC) accounts
for the remaining 15% (REFS 4,5). This pathological clas-
sification of lung cancer is continuously adapting, and
specific terminology and criteria are used to distinguish
squamous cell carcinoma from adenocarcinoma, par-
ticularly in poorly differentiated tumours. Defining the
exact histological subtype of lung cancer has become
more important in the past few years owing to the avail-
ability of an increasing number of therapeutic agents for
specific subtypes. Indeed, tumours that previously failed
to be subtyped because of the lack of clear squamous or
adenocarcinoma morphology can now be re‑evaluated
using a limited immunohistochemical workup to pre-
serve tissue for molecular testing 5. Our understanding
of lung cancer is rapidly evolving and increasing, par-
ticularly in relation to the molecular underpinnings of
this disease. This enhanced knowledge will prove to be
essential for developing a complete and accurate TNM
classification system5,6, and for improvements in patient
care and clinical trial design.
In this Primer, we discuss the molecular mecha-
nisms, risk factors, diagnostic procedures and screen-
ing methods for NSCLC. We describe the standard of
care for each stage of this disease and its impact on
patient quality of life, as well as the emerging technolo-
gies and advances that are likely to influence treatment
in the next 5–10 years.
Epidemiology
Lung cancer accounts for more than 1.8 million newly
diagnosed cancer cases (13% of the total diagnosed can-
cer cases) and 1.6 million cancer-related deaths (19.4%
of the total) worldwide every year 1. In the United States,
the estimated number of new cases of lung cancer in
2014 was 224,210 with 159,260 estimated deaths7. In
Europe, the estimated number of new cases of lung can-
cer in 2012 was 410,000 with 353,000 estimated deaths8.
The estimated incidence and mortality of lung cancer in
Africa in 2012, derived from GLOBOCAN 2012 (http://
globocan.iarc.fr/Default.aspx), was 30,314 and 27,083,
respectively. These surprisingly low numbers for lung

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PRIMER

Author addresses
Mechanisms/pathophysiology
The lung is a complex yet fragile organ composed of
1
Division of Medical Oncology, S.G. Moscati Hospital, many cell types with discrete functions that support
Avellino, Italy. gas exchange. With 2,000 km of airway and more than
2
James Thoracic Center, Ohio State University Medical 50 m2 of extremely thin alveolar membranes, the effi-
Center, Columbus, Ohio, USA.
cient passage of oxygen and carbon dioxide between
3
Department of Thoracic Surgery, European Institute of
Oncology, Milan, Italy.
the blood and the environment occurs against a back-
4
Catalan Institute of Oncology, Hospital Universitari drop of exposure to toxic gases and fine particulate
Germans Trias i Pujol, Barcelona, Spain. contaminants as well as infectious agents. Large inhaled
5
Department of Clinical Oncology, The Chinese University particulates are cleared by ciliary action in the larger
of Hong Kong, Shatin, Hong Kong. airways, whereas infectious agents are eliminated by
immune and phagocytic cells. Mucus-producing cells
and neuroendocrine cells also have roles in maintaining
cancer in Africa are probably due to under-reporting the gas exchange function.
rather than low incidence. In Asia, 1,045,000 detections This complex community of cells can undergo an
and 936,051 deaths were observed1. accumulation of cell autonomous and microenviron-
Although the incidence of lung cancer is decreasing mental adaptations that alter the balance of cell division
in developed countries, rates are rising in less devel- and death and enable avoidance of immune recogni-
oped parts of the world (Africa, South America, Eastern tion, leading to cancer 12. The accumulation of regula-
Europe and China). Indeed, in 2012, 58% of the estimated tory alterations that lead to cancer can arise from years
1.8 million new cases worldwide occurred in less devel- of exposure to tobacco smoke, resulting in structural
oped regions (12.9% of the total)1. A possible explanation damage that manifests as chronic obstructive pulmo-
for this finding is that these countries have less rigorous nary disease and emphysema. Smoke exposure can lead
smoking regulations. Nevertheless, the highest lung can- to a well-characterized series of morphological changes
cer incidence rates in men are in North America, Europe, of the bronchial epithelium progressing from basal cell
eastern Asia, Argentina and Uruguay, and the lowest rates hyperplasia to metaplasia, severe dysplasia to carcinoma
are in sub-Saharan Africa (FIG. 2). In women, the highest in situ and, finally, frank carcinoma13. This series of
lung cancer rates are in North America, northern Europe, changes is primarily associated with the squamous sub-
Australia, New Zealand and China1,9. type of NSCLC. By contrast, adenocarcinomas can also
Furthermore, in the past 30 years, an epidemiologi- arise in the context of heavy carcinogen exposure and
cal shift from squamous histology to adenocarcinoma underlying lung damage, but they are generally consid-
histology has been noted. This shift is believed to be due ered to be the dominant subtype in never-smokers with
to changes in smoking behaviour and cigarette manu- low carcinogen exposure14. The progression of adeno-
facturing practices10,11. Specifically, filter cigarettes and carcinomas is associated with less well-­characterized
‘light’ cigarettes enable the smoker to take a deeper aspi- pre­malignant lesions called atypical adenomatous hyper-
ration; the smoke reaches the deeper parts of the bronchi plasia. New concepts for small solitary adenocarcinomas
and alveoli, where adenocarcinoma arises. are introduced such as adenocarcinoma in situ with pure
lepidic growth and minimally invasive adenocarcinoma
with predominantly lepidic growth and ≤5 mm inva-
Table 1 | Stage groupings for non-small-cell lung cancer* sion4,15. The pathological classification of lung cancer is
Stage Tumour (T) Node (N) Metastasis (M) continually changing, with a need for specific terminol-
ogy and criteria to distinguish squamous cell carcinoma
0 T in situ N0 M0
from adenocarcinoma, particularly in poorly differenti-
Ia T1a, T1b N0 M0 ated tumours16. SCLCs also typically occur in the context
Ib T2a N0 M0 of heavy carcinogen exposure, but they arise from the
IIa T1a, T1b N1 M0 rare pulmonary neuroendocrine cells and do not have
well-characterized preneoplastic lesions.
T2a N1 M0
T2b N0 M0 Genetic alterations and pathways
IIb T2b N1 M0 A wide variety of lung cancers with different character­
T3 N0 M0 istics exist, ranging from relatively indolent and surgi-
cally resectable SCLCs to highly aggressive and widely
IIIa T1, T2 N2 M0
metastatic NSCLCs. The identification of driver onco-
T3 N1, N2 M0 gene mutations in a subset of tumours was pivotal
T4 N0, N1 M0 in understanding these differences in lung cancer. These
IIIb T4 N2 M0 acquired genetic mutations in kinases result in consti-
Any T N3 M0 tutive signalling and, in susceptible cells, this leads to
oncogenic transformation that is nearly independent
IV Any T Any N M1a
of other alterations. Oncogenes implicated in NSCLC
Any T Any N M1b include activating mutations in the epidermal growth
*According to the seventh edition of the Tumour-Node-Metastasis (TNM) classification system2. factor receptor (EGFR) gene and trans­locations of the

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 PRIMER

Lung cancer somatic mutations as those from smokers. At this level

of analytic detail, every tumour is unique, and a more
comprehensive understanding of the roles of these
15% 85%
abnormalities should result in better therapies in the
future. The EGFR and ALK driver abnormalities occur
Small-cell lung cancer Non-small-cell lung cancer
primarily in adenocarcinomas (10–60%), with a strong
variation by smoking habits (more frequent in never-
30% 70% smokers)23. This variation also extends to geographical
region; the prevalence of these driver abnormalities is
Squamous Non-squamous low in white individuals of European descent (~10%)
and high in those of Asian descent (~60%) for unclear
10% 90% reasons. Several targeted therapies have been devel-
oped for tumours harbouring EGFR and ALK muta-
Adenocarcinoma tions, which have a very high fractional response rate.
■ Mixed subtypes
■ Lepidic (non-mucinous or However, not all mutations are alike (FIG. 4). The most
mucinous) common EGFR mutations are the exon 19 deletion
■ Acinar (E746–A750), and the exon 21 (L858R) and exon 18
Large-cell carcinoma ■ Papillary
■ Large-cell neuroendocrine ■ Micropapillary (G719C, G719S, G719A) substitutions, all of which are
carcinoma ■ Solid responsive to therapy 23. However, the exon 20 inser-
tion is also a driver mutation, but it is not inhibited
Figure 1 | Lung cancer classification.  Terminology and
| Disease Primers
Nature Reviews by any of the current therapies24. Tumours eventually
criteria for adenocarcinoma, squamous cell carcinoma and
large-cell carcinoma in small biopsies and cytology5. acquire resistance to these targeted therapies; however,
the mechanisms by which resistance occurs are not yet
completely understood. Nevertheless, the most com-
anaplastic lymphoma kinase (ALK) gene. Translocations mon resistance mutation that arises in EGFR-mutated
of ALK place the ALK kinase domain under the control lung cancers is the T790M mutation (also on exon 20),
of 5′ sequences and promoter elements of multiple other and highly effective third-generation inhibitors are
partners, most commonly echinoderm microtubule- now available25. It is fascinating to note that the same
associated protein-like 4 (EMAP4; encoded by EMAL4), EGFRT790M mutation that causes acquired resistance to
but also kinesin 1 heavy chain (UKHC; encoded by first-generation EGFR inhibitors is rarely seen in the
KIF5B), among others 17. Comprehensive genomic germ line, and thus is rarely associated with inherited
studies have determined the genomic landscape of susceptibility to lung cancer 26–28.
lung cancers18–22 (FIG. 3). Less common abnormalities have also been estab-
Lung tumours from smokers have among the high- lished as targets, including translocations of RET, ROS1
est number of somatic alterations, with approximately and receptor tyrosine kinases, mutations in BRAF, MET
ten mutations per megabase. Tumours from never- (encoding the hepatocyte growth factor (HGF) receptor)
smokers have approximately one-tenth the number of and HER2 (also known as ERBB2), and amplifications

Annual incidence
per 100,000 people
0–10
11–20
21–30
31–40
41–>50

Nature
Figure 2 | Annual incidence of lung cancer per 100,000 people in 2012.  Figure from Reviews
REF. 168 | Disease
, Nature Primers
Publishing
Group. Data from GLOBOCAN 2012 (http://globocan.iarc.fr/Default.aspx).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 3

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PRIMER

a 100
Histological subtypes (such as those in EGFR or ALK) occur early in tumour
90 Lung adenocarcinoma progression and are uniformly present in all tumour cells
Copy number alterations

80 Lung squamous cell carcinoma (truncal mutation). By contrast, branch mutations are
Small-cell lung cancer
70 confined to specific subclones within one tumour,
60 leading to considerable intratumoural heterogeneity.
50 Branch mutations can occur early or late in tumour
40 progression and are probably the cause of resistance
30 pressure to therapy. Interestingly, these branches can
20 have different nucleotide substitution patterns, from
10 the typical transversion pattern observed in smoking-
0 related cancers to a transition pattern characteristic
of tumours with high expression of apolipoprotein
R B ut

PI X A t
CA p

AS p

CD 3 A t
CD N2A p
2 el
AP ut
K1 ut
FR ut

NF mp

NO FR t
H t
CA ut

AR AF M t
SM ID1 ut
CA ut

ET t
R2 p
p
SO Mu

TP Mu

EG Mu
TC Mu

BR Mu

M Mu
K3 m

KR Am

K m

HE Am
Am
KN D

B mRNA editing enzyme, catalytic polypeptide-like

M

KE A M
ST 1 M
FG 1 M

PI 1 M

AR A M
A
53

4
1
6
TP

(APOBEC) cytidine deaminases30. The APOBEC fam-

K3
Mutation ily of enzymes can deaminate cytosine to guanine or
b thymine, primarily when the cytosine follows a thy-
mine. This deamination results in non-carcinogen-
Lung squamous
mediated mutagenesis and contributes to tumour
FGFR1 cell carcinoma evolution33. If a patient has two sites of disease and
ALK (2–4%) (<1%) both sites harbour EGFRL858R truncal mutations but
RET (~1%) have completely different patterns of other mutations,
Lung
adenocarcinoma ROS1 (~1%) then this profile suggests that these are independent
NTRK1 (~3%) synchronous primary tumours with identical driver
NRG1 (~1%) MYC Small-cell mutations. However, sequencing depth must be con-
(9%) lung cancer sidered in these analyses because a greater depth of
analysis may reveal that subclonal alterations are in
fact truncal mutations31.
Figure 3 | Genetic adaptation in non-small-cell lung cancer.  The most
Nature Reviews commonPrimers
| Disease Branch mutations are generally considered to drive
mutations — copy number alterations (part a) and translocations (part b) — according to tumour cell autonomous adaptations to external stim-
histological subtypes21,22. ALK, anaplastic lymphoma kinase; Amp, amplification; ARID1A, uli; that is, the ‘fittest’ clone will outcompete all others.
AT-rich interactive domain 1A; CDKN2A, cyclin-dependent kinase inhibitor 2A; Del, However, certain subclones that provide survival advan-
deletion; EGFR, epidermal growth factor receptor; FGFR1, fibroblast growth factor tage to the bulk tumour are stably maintained in animal
receptor 1; KEAP1, kelch-like ECH-associated protein 1; Mut, mutation; NF1, models. Thus, tumour heterogeneity might actually rep-
neurofibromin 1; NRG1, neuregulin 1; NTRK1, neurotrophic tyrosine kinase, receptor,
resent a symbiotic community of tumour cell subclones,
type 1; PIK3CA, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase, catalytic subunit alpha;
SMARCA4, SWI/SNF related, matrix associated, actin-dependent regulator of chromatin,
each independently providing factors or environments
subfamily A, member 4; STK11, serine/threonine kinase 11. that support tumour growth34,35.

of MET, HER2 and fibroblast growth factor receptor 1
(FGFR1) (FIG. 4). Although mutations in the tumour sup-
pressor genes TP53 and RB1 frequently occur in all lung
cancer subtypes, they are not yet therapeutically targeta-
ble. Both TP53 and RB1 are universally lost in all SCLCs
and are frequently lost in NSCLCs. Mutations in the
KRAS oncogene are common in lung adeno­carcinomas,
uncommon in squamous tumours and absent in SCLCs;
data suggest that it is possible to target KRAS using newly
developed compounds29. Mutations in the tumour sup-
pressor serine/threonine kinase 11 (STK11; also known
as LKB1) are also common, although the therapeu-
tic implications of mutations in this gene are unclear.
Dozens of other mutations are recurrently being iden-
tified in genetic analyses, and include mutations in the
AKT pathway, MAPK (MEK) pathway, cyclins and many
others18, and studies are underway to determine how to
take therapeutic advantage of such mutations.
Intratumoural heterogeneity
Lung tumours are heterogeneous, with diverse genetic
abnormalities in a single tumour and between a tumour
of origin and its metastases30–32 (FIG. 5). Driver mutations
Stromal alterations
No tumour can grow without a host, and, consequently,
tumours must secrete factors or use other means to pro-
duce an environment that is conducive to growth and
meta­stasis36,37. Tumour cells secrete vascular endothelial
growth factor (VEGF) to ensure an adequate blood sup-
ply. Other secreted factors conducive to growth include
fibroblast growth factors, platelet-derived growth factor,
HGF and sonic hedgehog (SHH)38. Some of these factors
are currently targeted therapeutically to inhibit tumour
progression; for example, VEGF is targeted by the mono-
clonal antibody bevacizumab and by the tyrosine kinase
inhibitors (TKIs) sunitinib and sorafenib. Compared with
their normal counterparts, cancer-associated fibroblasts
have been shown to promote tumour growth39,40, and
alterations in PTEN expression in these stromal cells, as
an example, dramatically enhance tumour growth41.
Immune avoidance
Tumours must acquire genetic alterations that protect
them from an effective immune response. Immune
avoidance can be accomplished by hiding structural-
alteration-induced neoantigens from cytotoxic T cells,
such as mutations or deletions in genes encoding class I

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 PRIMER

EGFR signalling HER2 signalling Other receptors

■ HGFR
EGF, TGFα, ■ FGFR1
amphiregulin, ■ EGFR
β-cellulin, HB-EGF,
epiregulin Unknown ■ ALK
■ ROS1
■ RET
EGFR HER2

EGFR mutations Activation of RAS HER2 mutations

in 15–50% signalling in smokers in 2–4% of lung
of lung cancer cases in 20–30% of lung cancer cases
Mainly in cancer cases
PI3K/ MAPK
never-smokers AKT
Most frequent
mutations: SOS
STAT3 RAS MYC Other signalling
■ Exon 18 (G719C, and GRB2 molecules
G719S, G719A) STAT5 ■ BRAF
■ Exon 19 (E746–A750) PI3K RAF Cyclin D ■ RB1
■ Exon 21 (L858R) ■ p53
EGFR mutations Gene AKT MEK p27 ■ Cyclins
associated with transcription
drug resistance: Cell cycle
■ Exon 20 (T790M) proliferation Cell survival ERK Proliferation Cyclin E–CDK2

Figure 4 | Implications of EGFR and HER2 mutations.  Epidermal growth factor receptor (EGFR) engagement
Nature Reviews | Disease Primers
induces receptor homo- and heterodimerization, which activates downstream effectors and pathways that lead to
cell proliferation, survival, gene transcription and cell cycle progression. Activating mutations in EGFR are frequently
observed in never-smokers, whereas in smokers, mutations of the KRAS gene lead to the release of growth factors
that further stimulate EGFR signalling. The receptor tyrosine kinase HER2 is a transmembrane receptor for which no
ligands are known. Activation of HER2 induces homo- and heterodimerization, which leads to the activation of
downstream effectors and pathways resulting in several cellular effects. Frequently mutated genes are indicated in
pink and red boxes; characteristics of the main mutations are described in boxes. CDK2, cyclin-dependent kinase 2;
FGFR1, fibroblast growth factor receptor 1; GRB2, growth factor receptor-bound protein 2; HB-EGF, proheparin-­
binding EGF-like growth factor; HGFR, hepatocyte growth factor receptor; STAT, signal transducer and activator of
transcription; TGFα, transforming growth factor-α.

MHC19, β2‑microglobulin42, the TAP peptide trans-
porter 43, or other factors involved in antigen presentation.
Some data support that these structural changes occur
alongside TP53 mutations; the unique peptide sequences
arising from mutated TP53 showed a significant negative
correlation with the predicted optimal binding sequences
for a patient’s class I MHC44.
The majority of tumours avoid immune recogni-
tion and elimination by subversion of normal regula-
tory signals, including the CD80, CD86 and cytotoxic
T lymphocyte-associated antigen 4 (CTLA4) axis, which
is involved in T cell priming, and the programmed cell
death protein 1 (PD1) and PD1 ligand 1 (PDL1) axis,
which is involved in T cell killing 45. Many NSCLCs show
upregulated expression of PDL1, which binds to PD1 and
thus inactivates PD1-expressing T lymphocytes. A subset
of patients show objective and durable responses when
treated with antibodies targeting this pathway, although
PDL1 protein expression might be an imperfect pre-
dictor of response46. It is of clear clinical importance to
define the mechanisms of immune avoidance and find
approaches to overcome them.
Risk factors
Smoking is the primary risk factor for lung cancer devel-
opment; globally, 80% of men and 50% of women with
lung cancer are or were smokers. Together with respira-
tory and cardiovascular diseases, lung cancer is the most
common cause of death associated with tobacco use47.
Cigarette consumption rates are increasing in low-
income and middle-income countries, and a significant
increase of lung cancer incidence is, therefore, expected
in these countries, particularly in China47.
An estimated 10–25% of lung cancer cases occur
in never-smokers (defined as individuals who have
smoked fewer than 100 cigarettes in their lifetime)48.
Other risk factors have been described: for example,
passive smoking is associated with an increased risk of
lung cancer and is designated as a known human car-
cinogen by the International Agency for Research on
Cancer 49. A statistically significant association between
lung cancer and air pollution has also been observed. In
particular, an ambient level of particulate matter with
diameters of <10 μm is associated with an increased
risk of lung adenocarcinoma50.
Exposure to radon — which arises naturally from
the decay of uranium (238U) — and its inhalation are
responsible for approximately 9% of deaths from lung
cancer and approximately 2% of all deaths from cancer
in Europe51. When inhaled, radon is mostly exhaled
immediately but its solid progeny (decay products of
radon gas) tend to be deposited on the bronchial epi-
thelium, with a subsequent emission of α-particles and
irradiation of bronchial cells47.
Genetic susceptibility might contribute to the risk of
developing lung cancer in never-smokers, particularly

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PRIMER
in those who develop the disease at a younger age
(<50 years)52. Smokers who develop lung cancer are less
likely to have a family history than non-smokers who
develop lung cancer. However, for those who have a
genetic predisposition to lung cancer, smoking seems to
amplify that risk. A pooled analysis showed that a posi-
tive family history of lung cancer predisposes individuals
to develop lung cancer 53. Lung adenocarcinoma is more
likely to have a genetic component than other histotypes.
Recent findings suggest that germline exon 20 T790M
mutations of EGFR and mutations in the transmembrane
domain of HER2 may be oncogenic, causing hereditary
and sporadic lung adenocarcinomas27,54 (FIG. 4).
Diagnosis, screening and prevention
Diagnosis
The diagnostic process usually begins when the patient
recognizes suspicious symptoms and signs. Once the
lesion is located by imaging techniques, the next step
is to select the appropriate technique to obtain a biopsy
sample and confirm a pathological diagnosis55 (FIG. 6).
Clinical findings. Clinical findings such as cough,
chest pain, haemoptysis, weight loss and dyspnoea
present in up to 75% of patients with lung cancer 56.
Other symptoms include venous congestion in the
upper chest suggestive of superior vena cava syn-
drome, shoulder pain together with the ulnar aspect
of the arm and forearm, and Horner syndrome,
which is caused by apical lung tumours infiltrat-
ing the stellate ganglion and the lower branches of
the brachial plexus55.
Early stages Advanced stages
Primary Primary
tumour tumour
Brain
and liver
metastases
Trunk mutations Branch mutations
Ubiquitously present Subclonal
Driver mutations Transition mutation pattern typical
High transversion mutation rate of APOBEC activity
(smoking-related) Might lead to adaptive advantage
Treatments available No treatment available
APOBEC
External carcinogens (such as smoking)
Figure 5 | Illustration of intratumour heterogeneityNature
in non-small-cell lung cancer
Reviews | Disease Primers
development.  Trunk mutations occur early in tumour development, are ubiquitous
across stages and include most oncogenic drivers of lung cancer. Branch mutations
occur late and are responsible for most of the heterogeneity observed. APOBEC,
apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like.
6 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
Imaging. Posterolateral and lateral chest radiography
are usually the first imaging tests performed if a patient
has symptoms. However, results are normal in up to 4%
of patients with lung cancer 56. Accordingly, all patients
clinically and radiologically suspected of having a lung
tumour must undergo a contrast-enhanced CT scan of
the chest and the upper abdomen. A chest CT scan will
delineate the size and shape of the lesions, their loca-
tion and their relationship to neighbouring structures,
such as vessels, the heart, chest wall and oesophagus.
Moreover it is very important for the assessment of the
mediastinum, which is crucial for a correct staging 55.
Given that lung cancer commonly metastasizes to the
brain, assessment of the brain is warranted. However, in
most studies, CT and MRI of the brains of patients with
NSCLC with negative clinical examination results in a
detection rate of 0–10% of brain metastasis, possibly ren-
dering the test cost-ineffective56. False-positive results can
be a problem in up to 11% of patients owing to brain
abscesses, gliomas or other lesions. Regardless, brain
imaging should be performed in patients with early-
stage lung cancer who are eligible for surgery on the lung
lesion. MRI is more sensitive than CT when scanning the
brain and identifies more and smaller lesions, but this
does not always translate into a clinically meaningful dif-
ference in terms of survival57, although it is essential when
planning brain stereotactic radiotherapy or neurosurgery.
As well as CT, 18‑fluorodeoxyglucose (FDG) positron
emission tomography (PET) is used to provide informa-
tion about the metabolic nature of the lung tumour and
its possible related lesions (lymphonodal invasion or
metastases). Understanding of the metabolic profile of
the tumour might help in determining whether patients
are eligible for surgery or radiotherapy. Although no
specific uptake value that defines malignancy exists, a
maximum FDG standardized uptake value (SUV) of
2.5 has been used to differentiate benign tumours from
malignant tumours. However, low-grade tumours might
have SUVs of less than 2.5, yielding false-negative results,
whereas inflammatory and infectious lesions might have
SUVs of higher than 2.5, yielding false-positive results58.
Staging of patients selected for surgery is mandatory to
reduce needless exploratory thoracotomy. However, the
limitations of PET scanning include that it is not able
to define the size of the lesion and that positive lesions
require histological confirmation. The latter feature is
of paramount importance, particularly in the field of
mediastinal staging.
Sputum cytology. Sputum samples for cytological exami-
nations can be obtained spontaneously or by stimulation
with nebulized saline. Its mean sensitivity and speci­ficity
to detect lung cancer are 0.66 and 0.99, respectively, ren-
dering high diagnostic values in patients with chronic
obstructive pulmonary disease or with haemoptysis59,60.
Bronchoscopy. Flexible bronchoscopy is a recommended
approach in patients suspected of having a centrally
located lung tumour. An added benefit of broncho­
scopy over other imaging techniques is that diagnostic
specimens can be obtained simultaneously using biopsy
 PRIMER

a Chest X-ray b CT c PET

d Cytology e Bronchoscopy f Transthoracic needle

aspiration biopsy
Visual image
EBUS–TBNA
EBUS–radial
probe
Transbronchial
lung biopsy

g Mediastinoscopy h Thorascopy i Thoracentesis

Pleural
fluid

Figure 6 | Diagnosis of lung cancer.  Chest X‑ray (part a), CT scan (part b) and positron emission tomography (PET) scan
Nature Reviews | Disease Primers
(part c) showing the lung tumour (arrows). Schematic representations of different techniques (parts d–i) that are used to
obtain a tumour specimen. EBUS, endobronchial ultrasonography; TBNA, transbronchial needle aspiration.

forceps; brushing and bronchoalveolar lavage have a
marginal contribution to diagnosis due to their low sen-
sitivity and specificity 61,62. Nowadays, other technologies
such as ultrasonography and radiography can be com-
bined with conventional bronchoscopy to sample sus-
pected lung tumours that are not directly invading the
bronchi or those that are in the periphery of the lung.
Endobronchial ultrasonography (EBUS) transbron-
chial needle aspiration (TBNA) is indicated to sample
peribronchial mass, enlarged mediastinal or hilar lymph
nodes and other mediastinal tumours. EBUS–TBNA is
a less invasive method for staging and diagnosing lung
cancer than mediastinoscopy, but it has equivalent high
specificity and sensitivity 63. This technique obtains suffi-
cient tumour sample for complete histological evaluation,
immunohistochemistry and molecular testing 64.
Peripheral pulmonary nodules can be diagnosed
endoscopically with transbronchial lung biopsy or, more
rarely, with transbronchial needle aspiration. The diag-
nostic yield of transbronchial lung biopsies in periph-
eral lesions varies depending on the morphology and
size of the lesion. The use of miniaturized ultrasound
probes (known as radial EBUS probes) has been shown
to enhance the diagnostic accuracy of transbronchial
lung biopsy 65. Electromagnetic navigation also seems
to enhance the diagnostic yield of conventional trans-
bronchial lung biopsies. Electromagnetic navigation is,
however, time consuming and costly.
Transthoracic needle aspiration. Transthoracic needle
aspiration biopsy is the diagnostic procedure of choice
for peripheral lesions when bronchoscopy returns a neg-
ative result. The sensitivity of this procedure is 0.9 but
tends to be lower for lesions <2 cm in diameter 55. Rapid
on‑site evaluation is required in which the adequacy of
the specimen is analysed by a cytopathologist during
the procedure. Different techniques are used: an aspira-
tion biopsy through a fine needle to obtain a cytologi-
cal specimen, and a Tru-Cut needle (CareFusion, San
Diego, USA) biopsy to obtain a sample for histological
analysis. There is an acceptable incidence of related com-
plications such as pneumothorax (5–61%), for which
the frequency of serious complication that requires
any intervention is relatively low, and pulmonary
haemorrhage (5–10%).
Mediastinal staging. The EBUS–TBNA is now rec-
ommended as the procedure of choice for invasive
media­stinal staging in lung cancer 66. EBUS is a less
invasive method than mediastinoscopy and can reach
the inter­lobar, mediastinal and hilar lymph node sta-
tions. All hilar and mediastinal lymph node stations
can be sampled with the exception of stations 5 (sub-
aortic) and 6 (para-aortic) (FIG. 7a). When performed
with rapid on‑site evaluation by experienced personnel,
EBUS–TBNA for mediastinal staging has the same sen-
sitivity and specificity as mediastinoscopy. Moreover,

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER
a b
Lymph Needle
node
Lymph
node
Figure 7 | Strategy for invasive mediastinal staging.  Nature
a | Chest CT scan
Reviews showingPrimers
| Disease a
station 6 lymph node not amenable for endobronchial ultrasonography transbronchial
needle aspiration biopsy. b | Echoendoscopic view of the needle entering the core of the
pathology in the left paratracheal lymph node.
EBUS–TBNA has the advantages of being a less invasive
procedure and can be performed in an outpatient setting
without major complications67 (FIG. 7b).
Surgical exploration of the mediastinum. Media­
stinoscopy, parasternal mediastinotomy and extended
cervical spine mediastinoscopy can be used to diagnose
and stage lesions when less invasive approaches have failed
to do so. These techniques provide tissue for histo­logical
diagnosis and information on the mediastinal nodal
status (N2 or N3 disease) and direct mediastinal invasion
of the primary tumour (T4 disease).
Pleural diagnostic techniques. Thoracentesis and cyto-
pathological analysis of the pleural fluid should be per-
formed in all patients with confirmed or suspected lung
cancer with pleural effusion. If two thoracentesis pro­
cedures are negative, thoracoscopy is recommended to
rule out pleural involvement 55.
Screening
The most important aims of an ideal lung cancer screen-
ing programme should be to detect lung cancer at an
early stage to modify prognosis, have a low percentage of
false-positives, minimize adverse effects for the patient,
and be cost-effective for the health system68.
Many scientific societies recommend low-dose CT for
lung cancer screening in individuals who fulfil the selec-
tion criteria specified by the National Lung Screening
Trial (NLST): namely, that they are smokers over 55 years
of age. This recommendation is based on the finding of a
20% relative risk reduction in lung cancer mortality and
a 6.7% reduction in all-cause mortality with low-dose CT
screening versus chest X‑ray in the NLST69.
However, the use of low-dose CT scanning for
screening­-eligible populations is not without harm68.
First, the false-positive rate is high. Based on the NLST
data, we estimate that for each 1,000 people having three
rounds of screening, 242 individuals would have expe-
rienced a false-positive and four would have undergone
surgery for something later shown to be benign68–71.
Second, approximately 18% of the detected cancers
are likely to be overdiagnosed (NLST data)69, which
8 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
increases the cost and reduces the efficacy of a screening
programme. Third, lung cancer screening with low-dose
CT is not always effective68. For example, the NLST had a
6% false-negative rate; 66% of tumours detected after an
initial negative screen were found to be grades IIIB–IV,
suggesting extremely rapid tumour growth68. Fourth, the
radiation associated with CT itself might increase the
risk of lung cancer; CT is thought to cause an estimated
24 deaths per 100,000 screened people72.
One of the most important objectives of a screening
programme, if not the most important, is to achieve a
modification of the clinical outcome of the disease. Thus,
tumours need to be detected early when interventions
(surgery plus other treatments) are most effective68.
Perhaps the most striking issue related to lung cancer
screening with low-dose CT is that more low-stage
tumours are detected in the incidence rounds (second
and third follow‑up) compared with the prevalence
round (first scan). The percentage of lung cancers at
stages IIIA, IIIB and IV was 37.8% at the prevalence
round, compared with 30% in the third round. These fig-
ures for stages IA and IB, were 54.6% and 63.9% for the
prevalence and third rounds, respectively. These results
strongly suggest that approximately 30% of screen-
detected lung cancers would not benefit from screening
because surgical resection would not be possible due to
the high stage or would not be effective.
Combining low-dose CT with plasma microRNA
profiling could improve the effectiveness of screening
by avoiding unnecessary CT scans and invasive diag-
nostic follow‑up73. Indeed, in a retrospective analysis
of samples prospectively collected from smokers within
the randomized Multicenter Italian Lung Detection
(MILD) trial, the plasma microRNA signature showed
excellent diagnostic performance for malignant disease
presence73. The trial also demonstrated that plasma
microRNA levels were predictive of the risk of future
malignancy and were able to distinguish lung cancers
from the large majority of benign pulmonary nodules
detected by low-dose CT73.
Prevention
Of all the lifestyle factors, smoking cessation has the
highest positive effect on reducing the risk of sub-
sequently developing lung cancer. The lifelong male
smoker has a cumulative risk of 15.9% of dying from
lung cancer by the age of 75 years, but the cumulative
risk for men who cease smoking at the ages of 60, 50,
40 and 30 years falls to 9.9%, 6%, 3% and 1.7%, respec-
tively. Thus, termination of smoking should be strongly
encouraged in both sexes and at all ages47. Although
these data only deal with benefits before lung can-
cer development, smoking cessation after diagnosis
increases survival by months, which is an improvement
on the outcomes achieved by conventional therapy 74–76.
In contrast to other malignant tumours, especially those
of the gastrointestinal tract, the association between diet
and the risk of lung cancer is not strong. A slight but sta-
tistically significant protective effect of consuming fruit
and vegetables has been described, probably owing to
their antioxidant and cell growth inhibitory activities77.

Environmentally, a reduced level of exposure to par-
ticulate matter air pollution could contribute to a reduc-
tion in the incidence of lung cancer. However, the increase
in an individual’s risk of lung cancer owing to air pollu-
tion is far lower than the risk due to tobacco smoking 47.
Finally, radon-related deaths are not caused by very high
radon concentrations but by exposure to moderate con-
centrations. Policies should, therefore, aim to eliminate
the use of radon in all new buildings, which could avoid
a substantial proportion of radon-related lung cancers
and has been suggested to be highly cost-effective78.
Management
NSCLC is a heterogeneous disease; thus, treatment
should be personalized according to the patient’s clini-
cal condition (performance status), stage of disease,
histological cell type and molecular profile. Tumours
are generally classified into three treatment categories:
resectable, locally advanced and advanced NSCLC.
Resectable NSCLC
Standard curative treatment for patients with resectable
NSCLC is lobectomy by video-assisted thoracoscopic
surgery 79. This minimally invasive approach can reduce
postoperative morbidity and duration of hospitalization,
but eligibility depends on the individual patient, the loca-
tion of the tumour and the expertise of the centre. The
adequacy of small-volume resection such as wedge resec-
tion (whereby a triangle-shaped slice of tissue is removed)
and segmentectomy (whereby tissue is removed using
veins, arteries and airways as guidelines) continues
to be controversial. Standardized resection of media­
stinal lymph nodes remains a crucial part of successful
thoracic surgery, and lymph node dissection instead of
node sampling alone should be the standard.
For patients who are not surgical candidates owing
to medical reasons (for example, cardiac or pulmonary
failure), stereotactic ablative radiotherapy is a poten-
tial treatment option with similar efficacy to surgery 80.
A population-based study involving elderly patients
(>75 years of age) reported an arrest of tumour growth
(local control) in more than 90% of patients.
Adjuvant chemotherapy is an established therapy for
patients with stage II/III resectable NSCLC. Multiple
large randomized studies have demonstrated improve-
ment in overall survival. A meta-analysis of these trials
estimated the benefit to be a 4% increase in 5‑year sur-
vival rate (hazard ratio (HR) 0.86, P <0.0001)81. However,
the role of adjuvant chemotherapy for patients with
stage IB disease remains debatable.
Furthermore, the use of adjuvant radiotherapy is lim-
ited to selected patients (those with N2 disease). Indeed,
meta-analyses of postoperative radiotherapy reported
detrimental effects on patients with stage I/II disease82;
only patients with N2 disease (stage III) or known posi-
tive resection margins might benefit from postoperative
radiotherapy. However, this question is being prospec-
tively addressed in the ongoing randomized Phase III
study, the Lung Adjuvant Radiotherapy Trial (Lung-
ART), which is enrolling patients with radically resected
stage IIIA–N2 cancers83.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
Locally advanced NSCLC
Multimodal therapy is indicated for patients with
stage III disease. Sequential chemotherapy followed
by radio­therapy has been compared with concurrent
administration of chemotherapy and radiotherapy in
several randomized studies. Meta-analyses of these
studies showed that overall survival was improved
by 16% (HR 0.84, P = 0.004), favouring concurrent
administration84. However, the concurrent approach
is associated with higher incidence of oesophagitis
and pneumonitis and should be avoided in patients
with comorbities or poor health. Addition of induc-
tion chemotherapy prior to chemoradiotherapy is
associated with slightly higher response rates, but no
improvement in overall survival, and with higher toxi­
city 85. For consolidation chemotherapy after chemo­
radiotherapy, the Hoosier Oncology Group performed
a randomized study that demonstrated similar overall
survival but more toxicity associated with single agent
docetaxel versus no further treatment after concur-
rent chemoradiotherapy 86. The study was prematurely
terminated for this reason.
Consolidation immunotherapy has also been investi-
gated, for example, with tecemotide, which is a tumour
vaccine against the mucin 1 cancer antigen. The drug was
investigated in a randomized Phase III study (START)
in patients with stage III NSCLC87. The study outcomes
were negative, with no evidence of improvement in over-
all survival (median 25.6 months versus 22.3 months;
P = 0.123). Only in the subgroup analysis of patients
who completed concurrent chemotherapy did overall
survival tend to be improved (median 30.8 months ver-
sus 20.6 months; P = 0.016). A subsequent randomized
study focusing on the patients who completed concur-
rent chemoradiotherapy was initiated to confirm this
observation; however, the study was terminated pre-
maturely after interim analysis showed no benefit with
this experimental treatment. In summary, the standard
therapy for patients with unresectable stage III NSCLC
remains concurrent chemoradiotherapy, even though
patients with stage III are highly variable and require an
individualized treatment plan.
Advanced-stage NSCLC
Treatment of advanced-stage lung cancer should be per-
sonalized according to histological cell type, genomic
mutation profile and performance status. All patients
with histologically confirmed adenocarcinoma should
be tested for EGFR mutations and ALK rearrangement88.
In advanced-stage disease, molecular targeted therapy is
the standard first-line treatment for patients with these
identified driver mutations (FIG. 8), whereas systemic
cytotoxic chemotherapy is the standard treatment for
patients without EGFR mutations or ALK rearrangement
or those with unknown mutation status.
Patients with EGFR mutations. A total of eight rand-
omized studied have confirmed that first-line EGFR
TKIs are superior to standard platinum-based chemo­
therapy 89. EGFR TKIs are associated with a high
tumour response rate (ranging from 56% to 86%),
PRIMER
VEGF-specific antibodies EGFR-specific antibodies
Bevacizumab Necitumumab*
VEGFR EGFR ALK
EGFR TKIs
Erlotinib ALK TKIs
VEGFR-specific antibodies Gefitinib Crizotinib
Ramucirumab Afatinib Ceritinib
Figure 8 | Management of non-small-cell lung cancer.Nature
DrugsReviews
approved| Disease Primers
by the FDA for
the treatment of non-small-cell lung cancer. ALK, anaplastic lymphoma kinase; EGFR,
epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; VEGF, vascular
endothelial growth factor; VEGFR, VEGF receptor. *Approval pending.
prolonged progression-­free survival (ranging from 8.4
to 11.0 months) and improved health-related quality of
life compared with standard chemotherapy. Although
second-line EGFR TKIs after chemotherapy are suggested
to be equally effective, it is preferable to start with EGFR
TKI to maximize benefit, especially given that approxi-
mately 25% of patients are not eligible for TKI therapy
owing to rapid progression. Most patients would respond
to EGFR TKIs but will then almost always develop resist-
ance. However, the pattern of resistance is variable. Many
patients have oligoprogression, with fewer than four
sites of progression. Local treatment of these sites, such
as radiotherapy or radiofrequency ablation, is effective
in controlling the oligoprogression, and continuation
of EGFR TKI therapy might sustain systemic control.
A recent study (ASPIRATION) suggested that treatment
beyond the progression level as specified by the RECIST
(Response Evaluation Criteria In Solid Tumours) guide-
line might extend the duration of TKI benefit by an
additional 3 months90. For patients who have systemic
progression associated with symptoms or rapid progres-
sion, EGFR TKI therapy should be stopped and changed
to standard platinum-based chemo­therapy. In the
IMPRESS study, continuation of the EGFR TKI gefitinib
in combination with standard platinum-based chemo-
therapy was compared to chemotherapy alone; similar
progression-free survival was demonstrated (median
5.4 months versus 5.4 months; HR 0.86, P = 0.27)91. Thus,
patients with EGFR mutations should receive a first-line
EGFR TKI and patients with oligoprogression should
consider local treatment and EGFR TKI continuation
treatment. Only upon systemic and/or symptomatic pro-
gression should patients be switched to platinum-based
doublet chemotherapy.
The mechanisms underlying EGFR TKI resistance
include the presence of exon 20 T790M gatekeeper
mutation, MET amplification and mesenchymal trans-
formation, among others. The most common cause of
resistance is the T790M mutation, which accounts for
approximately 60% of all cases of EGFR TKI resistance92.
Mutation of a single amino acid changes the ATP binding
affinity of the kinase and reduces the sensitivity to ATP-
competitive TKIs. The second-generation EGFR TKIs,
10 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
such as afatinib and dacomitinib, can inhibit lung cancer
cell lines with the T790M mutation93; however, the thera-
peutic dose of these drugs might prove to be too toxic
for clinical use. The third-generation TKIs selectively
target the T790M mutation; they have lower activity on
wild-type EGFR and, accordingly, lower toxicity. Novel
agents — including AZ9291, CO1686, H61713 and
WZ4002 — are under intensive investigation94.
Patients with ALK rearrangement. Similar to muta-
tions in EGFR, rearrangements in ALK are driver onco-
genes, and patients with ALK-positive lung cancer are
highly responsive to TKIs95. Crizotinib was the first TKI
approved for first and subsequent lines of treatment of
ALK-positive NSCLC. This ATP-competitive kinase
inhibitor specifically targets human ALK and HGF recep-
tor. A Phase I/II study (PROFILE 1001) on a biomarker-
selected population with ALK rearrangement reported
tumour response rates of 60% (REF. 96). A follow‑up
expanded cohort of 261 patients with ALK-positive lung
cancer confirmed tumour response rates of 59.8% and
median progression-free survival of 8.1 months. Two
randomized studies have independently confirmed the
role of crizotinib as a first-line and second-line therapy,
respectively97,98. PROFILE 1014 compared first-line crizo-
tinib with doublet chemotherapy and reported superior
response rates (74% versus 46%, respectively; P <0.001)
and prolonged progression-free survival (median
10.1 months versus 7 months, respectively; HR 0.45,
P <0.001). The second-­line study (PROFILE 1007) also
reported superior response rates and progression-free
survival over single-agent chemotherapy. Furthermore,
crizotinib is generally well tolerated; common toxicities
include visual disorders, nausea, vomiting, diarrhoea
and oedema. Uncommon but potentially fatal toxici-
ties include hepatic toxicity and interstitial lung disease.
Thus, all patients with adenocarcinoma should be tested
for ALK rearrangement and first-line crizotinib should be
offered to patients with ALK-positive lung cancer.
Similar to EGFR TKIs, almost all patients will eventu-
ally develop resistance to ALK inhibitors. Mechanisms of
resistance are diverse and might include ALK alteration
or activation of bypassing signalling pathways99. Multiple
gatekeeper mutations in ALK have been reported and
the most common mutations include L1196M, L1152R,
C1156Y, S1206Y and G1269A. Bypass pathways can
include activation of pathways involving EGFR, KRAS
and KIT. Ceritinib, a potent second-generation ALK
inhibitor for patients who failed to respond to crizo-
tinib, was investigated in a single-group dose-escalation
study. The tumour response rate in those receiving ceri-
tinib was 56% and median progression-free survival was
7 months100. Despite limited data and the fact that two
randomized studies comparing first-line101 and second-
line102 ceritinib with standard chemotherapy are cur-
rently ongoing, ceritinib has already been approved
by the FDA. Other second-generation ALK inhibitors,
including alectinib and AP26113, are also under inten-
sive investigation. Interestingly, preliminary results
showed that these second-generation ALK inhibitors
seem to have rapid clinical activity in brain metastases.
 PRIMER

Patients with ROS1 rearrangement. ROS1 rearrangement (a VEGFR2‑specific antibody) plus docetaxel to docetaxel
is another driver oncogene that is highly responsive to alone also reported a modest improvement in median
crizotinib. In an expansion cohort of the Phase I study 103, overall survival from 9.1 months to 10.5 months (HR
50 patients with ROS1‑positive NSCLC received crizo- 0.86, P = 0.023) (REF. 112). Nintedanib is now approved
tinib and showed an objective response rate of 72% with a in Europe, whereas ramucirumab is approved in the
median duration of response of 17.6 months and a median United States. Thus, it is a reasonable to assume that anti-
progression-free survival of 19.2 months. The safety pro- angiogenic therapy will be integrated into second-line
file of crizotinib was similar to that in patients with ALK- treatment of advanced NSCLC in future.
rearranged NSCLC. To date, crizotinib is available on the
market for the treatment of patients with ROS1‑positive Quality of life
NSCLC in the United States but not in Europe103. Most patients with NSCLC who are diagnosed with
advanced-stage disease experience disease-related
Patients without driver oncogene mutations or with symptoms such as cough, dyspnoea, pain, anorexia and
unknown mutation status. Standard first-line therapy fatigue, which might have a negative impact on their
should be one of the platinum-based doublet chemo- quality of life. Life expectancy of the majority of these
therapy regimens for patients with unknown mutational patients is very poor; median overall survival is approxi-
status or those with tumours that have no known driver mately 10–12 months. Thus, an important goal of the
mutation104,105. Pemetrexed-based combinations were treatment of these patients is palliation, both through
shown to be superior to gemcitabine-based combina- improvement in quality of life and prolongation of sur-
tions for patients with adenocarcinoma, but otherwise, vival113. The Elderly Lung cancer Vinorelbine Italian
efficacy is similar between the standard regimens (plati- Study (ELVIS), the first Phase III trial in lung cancer in
num in combination with any of paclitaxel, gemcitabine, which the quality of life was the primary end-point, com-
docetaxel and vinorelbine). Addition of bevacizumab, pared single-agent vinorelbine chemotherapy to standard
a VEGF-specific monoclonal antibody, to standard supportive care in elderly patients (>70 years of age) with
chemotherapy improves efficacy, but the drug is contra­ advanced-stage NSCLC. Results from the study showed
indicated in patients with squamous cell carcinoma, that survival and quality of life was better in the chem-
haemoptysis or both106. In patients with non-squamous otherapy-treated group114. Recently, a literature search
histology when first-line chemotherapy triggers a showed that platinum-based regimens and even single-
response or stabilizes disease, maintenance therapy with agent chemotherapy had a positive impact on quality
single-agent pemetrexed can be considered107. of life and disease-specific symptoms115. This finding is
Patients who received four cycles of first-line in line with those of a survey in which 68% of patients
pemetrexed and cisplatin were randomly assigned to preferred a therapy that would improve disease-related
receive maintenance pemetrexed or placebo in the symptoms without prolonging their life as opposed to
PARAMOUNT study, and median overall survival from therapies that slightly prolonged their survival without
randomization of the study group was 13.9 months com- improving symptoms116.
During clinical trials, patient-
pared with 11.0 months in the placebo group (HR 0.78, reported outcomes and quality of life benefits are usu-
P = 0.019)107. Moreover, switching to maintenance ther- ally assessed using the following self-administered
apy with pemetrexed or erlotinib in non-squamous and questionnaires: European Organization for Research
erlotinib in squamous NSCLC is another option for and Treatment of Cancer (EORTC) QLQ C30, lung can-
patients who do not show disease progression after four cer EORTC QLQ LC13 (REF. 117), Euro QOL EQ‑5D118
cycles of platinum-based chemotherapy 108,109. If patients and the Lung Cancer Subscale (LCS) of the Functional
progress but have good performance status, second-line Assessment of Cancer Therapy-Lung (FACT‑L)119.
single-agent chemotherapy with either doce­taxel or In this era of personalized medicine, the higher over-
pemetrexed is indicated (if the patient had no prior expo- all benefit reported for targeted therapies compared with
sure to either of these drugs)110. However, the tumour chemotherapy included a positive effect on quality of life
response rate is <10% and associated with only slight (TABLE 2). The ability to improve quality of life by con-
improvement in overall survival110. Adding an oral VEGF trolling cancer-related symptoms is an important part
receptor (VEGFR) inhibitor, nintedanib, to second-­ of clinical practice120–124.
line docetaxel can improve progression-free survival Palliative care has an important role in the man-
(median 3.4 months with the combination therapy versus agement of patients with lung cancer. In fact, patients
2.7 months with docetaxel alone; HR 0.79, P = 0.0019)111. receiving palliative care (which provides control of pain
Overall survival was also modestly improved, but only and other symptoms, and emotional support) early in
in patients with adenocarcinoma (median 12.6 months the course of their cancer treatments reported better
with the combination therapy versus 10.3 months with quality of life, were less likely to be depressed and had a
docetaxel alone; HR 0.83, P = 0.0359). Patients with 3‑month longer median survival than those who did not
adenocarcinoma whose disease progressed within receive such specific support 125. Although this finding
9 months after starting first-line therapy showed a needs to be confirmed in additional trials, such results
median overall survival of 10.9 months with the combi- could influence perceptions of oncologists and lead to
nation therapy versus 7.9 months with docetaxel alone earlier use of palliative care. Lung cancer is associated
(HR 0.75, P = 0.0073)111. Another randomized Phase III with smoking and age, both of which are associated with
study comparing a combination of ramucirumab comorbidities such as cardiovascular and respiratory

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

illnesses, including hypertension, angina, myocardial
infarction, congestive heart failure and chronic obstruc-
tive pulmonary disease. Balancing the decision to treat
patients with NSCLC should, therefore, take the benefits
and toxicity of therapies and comorbidities into account.
Outlook
Lung adenocarcinoma comprises distinct mutational
subtypes in receptor tyrosine kinases and RAS pathway
members, including KRAS, EGFR, BRAF and HER2,
and translocations involving ALK, ROS1 and RET.
Identification of these genetic lesions permits the appli-
cation of specific targeted therapies. However, such
mutations have only been reported in 55% of lung
adeno­carcinomas. Other oncogenic mutations have
been noted in MAP2K1, HRAS, NRAS and MET18. Also,
RIT1 (which encodes RAS-like in all tissues) has been
found to be mutated in 2% of lung adenocarcinomas;
PI3K and MEK inhibition is a potential therapeutic for
such tumours18,126. Several mechanisms of resistance in
preclinical models and in tumour tissue from patients
harbouring EGFR mutations have been reported, includ-
ing HER2 (REF.  127) or MET amplification128, BRAF
mutations129, neurofibromin 1 (NF1) loss130 and AXL
overexpression131. However, the best-established mech-
anism of acquired resistance is the EGFR gatekeeper
mutation exon 20 T790M. Although second-generation,
irreversible TKIs that target HER2 (including afatinib
and dacomitinib) are able to inhibit EGFRT790M in vitro,
these agents have not been shown to induce meaning-
ful benefits in clinical trials in patients who have failed
to respond to first-generation TKIs132. The combination
of afatinib plus the EGFR-specific antibody cetuximab
yielded a response rate of 29% in patients harbouring
EGFR mutations whose disease had progressed on the
first-generation reversible EGFR inhibitors erlotinib or
gefitinib133. New drugs were designed to target activat-
ing mutations in EGFR (T790M and others) more selec-
tively than wild-type EGFR134,135. The agents AZD9291,
CO1686, H61713 and WZ4002 showed response rates
of up to 64% in early Phase I clinical trials in patients
with tumours harbouring activating mutations in EGFR
at diagnosis who had clinically acquired resistance to
first- and second-generation EGFR TKIs and the T790M
mutation136. Both AZD9291 and CO1686 are under fast-
track review by the FDA. Large single-arm Phase II stud-
ies, namely AURA 2 (REF. 137) and TIGER 2 (REF. 138),
and randomized Phase  III trials, named AURA  3
(REF. 139) and TIGER 3 (REF. 140), will further support
approval of AZD9291 and CO1686.
Importantly, the T790M mutation was experimen-
tally detected in multiple independent clones of PC9
cells, a cell line derived from adenocarcinoma cells with
acquired resistance to gefitinib or afatinib, but not in
clones resistant to AZD9291 (REF. 134). Interestingly,
CO1686‑resistant NSCLC cell lines are sensitive to AKT
inhibition. AKT3 and ALX overexpression was identified
in these resistant cell lines. The receptor tyrosine kinase
AXL can be inhibited using several selective inhibitors131,
as well as a VEGFR inhibitor and MET inhibitors, such
as foretinib and exelixis. Pharmacological inhibition of
AXL kinase activity restored partial sensitivity of EGFR
TKI-resistant (CO1686) cells132. Administration of third-
generation selective EGFR inhibitors to patients with
NSCLC harbouring T790M mutation at diagnosis would
be interesting. Although the T790M mutation is rare in
untreated patients, the EURTAC study reported the pres-
ence of the T790M mutation in >50% of treatment-naive

Table 2 | QOL assessment in EGFR TKIs versus chemotherapy in patients with advanced-stage NSCLC with EGFR mutations
Study* Regimen Assessment Assessment Results
time points
IPASS120 Gefitinib versus At baseline, week Improvement ≥6 points in FACT‑L and • FACT‑L: OR = 3.01, 95% CI = 1.79–0.07;
chemotherapy 1, once every TOI scores or ≥2 points in LCS scores P <0.0001
3 weeks until day maintained for at least 21 days • TOI: OR = 3.96, 95% CI = 2.33–6.71; P < 0.0001
127, then every • LCS: OR = 2.70, 95% CI = 1.58–4.62; P = 0.0003
6 weeks until PD
NEJ002 Gefitinib versus Weekly from Time to definitive deterioration from • Physical well-being: P <0.001
(REF. 121) chemotherapy baseline until PD baseline by 9% on each questionnaires • Mental well-being: P = 0.458
• Life well-being: P <0.001
OPTIMAL122 Erlotinib versus Baseline, every Clinically relevant improvement at each • FACT‑L: P <0.001
chemotherapy 6 weeks cycle was predefined as an improvement • TOI: P <0.001
of ≥6 points in scores on the FACT‑L and • LCS: P <0.001
TOI, or an improvement of ≥2 points in
scores on the LCS of the FACT‑L
LUX-Lung 3 Afatinib versus Baseline, every A 10‑point change in an item or domain • Global health status or QOL: P = 0.015
(REF. 124) chemotherapy 3 weeks is accepted as the threshold for being • Physical: P <0.001
clinically meaningful • Role: P = 0.004
• Cognitive: P = 0.007
LUX-Lung 6 Afatinib versus Baseline, every A 10‑point change in an item or domain • Global health status or QOL: P <0.0001
(REF. 123) chemotherapy 3 weeks is accepted as the threshold for being • Physical: P <0.0001
clinically meaningful • Role: P = 0.01
• Social: P <0.001
CI, confidence interval; EGFR, epidermal growth factor receptor; FACT‑L, Functional Assessment of Cancer Therapy–Lung; LCS, Lung Cancer Subscale; NSCLC,
non-small-cell lung cancer; OR, odds ratio; PD, progression of disease; QOL, quality of life; TKIs, tyrosine kinase inhibitors; TOI, Trial Outcome Index. *Phase III
randomized clinical trials.

12 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved


BCR EGFR FLT3
SFK
EGFR
SYK TKIs del19 P
L858R SYK
Igα
BTK Ibrutinib T790M PKC412
Igβ
P
PI3K P RAS P JAK1/2 IKKγ
IKKα IKKβ
AKT RAF STAT3 P
MEK1/2 NF-κB
Survival, proliferation,
MAPK1/2
invasion, metastasis
Nature Reviews
Figure 9 | Intersection of the FLT3, SYK and EGFR pathways.  | Disease
The activated Primers
receptors
epidermal growth factor receptor (EGFR), B cell receptor (BCR) and FMS-like tyrosine
kinase 3 (FLT3) trigger a number of intracellular mediators, including AKT, MAPK, signal
transducer and activator of transcription (STAT) and nuclear factor‑κB (NF‑κB), which have
a vital role in tumour progression. Ibrutinib, which irreversibly inhibits Bruton tyrosine
kinase (BTK), was found to selectively inhibit growth of non-small-cell lung cancer cells
with EGFR mutations including T790M, but the mechanism is unknown. PKC412, a
well-tolerated FLT3 inhibitor, has been identified as a potent and reversible inhibitor of
T790M. del19, exon 19 deletion; IKK, inhibitor of NF-κB kinase; JAK, Janus kinase; SFK, SRC
family protein kinase; SYK, spleen tyrosine kinase; TKIs, tyrosine kinase inhibitors.
patients with predictive significance for progression-free
survival: 9.7 months for patients with T790M mutations
and 15.8 months for patients without 141.
Intriguingly, PKC412 (also known as midostaurin),
an FMS-like tyrosine kinase 3 (FLT3) inhibitor used in
acute myeloid leukaemia142, was reported to selectively
inhibit T790M over wild-type EGFR 143. Moreover,
ibrutinib, which inhibits Bruton tyrosine kinase (BTK)
and was approved by the FDA for use in patients with
chronic lymphocytic leukaemia, was tested in EGFR-
positive NSCLC cell lines and inhibited the prolifera-
tion of erlotinib-resistant H1975 cells (which harbour
L858R and T790M mutations)144. Surprisingly, ibrutinib-
induced antitumour activity in these cells was not medi-
ated by the inhibition of BTK144. Instead, the interaction
of BTK with spleen tyrosine kinase (SYK) was implicated
in the resistance mechanism145. Indeed, in acute myeloid
leukaemia, SYK activation leads to resistance to FLT3
inhibitors in patients harbouring FLT3 mutations146.
Similarly, FLT3 and SYK could potentially intersect with
EGFR signalling pathways in patients with EGFR muta-
tions because gefitinib or erlotinib have been shown to
induce acute myeloid leukaemia differentiation via a
non-EGFR-medited mechanism147, with case reports of
clinical responses including complete remission148,149.
Altered SYK expression has been reported in several solid
tumours and a spliced SYK transcript (which encodes
a short form of SYK) induced epithelial–­mesenchymal
transition through the ERK pathway 150 (FIG. 9).
One unsolved aspect of the molecular biol-
ogy of NSCLC is that EGFR inhibitors never inhibit
the nuclear factor-κB (NF‑κB) pathway 151 or signal
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
transducer and activator of transcription 3 (STAT3)
signalling. An increasing amount of evidence even indi-
cates that EGFR inhibitors activate STAT3 (REFS 152,153)
almost immediately after treatment, via phosphorylation
of Tyr705. Eliminating STAT3 activation as well as inhib-
iting NF‑κB signalling can enhance the antiprolifera-
tive effects of EGFR inhibitors in vitro and in vivo154,155.
Thus, it is very important to identify biomarkers to select
patients with initial good responses, but rapid develop-
ment of resistance, to test and target novel therapeutic
approaches. An example is the BCL‑2‑like protein 11
(B2L11; also known as BIM)156. High levels of BIM
mRNA expression have been reported as a predictive
marker of response progression-free survival and over-
all survival in erlotinib-treated patients with NSCLC141.
In addition, one-third of patients with EGFR-mutant
NSCLC express high levels of BIM mRNA and have
immediate STAT3 phosphorylation and gradual eleva-
tion of STAT3 at the transcriptional level. Resistance to
ALK and ROS1 inhibitors depends on the type of com-
pound. Many tumours with secondary ALK mutations,
including the gatekeeper L1196M mutation, are resistant
to crizotinib but remain responsive to second-generation
ALK inhibitors such as ceritinib, alectinib and AP26113
(REFS 100,103,157). However, some specific mutations,
such as ALKG1202R and ROS1G2032, are not responsive to
any of these drugs158.
Recurrent alterations in receptor tyrosine kinases, such
as amplifications and translocations in genes encoding
FGFRs and mutations in discoidin domain receptor 2
(DDR2), have been identified in lung squamous cell car-
cinoma159,160. DDR2 mutations occur in 3–4% of patients
with lung squamous cell carcinoma and have been
reported in other cancer types at comparable frequen-
cies, including lung adenocarcinoma. Objective responses
have been observed with dasatinib, a DDR2 inhibitor 160.
Recently, mechanisms of acquired resistance to dasatinib
in NSCLC cell lines have been described, including acqui-
sition of the T654I gatekeeper mutation in DDR2 and loss
of NF1 (REF. 161). To better design drugs that provide dura-
ble responses for patients, we need to gain a more detailed
understanding of these resistance mechanisms.
Immunotherapy
Once considered an ineffective modality in lung cancer,
immunotherapy has now emerged as one of the most
promising therapeutic strategies. The CTLA4 and PD1
pathways, both expressed by T cells, are two examples
of immune checkpoint pathways that are being targeted
by potential anticancer therapies162,163. CTLA4 bind-
ing to its ligands (CD80 and CD86) on the surface of
antigen-presenting cells reduces T cell proliferation. PD1
binds to the PDL1 and PDL2, reducing T cell prolifera-
tion, altering cytokine production and inducing T cell
exhaustion and/or apoptosis164. Ipilimumab, a fully
human IgG1 CTLA4‑specific antibody that is already
approved for the treatment of melanoma, administered
in combination with carboplatin and paclitaxel in two
different schedules (phased or concurrent) has shown
promising results in 204 chemotherapy-naive patients
with advanced-stage NSCLC, particularly in those with
PRIMER
squamous histology 165. Among the PD1‑specific agents,
nivolumab (a fully human IgG4 antibody) and pem-
brolizumab (a humanized monoclonal IgG4 antibody
that is already approved by the FDA in a second-line
setting) have shown promising early clinical results and
are in advanced clinical development. The PDL1‑specific
1. Ferlay, J. et al. Cancer incidence and mortality
worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int. J. Cancer 136, E359–E386
(2014).
This paper provides up‑to‑date incidence and
mortality rates of cancer worldwide.
2. Goldstraw, P. et al. The IASLC Lung Cancer Staging
Project: proposals for the revision of the TNM stage
groupings in the forthcoming (seventh) edition of the
TNM classification of malignant tumours. J. Thorac.
Oncol. 2, 706–714 (2007).
3. Shepherd, F. A. et al. The International Association for
the Study of Lung Cancer lung cancer staging project:
proposals regarding the clinical staging of small cell
lung cancer in the forthcoming (seventh) edition of the
tumor, node, metastasis classification for lung cancer.
J. Thorac. Oncol. 2, 1067–1077 (2007).
4. Govindan, R. Changing epidemiology of small-cell lung
cancer in the United States over the last 30 years:
analysis of the surveillance, epidemiologic, and end
results database. J. Clin. Oncol. 24, 4539–4544
(2006).
5. Travis, W. D., Brambilla, E. & Riely, G. J. New
pathologic classification of lung cancer: relevance for
clinical practice and clinical trials. J. Clin. Oncol. 31,
992–1001 (2013).
This paper presents an up‑to‑date pathological
classification system of lung cancer.
6. Giroux, D. J. et al. The IASLC Lung Cancer Staging
Project. J. Thorac. Oncol. 4, 679–683 (2009).
7. Siegel, R., Ma, J., Zou, Z. & Jemal, A. Cancer statistics,
2014. CA. Cancer J. Clin. 64, 9–29 (2014).
8. Ferlay, J. et al. Cancer incidence and mortality
patterns in Europe: estimates for 40 countries in
2012. Eur. J. Cancer 49, 1374–1403 (2013).
9. American Cancer Society. Global cancer facts & figures
2nd edition. [online], http://www.cancer.org/acs/
groups/content/@epidemiologysurveilance/documents/
document/acspc-027766.pdf (2011).
10. Gabrielson, E. Worldwide trends in lung cancer
pathology. Respirology 11, 533–538 (2006).
11. Wahbah, M., Boroumand, N., Castro, C., El‑Zeky, F. &
Eltorky, M. Changing trends in the distribution of the
histologic types of lung cancer: a review of 4,439
cases. Ann. Diagn. Pathol. 11, 89–96 (2007).
12. Weibel, E. R. What makes a good lung? Swiss Med.
Wkly 139, 375–386 (2009).
13. Colby, T. V., Wistuba, I. I. & Gazdar, A. Precursors to
pulmonary neoplasia. Adv. Anat. Pathol. 5, 205–215
(1998).
14. Subramanian, J. & Govindan, R. Lung cancer in never
smokers: a review. J. Clin. Oncol. 25, 561–570
(2007).
15. Travis, W. D. et al. International Association for the
Study of Lung Cancer/American Thoracic Society/
European Respiratory Society: international
multidisciplinary classification of lung adenocarcinoma.
J. Thorac. Oncol. 6, 244–285 (2011).
16. Thunnissen, E. et al. Reproducibility of
histopathological diagnosis in poorly differentiated
NSCLC. J. Thorac. Oncol. 9, 1354–1362 (2014).
17. Shaw, A. T. & Engelman, J. A. ALK in lung cancer: past,
present, and future. J. Clin. Oncol. 31,
1105­–1111 (2013).
18. Collisson, E. A. et al. Comprehensive molecular
profiling of lung adenocarcinoma. Nature 511,
543–550 (2014).
An important paper describing lung
adenocarcinoma molecular profiling.
19. The Cancer Genome Atlas Research Network.
Comprehensive genomic characterization of squamous
cell lung cancers. Nature 489, 519–525 (2012).
An important paper describing squamous cell lung
carcinoma molecular profiling.
20. Rudin, C. M. et al. Comprehensive genomic analysis
identifies SOX2 as a frequently amplified gene in
small-cell lung cancer. Nat. Genet. 44, 1111–1116
(2012).
21. Cerami, E. et al. The cBio cancer genomics portal: an
open platform for exploring multidimensional cancer
14 | 2015 | VOLUME 1 www.nature.com/nrdp
monoclonal antibodies BMS‑936559 (a high-affinity
fully human IgG4), MPDL3280A (a human IgG1 that
contains an engineered Fc domain) and MEDI4736
(a human IgG1) have shown promising results in early-
phase trials and are currently being investigated in large
Phase III trials166,167.
genomics data. Cancer Discov. 2, 401–404 (2012).
This article presents an open-access resource of
cancer genomics data sets.
22. Gao, J. et al. Integrative analysis of complex cancer
genomics and clinical profiles using the cBioPortal.
Sci. Signal. 6, pl1 (2013).
This article provides an analysis of clinical profiles
based on cancer genomics.
23. Pao, W. & Miller, V. A. Epidermal growth factor
receptor mutations, small-molecule kinase inhibitors,
and non-small-cell lung cancer: current knowledge
and future directions. J. Clin. Oncol. 23, 2556–2568
(2005).
24. Oxnard, G. R. et al. Natural history and molecular
characteristics of lung cancers harboring EGFR exon
20 insertions. J. Thorac. Oncol. 8, 179–184 (2013).
25. Gazdar, A. F. Activating and resistance mutations of
EGFR in non-small-cell lung cancer: role in clinical
response to EGFR tyrosine kinase inhibitors.
Oncogene 28 (Suppl. 1), 24–31 (2009).
26. Carbone, D. P. An era of lung cancer iconoclasts.
J. Thorac. Oncol. 9, 436–437 (2014).
27. Gazdar, A. et al. Hereditary lung cancer syndrome
targets never smokers with germline EGFR gene
T790M mutations. J. Thorac. Oncol. 9, 456–463
(2014).
28. Yu, H. A. et al. Germline EGFR T790M mutation
found in multiple members of a familial cohort.
J. Thorac. Oncol. 9, 554–558 (2014).
29. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. &
Shokat, K. M. K‑Ras(G12C) inhibitors allosterically
control GTP affinity and effector interactions. Nature
503, 548–551 (2013).
30. De Bruin, E. C. et al. Spatial and temporal diversity in
genomic instability processes defines lung cancer
evolution. Science 346, 251–256 (2014).
31. Zhang, J. et al. Intratumor heterogeneity in localized
lung adenocarcinomas delineated by multiregion
sequencing. Science 346, 256–259 (2014).
32. Govindan, R. Cancer. Attack of the clones. Science
346, 169–170 (2014).
33. Roberts, S. A. et al. An APOBEC cytidine deaminase
mutagenesis pattern is widespread in human cancers.
Nat. Genet. 45, 970–976 (2013).
34. Marusyk, A. et al. Non-cell-autonomous driving of
tumour growth supports sub-clonal heterogeneity.
Nature 514, 54–58 (2014).
35. Polyak, K. & Marusyk, A. Cancer: clonal cooperation.
Nature 508, 52–53 (2014).
36. Bremnes, R. M. et al. The role of tumor stroma in
cancer progression and prognosis: emphasis on
carcinoma-associated fibroblasts and non-small cell
lung cancer. J. Thorac. Oncol. 6, 209–217 (2011).
37. Malanchi, I. et al. Interactions between cancer stem
cells and their niche govern metastatic colonization.
Nature 481, 85–89 (2012).
38. Weis, S. M. & Cheresh, D. A. Tumor angiogenesis:
molecular pathways and therapeutic targets.
Nat. Med. 17, 1359–1370 (2011).
39. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer.
Nat. Rev. Cancer 6, 392–401 (2006).
40. Madar, S. Goldstein, I. & Rotter, V. “Cancer associated
fibroblasts”— more than meets the eye. Trends Mol.
Med. 19, 447–453 (2013).
41. Trimboli, A. J. et al. Pten in stromal fibroblasts
suppresses mammary epithelial tumours. Nature
461, 1084–1091 (2009).
42. Chen, H. L. et al. Structural and functional analysis of
β2 microglobulin abnormalities in human lung and
breast cancer. Int. J. Cancer 67, 756–763 (1996).
43. Chen, H. L. et al. A functionally defective allele of
TAP1 results in loss of MHC class I antigen
presentation in a human lung cancer. Nat. Genet. 13,
210–213 (1996).
44. Wiedenfeld, E. A., Fernandez-Viña, M.,
Berzofsky, J. A. & Carbone, D. P. Evidence for
selection against human lung cancers bearing p53
missense mutations which occur within the
HLA A*0201 peptide consensus motif. Cancer Res.
54, 1175–1177 (1994).
© 2015 Macmillan Publishers Limited. All rights reserved
45. Pardoll, D. M. The blockade of immune checkpoints in
cancer immunotherapy. Nat. Rev. Cancer 12,
252–264 (2012).
46. Harvey, R. D. Immunologic and clinical effects of
targeting PD‑1 in lung cancer. Clin. Pharmacol. Ther.
96, 214–223 (2014).
47. Di Maio, M. et al. in ESTS Textbook of Thoracic
Surgery Ch. 41.1, 679–687 (European Society of
Thoracic Surgeons, 2014).
48. Couraud, S., Zalcman, G., Milleron, B., Morin, F. &
Souquet, P.‑J. Lung cancer in never smokers — a
review. Eur. J. Cancer 48, 1299–1311 (2012).
49. National Institutes of Health. National Cancer Institute
Smoking and Tobacco Control. Monograph 10: health
effect of exposure to environmental tobacco smoke
[online], http://cancercontrol.cancer.gov/brp/tcrb/
monographs/10/ (1999).
50. Raaschou-Nielsen, O. et al. Air pollution and lung
cancer incidence in 17 European cohorts: prospective
analyses from the European Study of Cohorts for Air
Pollution Effects (ESCAPE). Lancet. Oncol. 14,
813–822 (2013).
This paper provides the first evidence of a
correlation between air pollution and lung cancer.
51. Darby, S. Radon in homes and risk of lung cancer:
collaborative analysis of individual data from 13
European case–control studies. BMJ 330, 223
(2005).
52. Matakidou, A., Eisen, T. & Houlston, R. S. Systematic
review of the relationship between family history and
lung cancer risk. Br. J. Cancer 93, 825–833 (2005).
53. Coté, M. L. et al. Increased risk of lung cancer in
individuals with a family history of the disease: a
pooled analysis from the International Lung Cancer
Consortium. Eur. J. Cancer 48, 1957–1968 (2012).
54. Yamamoto, H. et al. Novel germline mutation in the
transmembrane domain of HER2 in familial lung
adenocarcinomas. J. Natl Cancer Inst. 106, djt338
(2014).
55. Rami-Porta, R. et al. in ESTS Textbook of Thoracic
Surgery Ch.44.1, 745 –773 (European Society of
Thoracic Surgeons, 2014).
56. Spiro, S. G., Gould, M. K. & Colice, G. L. Initial
evaluation of the patient with lung cancer: symptoms,
signs, laboratory tests, and paraneoplastic
syndromes: ACCP evidenced-based clinical practice
guidelines (2nd edition). Chest 132, 149S–160S
(2007).
57. Silvestri, G. A., Tanoue, L. T., Margolis, M. L.,
Barker, J. & Detterbeck, F. The noninvasive staging of
non-small cell lung cancer: the guidelines. Chest 123,
147S–156S (2003).
58. Antoch, G. et al. Non–small cell lung cancer: dual-
modality PET/CT in preoperative staging 1. Radiology
229, 526–533 (2003).
59. Thunnissen, F. B. J. M. Sputum examination for early
detection of lung cancer. J. Clin. Pathol. 56, 805–810
(2003).
60. Hubers, A. J., Prinsen, C. F. M., Sozzi, G., Witte, B. I.
& Thunnissen, E. Molecular sputum analysis for the
diagnosis of lung cancer. Br. J. Cancer 109, 530–537
(2013).
61. Rivera, M. P. & Mehta, A. C. Initial diagnosis of lung
cancer: ACCP evidence-based clinical practice
guidelines (2nd edition). Chest 132, 131S–148S
(2007).
62. Schreiber, G. & McCrory, D. C. Performance
characteristics of different modalities for diagnosis of
suspected lung cancer: summary of published
evidence. Chest 123, 115S–128S (2003).
63. Varela-Lema, L., Fernández-Villar, A. & Ruano-
Ravina, A. Effectiveness and safety of endobronchial
ultrasound-transbronchial needle aspiration: a
systematic review. Eur. Respir. J. 33, 1156–1164
(2009).
64. Nakajima, T. & Yasufuku, K. How I do it — optimal
methodology for multidirectional analysis of
endobronchial ultrasound-guided transbronchial
needle aspiration samples. J. Thorac. Oncol. 6,
203–206 (2011).

65. Kurimoto, N. Endobronchial ultrasonography using a
guide sheath increases the ability to diagnose
peripheral pulmonary lesions endoscopically. Chest
126, 959–965 (2004).
66. Detterbeck, F. C., Lewis, S. Z., Diekemper, R.,
Addrizzo-Harris, D. & Alberts, W. M. Executive
summary: diagnosis and management of lung cancer,
3rd ed: American College of Chest Physicians
evidence-based clinical practice guidelines. Chest 143,
7S–37S (2013).
67. Kinsey, C. M. & Arenberg, D. A. Endobronchial
ultrasound-guided transbronchial needle aspiration for
non-small cell lung cancer staging. Am. J. Respir. Crit.
Care Med. 189, 640–649 (2014).
68. Ruano-Ravina, A., Heleno, B. & Fernández-Villar, A.
Lung cancer screening with low-dose CT (LDCT), or
when a public health intervention is beyond the
patient’s benefit. J. Epidemiol. Commun. Health 69,
99–100 (2015).
69. Aberle, D. R. et al. Reduced lung-cancer mortality with
low-dose computed tomographic screening. N. Engl.
J. Med. 365, 395–409 (2011).
This article provides the first evidence of reduction
of lung cancer mortality through the use of
low-dose CT as a screening tool.
70. Kramer, B. S., Berg, C. D., Aberle, D. R. & Prorok, P. C.
Lung cancer screening with low-dose helical CT: results
from the National Lung Screening Trial (NLST). J. Med.
Screen. 18, 109–111 (2011).
71. Patz, E. F. et al. Overdiagnosis in low-dose computed
tomography screening for lung cancer. JAMA Intern.
Med. 174, 269–274 (2014).
72. Moyer, V. A. Screening for lung cancer: U. S.
Preventive Services Task Force recommendation
statement. Ann. Intern. Med. 160, 330–338 (2014).
73. Sozzi, G. et al. Clinical utility of a plasma-based
miRNA signature classifier within computed
tomography lung cancer screening: a correlative MILD
trial study. J. Clin. Oncol. 32, 768–773 (2014).
74. Videtic, G. M. M. et al. Continued cigarette smoking
by patients receiving concurrent chemoradiotherapy
for limited-stage small-cell lung cancer is associated
with decreased survival. J. Clin. Oncol. 21,
1544–1549 (2003).
75. Tammemagi, C. M., Neslund-Dudas, C., Simoff, M. &
Kvale, P. Smoking and lung cancer survival: the role of
comorbidity and treatment. Chest 125, 27–37
(2004).
76. Sardari Nia, P. et al. Prognostic value of smoking
status in operated non-small cell lung cancer. Lung
Cancer 47, 351–359 (2005).
77. Liu, Y. et al. Curcumin and resveratrol in combination
modulate drug-metabolizing enzymes as well as
antioxidant indices during lung carcinogenesis in mice.
Hum. Exp. Toxicol. http://dx.doi.org/10.1177/
0960327114551396 (2015).
78. Gray, A., Read, S., McGale, P. & Darby, S. Lung cancer
deaths from indoor radon and the cost effectiveness
and potential of policies to reduce them. BMJ 338,
a3110 (2009).
79. Farjah, F. et al. Safety and efficacy of video-assisted
versus conventional lung resection for lung cancer.
J. Thorac. Cardiovasc. Surg. 137, 1415–1421
(2009).
80. Haasbeek, C. J. A. et al. Early-stage lung cancer in
elderly patients: a population-based study of changes
in treatment patterns and survival in the Netherlands.
Ann. Oncol. 23, 2743–2747 (2012).
81. Arriagada, R. et al. Adjuvant chemotherapy, with or
without postoperative radiotherapy, in operable non-
small-cell lung cancer: two meta-analyses of individual
patient data. Lancet 375, 1267–1277 (2010).
82. [No authors listed.] Postoperative radiotherapy in non-
small-cell lung cancer: systematic review and meta-
analysis of individual patient data from nine
randomised controlled trials. PORT Meta-analysis
Trialists Group. Lancet 352, 257–263 (1998).
83. Le Pechoux, C. et al. Need for a new trial to evaluate
adjuvant postoperative radiotherapy in non-small-cell
lung cancer patients with N2 mediastinal involvement.
J. Clin. Oncol. 25, e10–e11 (2007).
84. Aupérin, A. et al. Meta-analysis of concomitant versus
sequential radiochemotherapy in locally advanced
non-small-cell lung cancer. J. Clin. Oncol. 28,
2181–2190 (2010).
85. Vokes, E. E. et al. Induction chemotherapy followed by
chemoradiotherapy compared with
chemoradiotherapy alone for regionally advanced
unresectable stage III Non-small-cell lung cancer:
Cancer and Leukemia Group B. J. Clin. Oncol. 25,
1698–1704 (2007).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15
86. Hanna, N. et al. Phase III study of cisplatin, etoposide,
and concurrent chest radiation with or without
consolidation docetaxel in patients with inoperable
stage III non-small-cell lung cancer: the Hoosier
Oncology Group and U. S. Oncology. J. Clin. Oncol. 26,
5755–5760 (2008).
87. Butts, C. et al. Tecemotide (L-BLP25) versus placebo
after chemoradiotherapy for stage III non-small-cell lung
cancer (START): a randomised, double-blind, phase 3
trial. Lancet. Oncol. 15, 59–68 (2014).
88. Lindeman, N. I. et al. Molecular testing guideline for
selection of lung cancer patients for EGFR and ALK
tyrosine kinase inhibitors: guideline from the College of
American Pathologists, International Association for the
Study of Lung Cancer, and Association for Molecular
Pathology. J. Thorac. Oncol. 8, 823–859 (2013).
89. Mok, T., Yang, J.‑J. & Lam, K.‑C. Treating patients with
EGFR-sensitizing mutations: first line or second line —
is there a difference? J. Clin. Oncol. 31, 1081–1088
(2013).
This review discusses the most appropriate
approach to treating patients with advanced NSCLC
harbouring activating EGFR mutations.
90. Park, K. et al. ASPIRATION: first-line erlotinib (E) until
and beyond RECIST progression (PD) in Asian patients
(pts) with EGFR mutation-positive (mut+) NSCLC. Ann.
Oncol. 25 (Suppl. 4), 1223O (2014).
91. Mok, T. S. et al. Gefitinib/chemotherapy vs
chemotherapy in epidermal growth factor receptor
(EGFR) mutation-positive non-small-cell lung cancer
(NSCLC) after progression on first-line gefitinib: the
Phase III, randomised IMPRESS study. Ann. Oncol.
25 (Suppl. 5), LBA2_PR (2014).
92. Chong, C. R. & Jänne, P. A. The quest to overcome
resistance to EGFR-targeted therapies in cancer.
Nat. Med. 19, 1389–1400 (2013).
93. Li, D. et al. BIBW2992, an irreversible EGFR/HER2
inhibitor highly effective in preclinical lung cancer
models. Oncogene 27, 4702–4711 (2008).
94. Janne, P. A. et al. Clinical activity of the mutant selective
EGFR inhibitor AZD9291 in patients with EGFR
inhibitor resistant non-small cell lung cancer (NSCLC).
J. Clin. Oncol. 32, (Suppl. 6) 8009 (2014).
95. Soda, M. et al. Identification of the transforming
EML4–ALK fusion gene in non-small-cell lung cancer.
Nature 448, 561–566 (2007).
96. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition
in non-small-cell lung cancer. N. Engl. J. Med. 363,
1693–1703 (2010).
97. Shaw, A. T. et al. Crizotinib versus chemotherapy in
advanced ALK-positive lung cancer. N. Engl. J. Med.
368, 2385–2394 (2013).
98. Solomon, B. J. et al. First-line crizotinib versus
chemotherapy in ALK-positive lung cancer. N. Engl.
J. Med. 371, 2167–2177 (2014).
This is the first paper to provide clinical evidence
that crizotinib is superior to chemotherapy as a
first-line treatment for patients with ALK-positive
advanced-stage NSCLC.
99. McDermott, U. et al. Genomic alterations of anaplastic
lymphoma kinase may sensitize tumors to anaplastic
lymphoma kinase inhibitors. Cancer Res. 68,
3389–3395 (2008).
100. Shaw, A. T. & Engelman, J. A. Ceritinib in ALK-
rearranged non-small-cell lung cancer. N. Engl. J. Med.
370, 2537–2539 (2014).
101. US National Library of Medicine. LDK378 versus
chemotherapy in previously untreated patients with
ALK rearranged non-small cell lung cancer.
ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/
show/NCT01828099?term=NCT01828099&rank=1
(2014).
102. US National Library of Medicine. LDK378 versus
chemotherapy in ALK rearranged (ALK positive) patients
previously treated with chemotherapy (platinum
doublet) and crizotinib. ClinicalTrials.gov [online], https://
clinicaltrials.gov/ct2/show/NCT01828112?term=
NCT01828112&rank=1 (2015).
103. Shaw, A. T. et al. Crizotinib in ROS1‑rearranged non-
small-cell lung cancer. N. Engl. J. Med. 371,
140927034510006 (2014).
This article provides the first clinical evidence of
crizotinib activity in patients with ROS1‑positive
advanced NSCLC.
104. Azzoli, C. G. et al. 2011 Focused update of 2009
American Society of Clinical Oncology Clinical Practice
Guideline update on chemotherapy for stage IV non-
small-cell lung cancer. J. Clin. Oncol. 29, 3825–3831
(2011).
105. Scagliotti, G. V. et al. Phase III study comparing
cisplatin plus gemcitabine with cisplatin plus
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
pemetrexed in chemotherapy-naive patients with
advanced-stage non-small-cell lung cancer. J. Clin.
Oncol. 26, 3543–3551 (2008).
106. Sandler, A. et al. Paclitaxel–carboplatin alone or with
bevacizumab for non-small-cell lung cancer. N. Engl.
J. Med. 355, 2542–2550 (2006).
107. Paz-Ares, L. G. et al. PARAMOUNT: final overall
survival results of the phase III study of maintenance
pemetrexed versus placebo immediately after
induction treatment with pemetrexed plus cisplatin for
advanced nonsquamous non-small-cell lung cancer.
J. Clin. Oncol. 31, 2895–2902 (2013).
This clinical study defines the continuation
maintenance approach with pemetrexed in
advanced-stage NSCLC.
108. Ciuleanu, T. et al. Maintenance pemetrexed plus best
supportive care versus placebo plus best supportive
care for non-small-cell lung cancer: a randomised,
double-blind, phase 3 study. Lancet 374, 1432–1440
(2009).
109. Coudert, B. et al. Survival benefit with erlotinib
maintenance therapy in patients with advanced non-
small-cell lung cancer (NSCLC) according to response
to first-line chemotherapy. Ann. Oncol. 23, 388–394
(2011).
110. Hanna, N. et al. Randomized phase III trial of
pemetrexed versus docetaxel in patients with non-
small-cell lung cancer previously treated with
chemotherapy. J. Clin. Oncol. 22, 1589–1597
(2004).
111. Reck, M. et al. Docetaxel plus nintedanib versus
docetaxel plus placebo in patients with previously
treated non-small-cell lung cancer (LUME-Lung 1):
a phase 3, double-blind, randomised controlled trial.
Lancet. Oncol. 15, 143–155 (2014).
112. Garon, E. B. et al. Ramucirumab plus docetaxel
versus placebo plus docetaxel for second-line
treatment of stage IV non-small-cell lung cancer after
disease progression on platinum-based therapy
(REVEL): a multicentre, double-blind, randomised
phase 3 trial. Lancet 384, 665–673 (2014).
113. Socinski, M. A. et al. Treatment of stage IV non-small
cell lung cancer. Diagnosis and management of lung
cancer, 3rd ed: American College of Chest Physicians
evidence-based clinical practice guidelines. Chest
143, e341S–e368S (2013).
114. The Elderly Lung Cancer Vinorelbine Italian Study
Group. Effects of vinorelbine on quality of life and
survival of elderly patients with advanced non-small-
cell lung cancer. J. Natl Cancer Inst. 91, 66–72
(1999).
This is the first Phase III study exploring
chemotherapy in elderly patients with advanced
NSCLC with quality of life as the primary end-point.
115. Mannion, E., Gilmartin, J. J., Donnellan, P., Keane, M.
& Waldron, D. Effect of chemotherapy on quality of
life in patients with non-small cell lung cancer.
Support. Care Cancer 22, 1417–1428 (2014).
116. Cella, D., Peterman, A., Hudgens, S., Webster, K. &
Socinski, M. A. Measuring the side effects of taxane
therapy in oncology. Cancer 98, 822–831 (2003).
117. Bergman, B., Aaronson, N. K., Ahmedzai, S., Kaasa, S.
& Sullivan, M. The EORTC QLQ‑LC13: a modular
supplement to the EORTC Core Quality of Life
Questionnaire (QLQ‑C30) for use in lung cancer
clinical trials. EORTC Study Group on Quality of Life.
Eur. J. Cancer 30A, 635–642 (1994).
118. Rabin, R. & de Charro, F. EQ‑5D: a measure of health
status from the EuroQol Group. Ann. Med. 33,
337–343 (2001).
119. Cella, D. F. et al. The Functional Assessment of
Cancer Therapy scale: development and validation of
the general measure. J. Clin. Oncol. 11, 570–579
(1993).
120. Mok, T. S. et al. Gefitinib or carboplatin–paclitaxel in
pulmonary adenocarcinoma. N. Engl. J. Med. 361,
947–957 (2009).
121. Oizumi, S. et al. Quality of life with gefitinib in
patients with EGFR-mutated non-small cell lung
cancer: quality of life analysis of North East Japan
Study Group 002 Trial. Oncologist 17, 863–870
(2012).
122. Chen, G. et al. Quality of life (QoL) analyses from
OPTIMAL (CTONG‑0802), a phase III, randomised,
open-label study of first-line erlotinib versus
chemotherapy in patients with advanced EGFR
mutation-positive non-small-cell lung cancer (NSCLC).
Ann. Oncol. 24, 1615–1622 (2013).
123. Geater, S. et al. LUX-lung 6: patient reported
outcomes (PROs) from a randomized open-label,
phase III study in 1st‑line advanced NSCLC patients
PRIMER
(pts) harboring epidermal growth factor receptor
(EGFR) mutations. J. Clin. Oncol. 31, (Suppl.) 8061
(2013).
124. Yang, J. C.‑H. et al. Symptom control and quality of
life in LUX-Lung 3: a Phase III study of afatinib or
cisplatin/pemetrexed in patients with advanced lung
adenocarcinoma with EGFR mutations. J. Clin. Oncol.
31, 3342–3350 (2013).
125. Temel, J. S. et al. Early palliative care for patients
with metastatic non-small-cell lung cancer. N. Engl.
J. Med. 363, 733–742 (2010).
126. Berger, A. H. et al. Oncogenic RIT1 mutations in lung
adenocarcinoma. Oncogene 33, 4418–4423 (2014).
127. Takezawa, K. et al. HER2 amplification: a potential
mechanism of acquired resistance to EGFR inhibition
in EGFR-mutant lung cancers that lack the second-
site EGFRT790M mutation. Cancer Discov. 2, 922–933
(2012).
128. Bean, J. et al. MET amplification occurs with or
without T790M mutations in EGFR mutant lung
tumors with acquired resistance to gefitinib or
erlotinib. Proc. Natl Acad. Sci. USA 104,
20932–20937 (2007).
129. Ohashi, K. et al. Lung cancers with acquired
resistance to EGFR inhibitors occasionally harbor
BRAF gene mutations but lack mutations in KRAS,
NRAS, or MEK1. Proc. Natl Acad. Sci. USA 109,
E2127–E2133 (2012).
130. De Bruin, E. C. et al. Reduced NF1 expression
confers resistance to EGFR inhibition in lung cancer.
Cancer Discov. 4, 606–619 (2014).
131. Zhang, Z. et al. Activation of the AXL kinase causes
resistance to EGFR-targeted therapy in lung cancer.
Nat. Genet. 44, 852–860 (2012).
132. Walter, A. O. et al. Discovery of a mutant-selective
covalent inhibitor of EGFR that overcomes
T790M‑mediated resistance in NSCLC. Cancer
Discov. 3, 1404–1415 (2013).
133. Janjigian, Y. Y. et al. Dual inhibition of EGFR with
afatinib and cetuximab in kinase inhibitor-resistant
EGFR-mutant lung cancer with and without T790M
mutations. Cancer Discov. 4, 1036–1045 (2014).
134. Cross, D. A. E. et al. AZD9291, an irreversible EGFR
TKI, overcomes T790M‑mediated resistance to EGFR
inhibitors in lung cancer. Cancer Discov. 4,
1046–1061 (2014).
135. Zhou, W. et al. Novel mutant-selective EGFR kinase
inhibitors against EGFR T790M. Nature 462,
1070–1074 (2009).
136. Akkermans, R. Third-generation EGFR-TKIs — a new
hope for NSCLC. Lancet. Respir. Med. 2, 520
(2014).
137. US National Library of Medicine. Phase II AZD9291
Open Label Study in NSCLC After Previous EGFR TKI
Therapy in EGFR and T790M Mutation Positive
Tumours (AURA2). ClinicalTrials.gov [online], https://
www.clinicaltrials.gov/ct2/show/NCT02094261?term
=NCT02094261&rank=1 (2015).
138. US National Library of Medicine. TIGER‑2: Open Label
Safety and Efficacy Study of Rociletinib (CO‑1686) in
Patients With T790M Positive NSCLC Who Have
Failed One Previous EGFR-Directed TKI. ClinicalTrials.
gov [online], https://www.clinicaltrials.gov/ct2/show/
NCT02147990?term=NCT02147990&rank=1
(2015).
139. US National Library of Medicine. AZD9291 Versus
Platinum-Based Doublet-Chemotherapy in Locally
Advanced or Metastatic Non-Small Cell Lung Cancer
16 | 2015 | VOLUME 1 www.nature.com/nrdp
(AURA3). ClinicalTrials.gov [online], https://
www.clinicaltrials.gov/ct2/show/NCT02151981?term
=NCT02151981&rank=1 (2015).
140. US National Library of Medicine. TIGER‑3: Open Label,
Multicenter Study of Rociletinib (CO‑1686) Mono
Therapy Versus Single-agent Cytotoxic Chemotherapy
in Patients With Mutant EGFR NSCLC Who Have Failed
at Least One Previous EGFR-Directed TKI and
Platinum-doublet Chemotherapy. ClinicalTrials.gov
[online], https://www.clinicaltrials.gov/ct2/show/
NCT02322281?term=NCT02322281&rank=1
(2015).
141. Costa, C. et al. The impact of EGFR T790M mutations
and BIM mRNA expression on outcome in patients
with EGFR-mutant NSCLC treated with erlotinib or
chemotherapy in the randomized phase III EURTAC
trial. Clin. Cancer Res. 20, 2001–2010 (2014).
142. Ma, H. S. et al. FLT3 kinase Inhibitor TTT‑3002
overcomes both activating and drug resistance
mutations in FLT3 in acute myeloid leukemia. Cancer
Res. 74, 5206–5217 (2014).
143. Lee, H.‑J. et al. Noncovalent wild-type-sparing
inhibitors of EGFR T790M. Cancer Discov. 3,
168–181 (2013).
144. Gao, W. et al. Selective antitumor activity of ibrutinib
in EGFR-mutant non-small cell lung cancer cells.
J. Natl Cancer Inst. 106, dju204 (2014).
145. Young, R. M. & Staudt, L. M. Ibrutinib treatment of
CLL: the cancer fights back. Cancer Cell 26, 11–13
(2014).
146. Puissant, A. et al. SYK is a critical regulator of FLT3 in
acute myeloid leukemia. Cancer Cell 25, 226–242
(2014).
147. Hahn, C. K. et al. Proteomic and genetic approaches
identify Syk as an AML target. Cancer Cell 16,
281–294 (2009).
148. Stegmaier, K. et al. Gefitinib induces myeloid
differentiation of acute myeloid leukemia. Blood 106,
2841–2848 (2005).
149. Boehrer, S. et al. Erlotinib exhibits antineoplastic off-
target effects in AML and MDS: a preclinical study.
Blood 111, 2170–2180 (2008).
150. Hong, J. et al. Expression of variant isoforms of the
tyrosine kinase SYK determines the prognosis of
hepatocellular carcinoma. Cancer Res. 74,
1845–1856 (2014).
151. Sethi, G., Ahn, K. S., Chaturvedi, M. M. &
Aggarwal, B. B. Epidermal growth factor (EGF)
activates nuclear factor-κB through IBα kinase-
independent but EGF receptor-kinase dependent
tyrosine 42 phosphorylation of IκBα. Oncogene 26,
7324–7332 (2007).
152. Gao, S. P. et al. Mutations in the EGFR kinase domain
mediate STAT3 activation via IL‑6 production in
human lung adenocarcinomas. J. Clin. Invest. 117,
3846–3856 (2007).
153. Fan, W. et al. MET-independent lung cancer cells
evading EGFR kinase inhibitors are therapeutically
susceptible to BH3 mimetic agents. Cancer Res. 71,
4494–4505 (2011).
154. Li, R. et al. Niclosamide overcomes acquired
resistance to erlotinib through suppression of STAT3
in non-small cell lung cancer. Mol. Cancer Ther. 12,
2200–2212 (2013).
155. Nan, J. et al. TPCA‑1 Is a direct dual inhibitor of STAT3
and NF-κB and regresses mutant EGFR-associated
human non-small cell lung cancers. Mol. Cancer Ther.
13, 617–629 (2014).
© 2015 Macmillan Publishers Limited. All rights reserved
156. Rosell, R., Bivona, T. G. & Karachaliou, N. Genetics and
biomarkers in personalisation of lung cancer
treatment. Lancet 382, 720–731 (2013).
This review describes personalized therapy in
patients with advanced-stage NSCLC.
157. Friboulet, L. et al. The ALK inhibitor ceritinib
overcomes crizotinib resistance in non-small cell lung
cancer. Cancer Discov. 4, 662–673 (2014).
158. Awad, M. M., Engelman, J. A. & Shaw, A. T.
Acquired resistance to crizotinib from a mutation
in CD74‑ROS1. N. Engl. J. Med. 369, 1173
(2013).
159. Sos, M. L. & Thomas, R. K. Genetic insight and
therapeutic targets in squamous-cell lung cancer.
Oncogene 31, 4811–4814 (2012).
160. Hammerman, P. S. et al. Mutations in the DDR2 kinase
gene identify a novel therapeutic target in squamous
cell lung cancer. Cancer Discov. 1, 78–89 (2011).
161. Beauchamp, E. M. et al. Acquired resistance to
dasatinib in lung cancer cell lines conferred by DDR2
gatekeeper mutation and NF1 loss. Mol. Cancer Ther.
13, 475–482 (2014).
162. Topalian, S. L. et al. Safety, activity, and immune
correlates of anti‑PD‑1 antibody in cancer. N. Engl.
J. Med. 366, 2443–2454 (2012).
163. Brahmer, J. R. et al. Safety and activity of anti‑PD‑L1
antibody in patients with advanced cancer. N. Engl.
J. Med. 366, 2455–2465 (2012).
164. Fife, B. T. & Bluestone, J. A. Control of peripheral T‑cell
tolerance and autoimmunity via the CTLA‑4 and PD‑1
pathways. Immunol. Rev. 224, 166–182 (2008).
165. Lynch, T. J. et al. Ipilimumab in combination with
paclitaxel and carboplatin as first-line treatment in
stage iiib/iv non-small-cell lung cancer: results from a
randomized, double-blind, multicenter phase II study.
J. Clin. Oncol. 30, 2046–2054 (2012).
166. Herbst, R. S. et al. Predictive correlates of response to
the anti‑PD‑L1 antibody MPDL3280A in cancer
patients. Nature 515, 563–567 (2014).
167. Casaluce, F. et al. Emerging drugs targeting PD‑1 and
PD‑L1: reality or hope? Expert Opin. Emerg. Drugs 19,
557–569 (2014).
168. Bender, E. Epidemiology: the dominant malignancy.
Nature 513, S2–S3 (2014).
Author contributions
Introduction (C.G. and A.R.); Epidemiology (C.G. and A.R.);
Mechanisms/pathophysiology (D.P.C.); Diagnosis, screening
and prevention (J.G., F.P. and L.S.); Management (T.M.);
Quality of life (C.G. and A.R.); Outlook (N.K.); overview of
Primer (C.G. and R.R.).
Competing interests statement
C.G. has received honoraria, speaker’s fees, research funding
and/or has served as an advisor to Eli Lilly, Roche, Novartis,
Bristol-Meyers Squibb, Pfizer, and Boehringer Ingelheim. A.R.
has received honoraria, speaker’s fees and/or has served as
an advisor to Eli Lilly, AstraZeneca and Boehringer
Ingelheim. D.P.C. has been a paid consultant for Roche/
Genentech, Pfizer, Novartis, BioDesix, Merck, EMD Serono,
GlaxoSmithKline, Boehringer Ingelheim and Amgen. T.M. has
received honoraria, speaker’s fees, research funding and/or
has served as an advisor to: AstraZeneca, Roche/Genentech,
Eli Lilly, EMD Serono, Eisai, Bristol-Meyers Squibb, AVEO,
P f i ze r, Ta i h o , B o e h r i n g e r I n g e l h e i m , N o v a r t i s,
GlaxoSmithKline Biologicals, Clovis Oncology, Amgen,
Janssen and BioMarin Pharmaceuticals. J.G., N.K., F.P., L.S.
and R.R. declare no competing interests.