91

Leading Article
Molecular Biomarkers for the Treatment
of Lung Cancer: Personalized Therapy
Beyond the EGFR Mutation
Kenichi Suda, MD, PhD^l and Tetsuya Mitsudomi, MD,
^Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University,
Fukuoka; ^Division of Thoracic Surgery, Department of Surgery, Kini<i University Faculty of
Medicine, Osaka-Sayama, Japan
CML - Lung Cancer 2013;5(4):91 -101.
Submit comments or questions for the authors at
iwww.currentmedicalliteraturei.comi
Lung cancer is the leading cause of cancer-
related mortality worldwide. For most
patients with lung cancer, excluding those
with stage I disease, systemic chemotherapy
is applied to prolong survival and improve
quality of life, or as adjuvant/neoadjuvant
therapy to improve the outcome of surgical
treatment. However, some patients not only
fail to obtain any benefit from these drugs,
but also suffer from adverse events because
of their toxicity. Because cancer cells are
originally derived from host cells, compared
with exogenous microbial infection, effective
dose levels of these anticancer drugs are often
close to or overlap with the toxic dose levels.
To solve this problem, it is very
important to discover specific markers for
tumors that predict higher responsiveness
to anticancer drugs. So far, many classes
of biomarkers and biomarker candidates
(such as clinical features, serum markers,
pathological distinction, polymorphisms,
levels of gene or protein expression, somatic
mutations, and gene or protein signatures).
have been reported in the literature. Among
these biomarkers, qualitative ones (such
as oncogenic driver mutations, which we
will focus on in this article) give "yes or no"
results when analyzing whether a specific
treatment is likely to be effective, and thus
yield fewer inter-observer variations and are
reproducible. On the other hand, quantitative
biomarkers (such as levels of expression of
mRNA or protein) are more subjective and
less reliable in general.
To apply biomarkers for the correct
selection of drugs, we have to clarify whether
the biomarker is predictive (identifies patients
who will or will not respond to a certain drug)
or prognostic (identifies patients who have
a favorable or poor prognosis irrespective of
treatment). For example, in the situation that
a subgroup of patients defined by "biomarker
A" has favorable prognosis compared with a
control group after treatment with "drug B",
it is not clear if biomarker A is a predictive
biomarker for drug B or the biomarker just
defines patients with a favorable prognosis.
92 Kenichi Suda and Tetsuya Mitsudomi
Regarding the treatment of lung cancer, a
number of predictive biomarkers have recently
been evaluated to select patients who will
benefit from treatment with specific drugs,
and some of these markers have already found
use in the clinic. In particular, oncogenic
driver mutations are now regarded not only
as key molecules for lung carcinogenesis but
also as distinctly useful molecular biomarkers
for lung cancers with targetable molecules
(Figure 1). A well-established example is
the mutation in the gene that encodes the
epidermal growth factor receptor (EGFR),
discovered in 2004 [1,2].
In this article, we will focus on molecular
predictive biomarkers that appear to be
particularly hopeful, especially those that
indicate potential benefits from treatment
with EGFR tyrosine kinase inhibitors (TKIs).
Personalized therapy based on
molecular biomarkers in lung cancer
At the beginning of the 21st century,
clinicians treated lung cancer as two
diseases, namely NSCLC and SCLC.
Treatment strategies, including choice of
drugs, were usually based on this distinction.
However, recent developments in molecular
diagnostic technology and the advent of
molecularly-targeted drugs are changing this
situation dramatically.
The initial trials of molecular biomarkers
in lung cancer were trial-and-error processes.
When the first ATP-competitive first-
generation EGFR-TKI (gefitinib) was
administered to patients, no biomarker was
known that would indicate the effectiveness
of this drug. Shortly after, initial observations
identified East-Asian ethnicity, female sex,
never-smoker status, and adenocarcinoma
histology as clinical biomarkers for a good
response to gefitinib treatment [3].
In 2004, two genetic aberrations of the
target molecule were proposed as molecular
biomarkers that predict response to gefitinib:
.EGF-activating somatic mutations [1,2]
and EGFR copy number gain [4]. As these
two molecular aberrations often overlap [5],
it was difficult to obtain the final conclusion
regarding the proper molecular biomarker
until the results of biomarker analyses from
the IPASS (Iressa Pan-Asian Study) were
reported [6]. IPASS was a randomized. Phase
III study of first-line treatment for never or
light smokers with adenocarcinoma histology
in Asia comparing gefitinib with carboplatin-
paclitaxel chemotherapy [7]. In the subset of
patients whose EGFR status was analyzable,
progression-free survival (PFS) was longer in
the gefitinib-treated group of patients with
an EGFR mutation regardless of high or low
EGFR copy number, whereas PFS was shorter
in the gefitinib-treated group of patients
without an EGFR mutation and high EGFR
copy number [6].
Molecular biomarkers for EGFR-TKIs
in lung adenocarcinoma
EGFR mutation as a molecular
biomarker for EGFR-TKIs
Lung cancers with an EGFR mutation account
for approximately 40% of adenocarcinomas in
East Asians and approximately 15% of those
in Caucasians. Many in vitro observations and
retrospective and prospective studies have
reported that lung cancers with an EGFR
mutation respond very well to EGFR-TKIs,
whereas those without EGFR mutations do
not [8]. For chemotherapy-naive patients with
lung cancer with EGFR mutations, five Phase
III trials have demonstrated that the rates of
PFS of patients who were treated with EGFR-
TKIs (gefitinib, erlotinib, or afatinib) were
superior to those of patients who received
platinum-doublet chemotherapy [9-13].
However, the question of whether EGFR-TKIs
prolong overall survival (OS) in lung cancer
patients with EGFR mutations could not be
answered in these trials because of the high
crossover rate between both arms. A historical
comparison between patients who were treated
before and after approval of gefitinib in Japan
has given a strong indication regarding this
matter [14]. OS was significantly longer among
those who were treated after gefitinib approval
compared with that in those who were treated
before gefitinib approval in patients with
an EGFR mutation (median survival time
[MST] 27.2 months vs. 13.6 months; p<0.001);
by contrast, no significant improvement in
Molecular Biomarkers for the Treatment of Lung Cancer
93
Figure 1 . Sub-classification of lung cancer patients for biomarker-based molecular targeted therapy.
Current and future sub-classification of patients with lung cancer based on driver oncogenes as
molecular biomarkers. A: The frequencies of these oncogenic driver mutations are different between
patients with differing pathological histology. Infrequent mutations that cause adenocarcinoma include
those caused by HER2. BRAF. RO S . and M ET . The frequencies and suitable molecular target drugs
for each driver oncogene are summarized in Tables 1 and 2. B: There is heterogeneity within lung
adenocarcinoma patients with an fCF/? mutation and molecular biomarkers beyond fCFR mutation.
Improvement of response might be obtained if the patients with inherent resistance or those with
low efficacy to gefitinib or eriotinib are treated with other EGFR-TKIs or with combination therapy.
Note that these molecular mechanisms that confer inherent resistance or low efficacy to gefitinib or
eriotinib are not necessarily mutually exclusive. Next-generation ECFR-TKIs include irreversible ECFR-
TKIs and/or T790M-specific ECFR-TKIs.
Histological
classification
Molecular classification
(biomarkers and candidates)
ECFR
Infrequent
ALK I mutations
Adenocarcinoma
MMMl
Ill 111 KRAS r i i ni nni ~r unknown
m
H HI H DDR2 ffl ffl eCFR VIII
Squamous cell fff
carcinoma w ^ji w w' f-^/.f~.^ ,, ,
ffl ffl U tu FCFR7 Unknown
Lung cancer patients Small cell carcinoma
Low efficacy to
gefitinib/erlotinib
Low IKB
T790M
HI 111 lU 111 HI UJ Minor clone
Lung cancer patients
with EQFR mutation
Higher response to
gefitinib/erlotinib
M/C UIIUUIIlllllllllIllll Unknown
Candidates for future treatment
Low BIM ECFR-TKIs + BH3 mimetics
ECFR-TKIs + IKK inhibitor
Next-generation ECFR-TKIs
C71 9X or other
rare mutation
Next-generation ECFR-TKIs
Inherent resistance to gefitinib/erlotinib
Exon 20 &
insertion ID T790M Next-generation ECFR-TKIs
High HCF expression ECFR-TKIs + MET inhibitor
PTEN" loss ECFR-TKIs + PBK/AKT inhibitor
ALK : anaplastic lymphoma kinase; BH3: BCL-2 homology domain 3; BIM: BCL-2-like-i 1 : D0R2: discoidin domain receptor tyrosine
kinase-2; ECFR: epidermal growth factor receptor: FGFRl: fibroblast growth factor receptor-i; HER2: human ECFR-2: IKB: inhibitor of KB;
IKK: IKB kinase; MET: hepatocyte growth factor receptor; PI3K: phosphoinositide-3-kinase; PTEN: phosphatase and tensin homolog;
TKI: tyrosine kinase inhibitor.
94 Kenichi Suda and Tetsuya Mitsudomi
survival was observed in patients without
EGFR mutations (MST 13.2 months vs. 10.4
months; p=0.13). Similar results have also
been obtained in patients with lung cancer
in analyses that were restricted to those with
post-surgical recurrences [15].
Biomarkers and candidates that
predict resistance to ECFR-TKIs
Unfortunately, even in patients with EGFR-
mutant lung cancer, clinicians have noticed
that some of these patients have poor responses
to treatment with gefitinib or erlotinib. Initial
reports attributed the difference in response
to the type of EGFR mutation. Patients with
the two most common mutations, exon 19
deletion and L858R point mutation, responded
very well to treatment with an EGFR-TKI;
those with a G719X point mutation responded
less well, whereas the presence of an exon
20 insertion mutation indicated intrinsic
resistance to treatment [8]. In addition, the
pretreatment T790M gatekeeper mutation
(which is present in approximately 0.5% of
patients with lung cancer with an activating
EGFR mutation) [16] and loss of the
phosphatase and tensin homolog (PTEN)
tumor suppressor gene [17] have also been
reported to cause inherent resistance to these
EGFR-TKIs (Figure 1). Furthermore, in
a recent analysis using clinical specimens
from EGFR-mutam lung cancer patients
who showed inherent resistance, Yano et al.
observed that high levels of expression of
hepatocyte growth factor (HGF; a ligand of
the HGF receptor [MET] proto-oncogene)
were detected in 29% of tumors and MET gtnc
amplification in 4%, suggesting that these
molecules might be biomarkers for intrinsic
resistance to EGFR-TKIs in patients with lung
canccT with EGFR mutations [18].
Biomarkers and condidates thot
predict low responses to EGFR-TKIs
Among patients who respond to gefitinib
or erlotinib, some patients have a shorter
length of PFS. To explain this phenomenon,
Maheswaran et al. analyzed pretreatment
tumor specimens for very minor clones of
the T790M EGFR mutation using a high-
sensitivity method [19]. Interestingly, very
minor clones of the T790M mutation were
detected in 38% of patients with lung cancer
with an EGFR mutation, and correlated with
reduced PFS following treatment with EGFR-
TKIs compared with patients who did not have
minor clones of the T790M mutation. However,
this is still controversial because Fujita et al.
have observed the opposite result [20].
Molecular biomarkers other than EGFR
have also been found to influence the response
to EGFR-TKI treatment. We observed that
EGFR-TKI-treated patients with high levels
of expression of PTEN showed favorable
survival compared with those who had lower
levels of PTEN expression [21]. In addition,
Bivona et al. identified that FAS and nuclear
factor-KB ( NF- KB) signaling mediated the
suppression of cell death induced by EGFR-
TKIs [22]. Following this observation, the
investigators analyzed the levels of expression
of NF- KB inhibitor-a (NFKBIA; also known
as IKB) in patients with lung cancer with
EGFR mutations and found that low levels of
NFKBIA expression (which induces a high
activation state of NF- KB) was predictive of
worse PFS, whereas NFKBIA expression did
not predict PFS in those who were treated
with chemotherapy. Recently, Fabor et al. and
Ng et al. have demonstrated that low levels of
expression of BCL-2-like-ll-EL (BIM-EL;
one of three isoforms of the BIM protein), and
an intronic deletion polymorphism of BIM
that provides decreased expression of BIM-
EL, predict worse response to EGFR-TKI
treatment in patients with EGFR-mutated
lung cancers [23,24].
In the future, these molecular biomarkers
that predict inherent resistance or low efficacy
to EGFR-TKIs in patients with lung cancer
with an EGFR mutation could be important
for further sub-classification of patients
with EGFR-mmam lung cancer for further
biomarker-directed treatment.
Biomarkers post-acquisition
of resistance to first-
generation EGFR-TKIs
Despite initial (potentially) dramatic
responses, almost all patients with lung
Molecular Biomarkers for the Treatment of Lung Cancer
95
cancer with an EGFR mutation eventually
develop acquired resistance to gefitinib or
erlotinib. Molecular mechanisms underlying
this acquired resistance have been extensively
analyzed. These mechanisms can be useful
biomarkers for selecting the appropriate
treatment for these patients after acquisition
of resistance to first-generation EGFR-TKIs.
Acquisition of the T790M gatekeeper
mutation of the EGPR is the most frequently
acquired resistance mechanism [25,26]; the
rate of development of this mutation has been
found to be up to 68% using a high-sensitivity
detection method [27]. To overcome resistance
caused by the T790M mutation, second-
generation EGER-TKIs that bind irreversibly
to EGFR or third-generation EGFR-TKIs
that are designed to inhibit mutant EGFR,
including T790M but not wild-type EGFR,
are now under development. These novel
EGFR-TKIs have been found to be highly
effective in preclinical models [28,29];
however, afatinib (a second-generation
TKI) failed to improve OS compared with
placebo in patients who experienced disease
progression following treatment with gefitinib
or erlotinib in a recent trial [30].
The second candidate of targetable
acquired resistance is MET activation
by gene amplification [31,32] or by high
expression of the ligand (HGF) [33]. In
vitro models of acquired resistance caused
by MET activation are highly responsive to
combination therapy with an EGFR-TKI and
a MET-TKI [31,33,34].
There are several other candidates of
acquired resistance mechanisms to EGFR-
TKIs in patients with lung cancer with EGFR
mutation, such as PTEN downregulation,
amplification of v-crk sarcoma virus CTIO
oncogene homolog (avian)-like (CRKL),
activation of NF- KB signaling; activation
of the AXL receptor tyrosine kinase
(AXL), HER2 amplification, epithelial-to-
mesenchymal transition, or conversion to
SCLC [35-37]. These molecular mechanisms
of acquired resistance might be good
molecular biomarkers for selecting treatment
to overcome resistance to first-generation
EGFR-TKIs in the near future.
/ILK^translocation and ALK-TKIs
Translocation and activation of the anaplastic
lymphoma kinase (ALK) proto-oncogene
in lung adenocarcinoma was first observed
in 2007 [38,39]. Using transgenic mouse
models, several ALK fusion genes (such as
echinoderm microtubule-associated protein
like-4 [EML4]-ALK, kinesin family member-
5B [KIF5B]-ALK, or kinesin light chain-1
[KLC1]-ALK) that have been identified in
patients with adenocarcinoma have been
shown to be oncogenic and highly sensitive to
ALK-TKIs [38,40,41]. Although lung cancers
with ALK translocations account for only 5%
of adenocarcinomas, development of the ALK
inhibitor crizotinib was focused on patients
with ALK fusion genes by applying lessons
that were learned from EGFR-TKIs [42]; this
resulted in rapid approval by the US Food
and Drug Administration - only 4 years later
- after the discovery of ALK fusion genes in
lung cancers. This is a typical success story of
drug development based on patient selection
using a molecular biomarker.
As with EGFR-TKIs, a retrospective study
has also been performed to demonstrate the
ability of crizotinib to prolong OS in patients
with lung cancer with an ALK translocation.
Shaw et al. compared 30 ^LA^-translocation-
positive patients who were given crizotinib in
the second- or third-line setting with 23 ALK-
translocation-positive controls who were given
other second-line therapy, and identified
significantly longer OS in the crizotinib-
treated group [43]. Currently, a Phase III
trial comparing crizotinib with platinum-
doublet chemotherapy in the first-line setting
in patients with lung cancer with an ALK
translocation is underway (www.clinicaltrials.
gov identifier: NCT01154140). In addition,
other ALK inhibitors are now undergoing
clinical development [44].
Oncogenic driver mutations
in adenocarcinoma: future
candidate biomarkers
Mutations in other driver oncogenes (such
as human EGFR-2 [HER2] [45,46], BRAF
[47], and mitogen-activated protein kinase
kinase 1 [MEKl] [48]), other fusion genes
96
Kenichi Suda and Tetsuya Mitsudomi
Table 1. Oncogenic driver mutations as molecular biomarkers in lung adenocarcinomas.
Biomarkers
ECFR mutation
KRA5 mutation
AL/ftranslocaticn
HERZ mutation
ROSI translocation
R7" translocation
MET amplification
6R/IF mutation
MEK1 mutation
Frequencies
40% in Asians;
15% in Caucasians
15% in Asians:
30% in Caucasians
5%
2%
3%
1-2%
2%
3-5%
1%
Effective drugs or candidates
Reversible ECFR-TKIs: gefitinib and erlotinib
Irreversible ECFR-TKIs: afatinib and dacomitinib
T790M-specific EGFR-TKIs: CO-1686 and WZ4002
Inhibition of molecular targets that cause synthetic lethality
Selumetinib combined chemotherapy
Sorafenib
Crizotinib
Other ALK inhibitors
Trastuzumab combined chemotherapy
Irreversible pan-HER-TKIs: afatinib and dacomitinib
Crizotinib
Vandetanib, sorafenib, sunitinib
Crizotinib
Sorafenib
Selumetinib
References
[9-12]
[13]
[29]
[64]
[65]
[66]
[42]
[44]
[57,58]
[56,59,60]
[61,62]
[51,63]
[54]
[66]
[48]
ALK: anaplastic lymphoma kinase: ECFR: epidermal growth factor receptor: HER2: human ECFR-2: MEK-1 : mitogen-actiuated protein
i<inase l<inase-l; TKi: tyrosine i<inase inhibitor.
(including ROSl [39] and RET [49-52]), and
gene amplification of MET [53,54], have also
been discovered as candidates for molecular
biomarkers in lung adenocarcinoma (Figure 1
and Table 1).
A lung cancer cell line with HER2
mutation (H1781) and a HER2 mutant
transgenic mouse model have both been found
to be sensitive to HER-2 inhibition [55,56]. In
addition, for patients with lung cancer with
a mutation in HER2., two case studies have
reported that trastuzumab (a monoclonal
antibody drug against HER-2) combined with
chemotherapy (paclitaxel [57] or vinorelbine
[58]) was very effective at treating the disease.
In addition, recent clinical trials of afatinib
or dacomitinib have revealed that these drugs
may have some effects in patients with lung
cancer with aHER2 mutation [59,60].
Activation of ROSl and RET occur
through gene translocation (such as with
ALK), and several fusion partner genes have
been reported for both proto-oncogenes. A
lung cancer cell line with a fusion between
ROSl and solute carrier family 34 (sodium
phosphate), member-2 {SLC34A2-ROS1;
cell line HCC78) was sensitive to ROSl
inhibition [61], and patients with lung cancer
with ROSl rearrangements have been shown
to be highly responsive to crizotinib [62].
On the other hand, a lung cancer cell line
with a fusion between RET and coiled-
coil-domain-containing-6 (CCDC6-RET;
cell line LC-2/ad) was reported to show
distinctive sensitivity to vandetanib [63],
and Ba/F3 cells with the KIFSB-RET fusion
were also sensitive to vandetanib, sorafenib,
and sunitinib [51].
These mutations should be examined in
patients with lung adenocarcinoma without
an EGFR mutation, KRAS mutation, oi ALK
fusion in the near future. However, diagnostic
strategies that include these and other
mutations need to be established, especially
for patients with advanced lung cancer who
only have small tumor biopsy samples.
KRAS mutation is the oldest known
driver oncogenic mutation (discovered
in 1982), and lung adenocarcinomas with
KRAS mutation account for approximately
15% of lung cancers in East Asians and
approximately 30% in Caucasians. However,
a KRAS mutation itself is difficult to target;
therefore, efforts to explore synthetic lethal
Molecular Biomarkers for the Treatment of Lung Cancer
97
Table 2. Oncogenic driver mutations as molecuiar
Biomarkers
eCf f i vi l l mutation
FCFR1 amplification
DDRZ mutation
MyCampiiflcation
Frequencies
5% in SqCLC
2 2 % in SqCLC
3.8% in SqCLC
3- 7% in SCLC
biomarkers in lung
Candidate drugs
HKI-2 72
PD173074
Dasatinib
SqCLC or SCLC.
References
[ 67]
[ 68]
[ 69]
Aurora kinase inhibitors [70]
DDR2: discoidin domain receptor tyrosine kinase-2 ; ECFR: epidermal growth factor receptor,
SqCLC; squamous cell lung carcinoma.
FCFRl : fibroblast growth factor receptor-l:
molecules for AT/i^S-mutation-driven lung
cancers are currently underway [64]. In
addition, a recent clinical trial suggested
the efficacy of a combination of selumetinib
(a MEKl/2 inhibitor) plus docetaxel [65], or
sorafenib monotherapy [66], in patients with
lung cancer with a KRAS mutation.
Oncogenic driver mutations in
squamous cell carcinomas and SCLC:
future candidate biomarkers
For the seeond and the third most
common types of lung cancer (squamous
cell carcinoma and SCLC, respectively),
no targeted therapies to inhibit driver
oncoproteins have been developed.
However, several studies have suggested
the existence of driver mutations in these
cancers (Figure 1 and Table 2). The EGFR
variant III (vIII) mutation that lacks exon
2-7 of its extracellular domain has been
detected in 5% of lung squamous cell
carcinomas [67]. EGFR vlll-driven murine
tumors have been shown to be sensitive to
HKI-272, an irreversible BGFR-TKI [67].
Recently, two other driver mutations - focal
amplification of the fibroblast growth factor
receptor-l (FGFRl) gene, and a mutation
in the gene that encodes discoidin domain
receptor tyrosine kinase-2 (DDR2) - have
been reported in 22% and 3.8% of lung
squamous cell carcinoma cases, respectively.
Lung cancer cell lines harboring FGFRl
amplifications (such as H1581 and H520)
were sensitive to a non-isoform-specific
FGFR inhibitor PD173074 [68]. Lung
cancer cell lines harboring DDR2 mutations
(H2286 and HCC366) were also sensitive to
the multi-target kinase inhibitor dasatinib.
In addition, a squamous cell lung cancer
patient who responded to combination
therapy with dasatinib and erlotinib was
reported to harbor a DDR2 mutation
but not an EGFR mutation [69]. Clinical
trials for Z)Di?2-mutated lung cancers are
currently underway.
In SCLC, MYC amplification reportedly
occurs in 3-7% of tumors. A recent study
identified that Aurora kinase inhibitors
(which inhibit kinase activity of Aurora
kinase B) are effective in SCLC cell lines
bearing MYC amplification [70].
These driver mutations in lung squamous
cell carcinoma or in SCLC might be used as
biomarkers in the near future.
Molecular biomarkers for drugs that
do not target driver mutations
Conventional cytotoxic chemotherapies are
still the "gold standard" for the treatment of
lung cancers. For cytotoxic drugs, although
no molecular biomarkers have been accepted
by the scientific community-at-large, the
usefulness of several molecular biomarkers
have been suggested from in vitro data or
from exploratory analyses, and some of
them are being evaluated in clinical trials.
Because many cytotoxic drugs kill cancer
cells by inducing DNA damage, the levels
of expression of several DNA repair genes,
some of which have also been reported as
prognostic markers, are candidate biomarkers.
For example, in the IALT-bio (International
Adjuvant Lung Trial-bio) study, patients
with excision repair cross-complementing
rodent repair deficiency, complementation
group-1 (ERCC-l)-positive tumors by
immunohistochemical analysis survived
98
Kenichi Suda and Tetsuya Mitsudomi
longer (i.e. ERCC-1 acted as a prognostic
marker), whereas platinum-based therapy
significantly prolonged survival among
patients with ERCC-1-negative tumors but not
with -positive tumors (and thus it acted as a
predictive biomarker for this therapy) [71].
Expression of target genes has also
been reported as a biomarker for cytotoxic
chemotherapy. Thymidylate synthase (TS) is
the main target of a multi-targeted antifolate,
pemetrexed. In a preplanned subset analysis
of a Phase III trial, cisplatin plus pemetrexed
resulted in longer OS in patients with non-
squamous histology but shorter OS in those
with squamous cell carcinoma compared
with cisplatin plus gemcitabine (cisplatin
plus gemcitabine showed similar OS in both
histology groups) [72]. Lower TS expression
in non-squamous histology carcinoma
compared with that in squamous cell
carcinoma is suggested to form the molecular
basis of this result [73]. In vitro analysis,
which found expression of TS to be predictive
of pemetrexed chemosensitivity, further
supports this hypothesis [74]. Other candidate
target genes as biomarkers are summarized in
Table 3 [75-78].
The addition of a third agent, a
monoclonal antibody targeting BGFR
(cetuximab) or vascular endothelial
growth factor (bevacizumab), to platinum
doublet chemotherapy has been reported
to be effective in some patients. Predictive
biomarkers have also been extensively
examined for these antibody drugs. In
biomarker analyses using data from the
Phase III FLEX (First-Line Erbitux
in Lung Cancer) study, high levels of
expression of EGFR (as determined by
immunohistochemistry) [79], but not EGER
mutation, EGFR copy number, KRAS
mutation, nor PTEN expression [80], was
reported as a positive predictive biomarker
for response to treatment with cetuximab.
For bevacizumab, no significant predictive
biomarker has been discovered; high baseline
plasma VEGF levels were reported to
correlate with higher response to treatment
including this antibody, but did not predict a
survival benefit [78].
Recent and ongoing clinical trials
utilizing molecular biomarkers
Platinum-doublet adjuvant chemotherapy,
the current standard of care for pathological
stage II-III NSCLC patients after "curative"
resection, improves the 5-year survival rate
by only 5.4% compared with surgery alone
[81]. Because pulmonary resection provides
abundant tumor tissues for molecular
analyses, several molecular-biomarker-
based clinical trials in the adjuvant setting
have been performed or are ongoing (for
further information in this area, see the
current authors' recent review [82]). Some
of these trials have included EGFR status
as a molecular biomarker for the selection
of adjuvant chemotherapy. Although the
prematurely terminated BR.19 trial could
not show the efficacy of adjuvant gefitinib
therapy compared with placebo even in a
subset of patients with EGER mutations
[83], one retrospective study found that
adjuvant EGFR-TKI was associated with a
lower risk of recurrence [84]. To confirm the
role of adjuvant EGFR-TKI prospectively in
NSCLC patients with an EGER mutation.
Phase III trials that compare gefitinib with
cisplatin plus vinorelbine are now ongoing.
In addition, to confirm the efficacy of
biomarker-tailored adjuvant therapy, several
Phase III trials that compare customized
treatment with standard treatment are now
ongoing. A specific example of such a trial is
the TASTE (Tailored Post-Surgical Therapy
in Early-Stage NSCLC) study, in which
patients are assigned to three groups in the
customized arm: eriotinib for those with an
EGER mutation, cisplatin plus pemetrexed
for those without an EGER mutation and low
levels of ERCC-1, and none for those without
an EGER mutation and high levels of ERCC-
1, whereas all of the patients in the standard
arm receive cisplatin plus pemetrexed.
A biopsy-mandated, biomarker-based,
adaptive-randomization prospective study
has also been performed for unresectable,
heavily-treated patients with NSCLC (the
BATTLE [Biomarker-Integrated Approaches
of Targeted Therapy for Lung Cancer
Elimination] trial) [66]. Following an initial
Molecular Biomarkers for the Treatment of Lung Cancer
99
Table 3. Candidate biomarkers for chemo-
therapeutic drugs that do not target driver
mutations [71-77].
ERCC-1
High expression
BRCA-1
Low expression
MSH-2
Low expression
RRM-1
High expression
TS
High expression
Low expression
Betatubuiin ili
Low expression
Resistance to platinum-
based therapy
Sensitive to cisplatin
Resistance to paclitaxel
and docetaxel
Resistance to cisplatin
Resistance to gemcitabine
Resistance to pemetrexed
Sensitive to uracil-tegafur (UFT)
Sensitive to vinorelbine-
based therapy
BRCA-l :breast cancer-1; ERCC-1 : excision repair cross-
complementation group-1: M5H-2: MutS homologue-2: RRM-1 :
ribonucleotide reductase messenger-1; TS: thymidylate symhasa
equal randomization period (97 patients),
158 patients were adaptively randomized
to erlotinib, vandetanib, erlotinib plus
bexarotene, or sorafenib based on 11 relevant
molecular biomarkers: mutational status of
EGFR, KRAS, and BRAF; fluorescence in
situ hybridization (FISH) analysis for EGFR
and CCNDl; and immunohistochemical
analysis for VEGF, VEGFR-2, cyclin Dl,
retinoid X receptor-a (RXR-a), RXR-, and
RXR-y. Overall results of the BATTLE trial
include a 46% 8-week disease control rate,
suggesting the feasibility of a new paradigm
for a molecular-biomarker-based clinical trial.
Future directions and
concluding remarks
As described above, lung cancer
patients with an EGFR mutation or
ALK translocation benefit greatly from
individualized molecularly targeted therapy.
In addition, biomarkers are also useful for
rapid drug development and successful
clinical trials. Establishment of detection
methods and the development of molecularly
targeted therapy to other driver mutations
is, therefore, the next step in biomarker
application. However, it is also true that a
subgroup defined by a single driver mutation
is not uniform, as shown by the heterogeneity
of lung cancers with EGFR mutations
(Figure 1). In addition, it is unclear whether
molecular biomarkers, usually quantitative
biomarkers, are useful for determining
treatment with cytotoxic chemotherapeutic
drugs or antibody drugs. To ensure the most
appropriate treatment for all patients with
lung cancer, new biomarker exploration as
well as method standardization and known
biomarker evaluation by investigators,
and efforts to obtain tumor specimens
for biomarker analyses by surgeons and
physicians, are needed.
Disclosures: Or. Suda has no relevant financial interests to disclose.
Or. Mitsudomi has declared the following financial relationships:
speaker's fees from AstraZeneca, Boehringer-lngelheim. Chugai,
and Taiho: research support grants from AstraZeneca, Boehringer-
lngelheim, Eli Lilly, Pfizer, and Taiho; and consultation fees from
AstraZeneca, Boehringer-lngelheim, Chugai, Clovis, Kyowa Hakko
Kirin, Novartis, Pfizer, Roche, and Synta.
Address for correspondence: Kenichi Suda, Department of
Surgery and Science, Graduate School of Medical Sciences, Kyushu
University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8S82,Japan.
Email: ascarisisisrg2.med.kyushu-u.ac.jp
References
1. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the
epidermal growth factor receptor underlying responsiveness
of non-small-cell lung cancer to gefitinib. N Engl] Med
2004:350:2129-39.
2. Paez JG, Janne PA, Lee JC et al. ECFR mutations in lung cancer:
correlation with clinical response to gefitinib therapy. Science
2004:304:1497-SOO.
3. Miller VA, Kris MG, Shah N et al. Bronchioloalveolar pathologic
subtype and smoking history predict sensitivity to gefitinib
in advanced non-small-cell lung cancer. ] Clin Oncol
2004:22:1103-9.
4. Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor
receptor gene and protein and gefitinib sensitivity in non-
small-cell lung cancer.; Now Concer/nst 200S:97:543-5S.
5. Yatabe Y, Takahashi T, Mitsudomi T. Epidermal growth factor
receptor gene amplification is acquired in association with
tumor progression of f CW-mutated lung cancer. Cancer Res
2008:68:2106-11.
6. Fukuoka M, Wu Yl , Thongprasert S et al. Biomarker analyses
and final overall survival results from a Phase III, randomized,
open-label, first-line study of gefitinib versus carboplatin/
paclitaxel in clinically selected patients with advanced
non-small-cell lung cancer in Asia (IPASS).) O/n Oncol
2011:29:2866-74.
7. Mok TS, Wu YL Thongprasert S et al. Gefitinib or carboplatin-
paclitaxel in pulmonary adenocarcinoma. N EnglJ Med
2009:361:947-57.
8. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth
factor receptor gene and related genes as determinants of
epidermal growth factor receptor tyrosine kinase inhibitors
sensitivity in lung cancer. Cancer Sei 2007:98:1817-24.
9. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin
plus docetaxel in patients with non-small-cell lung cancer
harbouring mutations of the epidermal growth factor receptor
(WJTOGB405): an open label, randomised Phase 3 trial. Lancet
Onco/2010:11:121-8.
10. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or
chemotherapy for non-small-cell lung cancer with mutated
EGFR. N EngI] Med 2010:362:2380-8.
100
Kenichi Suda and Tetsuya Mitsudomi
11. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard
chemotherapy as first-line treatrtient for European patients
with advanced ECFR mutation-positive non-small-cell lung
cancer (EURTAC): a multicentre. open-label, randomised
Phase 3 trial. Lancet Oncol 2012:13:239-46.
12. Zhou C, Wu YL, Chen C et al. Eflotinib versus chemotherapy
as first-line treatment for patients with advanced EGFR
mutation-positive non-small-cell lung cancer (OPTIMAL
CTONC-0802): a multicentre. open-label, randomised.
Phase 3 study. Lancet Onco/2011:12:735-42.
13. Yang JC-H, Schler MH, Yamamoto N et al. LUX-Lung 3:
a randomized, open-label. Phase III study of afatinib versus
pemetrexed and cisplatin as first-line treatment for patients
with advanced adenocarcinoma of the lung harboring ECFR-
activating mutations. ) Gin Oncal 2012;30(Suppl.): Abstr
LBA7500.
14. Takano T, f ukui T, Ohe Y et al. ECFR mutations predict
survival benefit from gefitinib in patients with advanced lung
adenocarcinoma: a historical comparison of patients treated
before and after gefitinib approval in Japan. I Clin Oncal
2008,26:5589-95.
15. Suda K, Ito S, Mizuuchi H et al. ECFR tyrosine kinase inhibitors
prolong overall survival in CfR mutated non-small-cell lung
cancer patients with postsurgical recurrence. J Cancer Res
Updotes 2012:1:102-7.
16. Toyooka S, Kiura K, Mitsudomi T. ECFR mutation and response
of lung cancer to gefitinib. N EngI] Med 2005:352:2136:
author reply.
17. Sos ML, Koker M, Weir 8A et al. PTEN loss contributes to
erlotinib resistance in f CFR-mutant lung cancer by activation
of Akt and ECFR. Cancer Res 2009:69:3256-61.
18. Yano 5, Yamada T Takeuchi 5 et al. Hepatocyte growth factor
expression in ECFR mutant lung cancer with intrinsic and
acquired resistance to tyrosine kinase inhibitors in a Japanese
cohort. I Thorac Oncal 2011:6:2011 -7.
19. Maheswaran 5, Sequist LV, Nagrath S et al. Detection of
mutations in ECFR in circulating lung-cancer cells. N EngI] Med
2008:359:366-77.
20. Fujita Y, Suda K, Kimura H et al. Highly sensitive detection of
ECFR T790M mutation using colony hybridization predicts
favorable prognosis of patients with lung cancer harboring
activating ECFR mutation. ) Tharac Onco/2012:7:1640-4.
21. Endoh H, Yatabe Y, Kosaka T et al. PTEN and PIK3CA expression
is associated with prolonged survival after gefitinib treatment
in fCFR-mutated lung cancer patients.) Tharac Oncal
2006:1:629-34.
22. Bivona TC, HIeronymus H, Parker J et al. FA5 and NF-kappaB
signalling modulate dependence of lung cancers on mutant
ECFR. Noture 2011:471:523-6.
23. Faber AC, Corcoran RB, Ebi H et al. 8IM expression in
treatment-naive cancers predicts responsiveness to kinase
inhibitors. Cancer Discov 2011:1:352-65.
24. Ng KP, Hillmer AM, Chuah CT et al. A common 8IM deletion
polymorphism mediates intrinsic resistance and inferior
responses to tyrosine kinase inhibitors in cancer. Not Med
2012:18:521-8.
25. Kobayashi S, Boggon TJ, Dayaram T et al. ECFR mutation
and resistance of non-small-cell lung cancer to gefitinib.
NEng/J Med 2005:352:786-92.
26. Pao W, Miller VA, Politi KA et al. Acquired resistance of lung
adenocarcinomas to gefitinib or erlotinib is associated with
a second mutation in the ECFR kinase domain. PLoS Med
2005:2:e73.
27. Arcila ME, Oxnard CR, Nafa K et al. Rebiopsy of lung cancer
patients with acquired resistance to ECFR inhibitors and
enhanced detection of the T790M mutation using a locked
nucleic acid-based assay. Clin Cancer Res 2011:17:1169-80.
28. Kwak EL Sordella R, 8ell DW et al. Irreversible inhibitors of the
ECF receptor may circumvent acquired resistance to gefitinib.
Prac Nati Acad Sei USA 2005:102:7665-70.
29. Zhou W, Ercan D, Chen L et al. Novel mutant-selective
ECFR kinase inhibitors against EGFR T790M. Nature
2009:462:1070-4.
30. Miller VA, Hirsh V, Cadranel J et al. Afatinib versus placebo
for patients with advanced, metastatic non-small-cell lung
cancer after failure of erlotinib, gefitinib, or both, and one
or two lines of chemotherapy (LUX-Lung 1): a Phase 2b/3
randomised trial. Lancet Oncal 2012:13:528-38.
31. Engelman JA, Zejnullahu K, Mitsudomi T et al. MET
amplification leads to gefitinib resistance in lung cancer by
activating ER8B3 signaling. Science 2007:316:1039-43.
32. Bean J, 8rennan C, Shih JY et al. MET amplification occurs with
or without T790M mutations in ECFR mutant lung tumors
with acquired resistance to gefitinib or erlotinib. Prac Nati
Acad Sei USA 2007:104:20932-7.
33. Yano S, Wang W, Li Q et al. Hepatocyte growth factor induces
gefitinib resistance of lung adenocarcinoma with epidermal
growth factor receptor-activating mutations. Concer Res
2008:68:9479-87.
34. Suda K, Murakami I, Katayama T et al. Reciprocal and
complementary role of MET amplification and ECFR T790M
mutation in acquired resistance to kinase inhibitors in lung
cancer. Gin Cancer Res 2010:16:5489-98.
35. Sequist LV, Waltman BA, Dias-Santagata 0 et al. Genotypic and
histological evolution of lung cancers acquiring resistance to
EGFR inhibitors. Sei Transi Med2011:3:75ra26.
36. Suda K, Mizuuchi H, Maehara Y et al. Acquired resistance
mechanisms to tyrosine kinase inhibitors in lung cancer with
activating epidermal growth factor receptor mutation-diversity,
ductility, and destiny. Cancer Metastasis Rev 2012:31:807-l 4.
37. Takezawa K, Pirazzoli V, Arcila ME et al. HER2 amplification: a
potential mechanism of acquired resistance to EGFR inhibition
in ECFR-mutant lung cancers that lack the second-site
ECFRT790M mutation. Concer 0/scov 2012:2:922-33.
38. 5oda M, Choi YL Enomoto M et al. Identification of the
transforming EMI.4-/)i.ff fusion gene in non-small-cell lung
cancer. Noture 2007:448:561-6.
39. Rikova K, Cuo A, Zeng 0 et al. Global survey of phospho-
tyrosine signaling identifies oncogenic kinases in lung cancer.
Ce//2007:131:1190-203.
40. Takeuchi K, Choi YL Togashi Y et al. KIFSB-ALK, a novel fusion
oncokinase identified by an immunohistochemistry-based
diagnostic system for /)L/(-positive lung cancer. Gin Cancer Res
2009:15:3143-9.
41. Togashi Y, Soda M, Sakata 5 et al. KLChALK: a novel fusion
in lung cancer identified using a formalin-fixed paraffin-
embedded tissue only. PloS One 2012:7:e31323.
42. Kwak EL Bang YJ, Camidge DR et al. Anaplastic lymphoma
kinase inhibition in non-small-cell lung cancer. N EnglJ Med
2011:363:1693-703.
43. Shaw AT, Yeap BY, Solomon BJ et al. Effect of crizotinib on
overall survival in patients with advanced non-small-cell lung
cancer harbouring ALK gene rearrangement: a retrospective
analysis. Lancet Oncal 2011:12:1004-12.
44. Casaluce F, Sgambato A, Maione P et al. ALK inhibitors: a new
targeted therapy in the treatment of advanced NSCLC.
7bfget Onco/2013:8:55-67.
45. Stephens P, Hunter C Bignell G et al. Lung cancer: intragenic
ERBBZ kinase mutations in tumours. Nature 2004:431:525-6.
46. Shigematsu H, Takahashi T, Nomura M et al. Somatic
mutations of the HERZ kinase domain in lung
adenocarcinomas. Cancer Res 2005:65:1642-6.
47. Paik PK, Arcila ME, Fara M et al. Clinical characteristics
of patients with lung adenocarcinomas harboring BRAF
mutations. ) Clin Oncal 2011:29:2046-51.
48. Marks JL Cong Y, Chtale D et al. Novel MEKl mutation
identified by mutational analysis of epidermal growth factor
receptor signaling pathway genes in lung adenocarcinoma.
Concer- Res 2008:68:5524-8.
49. Ju Y5, Lee WC, Shin JY et al. A transforming KIFSB and
RET gene fusion in lung adenocarcinoma revealed from
whole-genome and transcriptome sequencing. Genome Res
2012:22:436-45.
50. Takeuchi K, Soda M, Togashi Y et al. RET, ROSI and ALK
fusions in lung cancer. Not Med 2012:18:378-81.
51. Lipson D, Capelletti M, Yelensky R et al. Identification of new
ALK ana /?ET gene fusions from colorectal and lung cancer
biopsies. Not Med 2012:18:382-4.
52. Kohno T, Ichikawa H, Totoki Y et al. MFSS-RETfusions in lung
adenocarcinoma. Nat Med 2012:18:375-7.
53. Onozato R, Kosaka T. Kuwano H et al. Activation of MET
by gene amplification or by splice mutations deleting the
Juxtamembrane domain in primary resected lung cancers,
y r/ioroc Onco/2009:4:5-11.
Moiecuiar Biomari<ers for the Treatment of Lung Cancer
101
54. Ou SH, Kwak EL, Siwak-Tapp C et al. Activity of crizotinib
(PF02341066), a dual mesenchymal-epithelial transition
(MET) and anaplastic lymphoma kinase (ALK) inhibitor,
in a non-small cell lung cancer patient with de novo MET
amplification.; Thoroc Onco/2011,6:942-6.
55. Shimamura T, Ji H, Minami Y et al. Non-small-cell lung
cancer and Ba/F3 transformed cells harboring the ERBBZ
G776ins\/_C/C mutation are sensitive to the dual-specific
epidermal growth factor receptor and ERBB2 inhibitor HKI-
272. Cancer Res 2006:66:6487-91.
56. Perera SA, Li D, Shimamura T et al. HER2\\IMI\ drives rapid
development of adenosquamous lung tumors in mice that are
sensitive to BIBW2992 and rapamycin combination therapy.
ProcNatiAcadSei USA 2009:106:474-9.
57. Cappuzzo F, Bemis L, Varella-Garcia M. H6R2 mutation and
response to trastuzumab therapy in non-small-cell lung
cancer. N EngtJ Med 2006:354:2619-21.
58. Tomizawa K, Suda K, Onozato R et al. Prognostic and
predictive implications of HER2/ERBB2/neu gene mutations
in lung cancers. Lung C7ncer 2011:74:139-44.
59. De Grve J, Teugels E, Geers C et al. Clinical activity of afatinib
(BIBW 2992) in patients with lung adenocarcinoma with
mutations in the kinase domain of HERZ/neu. Lung Concer
2012:76:123-7.
60. Janne PA, Kris M, Goldberg Z et al. Dacomitinib (PF-
00299804), an irreversible pan-HER tyrosine kinase inhibitor
(TKI), for first-line treatment of eCFR-mutant or HER2-mutant
or -amplified lung cancers. Presented at: European Society of
Medical Oncoogy 2012 Congress; September 28-October 2;
Vienna, Austria. Abstract 1228.
61. Davies KD, Le AT, Theodoro MF et al. Identifying and targetiag
ROS) gene fusions in non-small cell lung cancer. Gin Canee:
Res 2012;18:4570-9.
62. Shaw AT, Camidge DR, Engelman JA et al. Clinical activity
of crizotinib in advanced non-small cell lung cancer
(NSCLC) harboring ROS) gene rearragement.y G/n Onco)
2012;30(Suppl.):Abstr 7508.
63. Matsubara D, Kanai Y, Ishikawa S et al. Identification of
CC0C6-Rer fusion in the human lung adenocarcinoma
cell line, LC-2/ad. y Thome Onco/2012:7:1872-6.
64. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical
significance of fR/lS mutations in lung cancer: an oncogenio
driver that contrasts with f CfR mutation. Concer Metostosii
Rei/2010:29:49-60.
65. Janne P, Shaw AT, Pereira J et al. Phase II double-blind,
randomized study of selumetinib (SEL) plus docetaxel
(DOC) versus DDC plus placebo as second-line treatment for-
advanced KRAS mutant non-small cell lung cancer (NSCLC).
y din Oncoi 2012;30(Suppl.): Abstr 7503.
66. Kim ES, Herbst RS, Wistuba, II et al. The BATTLE trial:
personalizing therapy for lung cancer. Cancer Discav
2011:1:44-53.
67. Ji H, Zhao X, Yuza Y et al. Epidermal growth factor receptor
variant III mutations in lung tumorigenesis and sensitivity
to tyrosine kinase inhibitors. Proc Nati Acod Sc'i USA
2006:103:7817-22.
68. Weiss J, Sos ML Seidel D et al. Frequent and focal FGFR1
amplification associates with therapeutically tractable FGFR1
dependency in squamous cell lung cancer. Sei Transi Med
2010:2:62ra93.
69. Hammerman PS, Sos ML Ramos AH et al. Mutations in the
DDR2 kinase gene identify a novel therapeutic target in
squamous cell lung cancer. Concer Discov 2011 ;1:78-89.
70. Sos ML, Dietlein F, Peifer M et al. A framework for
identification of aaionable cancer genome dependencies
in small cell lung cancer. Proc Nati Acod Sei USA
20l 2;109:l 7034-9.
71. Olaussen KA, Dunant A, Fouret P et al. DNA repair by ERCC1
in non-small-cell lung cancer and cisplatin-based adjuvant
chemotherapy. N Engi] Med 2006:355:983-91.
72. Scagliotti GU, Parikh P, von Pawel J et al. Phase III study
comparing cisplatin plus gemcitabine with cisplatin plus
pemetrexed in chemotherapy-naive patients with advanced-
stage non-small-cell lung cancer.y C//n Oncoi2008;26:3543-51.
73. Ceppi P, Volante M, Saviozzi S et al. Squamous cell carcinoma
of the lung compared with other histotypes shows higher
messenger RNA and protein levels for thymidylate synthase.
Concer 2006:107:1589-96.
74. Giovannetti E, Mey V, Nannizzi S et al. Cellular and
pharmacogenetics foundation of synergistic interaction of
pemetrexed and gemcitabine in human non-small-cell lung
cancer cells. Moi Phormocoi 2005;68:l 10-8.
75. Postel-Vinay S, Vanhecke E, Olaussen KA et al. The potential
of exploiting DNA-repair defects for optimizing lung cancer
treatment. Not Rev din Oncoi 2012:9:144-55.
76. Filipits M, Pirker R. Predictive markers in the adjuvant therapy
of non-small cell lung cancer. Lung Concer 2011:74:355-63.
77. Vilmar AC, Sorensen JB. Customising chemotherapy in
advanced nonsmall cell lung cancer: daily practice and
perspectives. Eur Respir Rev 2011:20:45-52.
78. Dowlati A, Cray R, Sandier AB et al. Cell adhesion molecules,
vascular endothelial growth factor, and basic fibroblast
growth factor in patients with non-small cell lung cancer
treated with chemotherapy with or without bevacizumab - an
Eastern Cooperative Oncology Group Study, din Concer Res
2008:14:1407-12.
79. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as
a predictor of survival for first-line chemotherapy plus
cetuximab in patients with advanced non-small-cell lung
cancer: analysis of data from the Phase 3 FLEX study. Lancet
Onco) 2012:13:33-42.
80. O'Byrne KJ, Catzemeier U, Bondarenko I et al. Molecular
biomarkers in non-small-cell lung cancer: a retrospective
analysis of data from the Phase 3 FLEX study. Loncet Oncai
2011:12:795-805.
81. Pignon JP, Tribodet H, Scagliotti GV et al. Lung adjuvant
cisplatin evaluation: a pooled analysis by the LACE
Collaborative Croup.y Gin Oncoi 2OOB:26:3552-9.
82. Mitsudomi T, Suda K, Yatabe Y. Surgery for NSCLC in the era of
personalized medicine. Not Rev din Oncoi 2D13 Feb 26; Epub
ahead of print.
83. Goss GD. A Phase III randomized, double-blind, placebo-
controlled trial of the epidermal growth factor receptor inhibitor
gefitinib in completely resected stage IB-IIIA non-small cell
lung cancer (NSCLC): NCIC CTG BT.19 (Abstract). J Gin Oncoi
2010:28(Suppl. 18):LBA7005.
84. D'Angelo SP, Janjigian YY, Ahye N et al. Distinct clinical course
of eCFR-mutant resected lung cancers: results of testing of
1118 surgical specimens and effects of adjuvant gefitinib and
eriotinib.y Thoroc Oncoi 2012;7:1 Bl 5-22.