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91
Leading ArticleMolecular Biomarkers for the Treatmentof Lung
Cancer: Personalized TherapyBeyond 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
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92 Kenichi Suda and Tetsuya Mitsudomi
Regarding the treatment of lung cancer, anumber of predictive
biomarkers have recentlybeen evaluated to select patients who
willbenefit from treatment with specific drugs,and some of these
markers have already founduse in the clinic. In particular,
oncogenicdriver mutations are now regarded not onlyas key molecules
for lung carcinogenesis butalso as distinctly useful molecular
biomarkersfor lung cancers with targetable molecules(Figure 1). A
well-established example isthe mutation in the gene that encodes
theepidermal growth factor receptor (EGFR),discovered in 2004
[1,2].
In this article, we will focus on molecularpredictive biomarkers
that appear to beparticularly hopeful, especially those
thatindicate potential benefits from treatmentwith EGFR tyrosine
kinase inhibitors (TKIs).
Personalized therapy based onmolecular biomarkers in lung
cancerAt the beginning of the 21st century,clinicians treated lung
cancer as twodiseases, namely NSCLC and SCLC.Treatment strategies,
including choice ofdrugs, were usually based on this
distinction.However, recent developments in moleculardiagnostic
technology and the advent ofmolecularly-targeted drugs are changing
thissituation dramatically.
The initial trials of molecular biomarkersin lung cancer were
trial-and-error processes.When the first ATP-competitive
first-generation EGFR-TKI (gefitinib) wasadministered to patients,
no biomarker wasknown that would indicate the effectivenessof this
drug. Shortly after, initial observationsidentified East-Asian
ethnicity, female sex,never-smoker status, and
adenocarcinomahistology as clinical biomarkers for a goodresponse
to gefitinib treatment [3].
In 2004, two genetic aberrations of thetarget molecule were
proposed as molecularbiomarkers that predict response to
gefitinib:.EGF-activating somatic mutations [1,2]and EGFR copy
number gain [4]. As thesetwo molecular aberrations often overlap
[5],it was difficult to obtain the final conclusionregarding the
proper molecular biomarker
until the results of biomarker analyses fromthe IPASS (Iressa
Pan-Asian Study) werereported [6]. IPASS was a randomized. PhaseIII
study of first-line treatment for never orlight smokers with
adenocarcinoma histologyin Asia comparing gefitinib with
carboplatin-paclitaxel chemotherapy [7]. In the subset ofpatients
whose EGFR status was analyzable,progression-free survival (PFS)
was longer inthe gefitinib-treated group of patients withan EGFR
mutation regardless of high or lowEGFR copy number, whereas PFS was
shorterin the gefitinib-treated group of patientswithout an EGFR
mutation and high EGFRcopy number [6].
Molecular biomarkers for EGFR-TKIsin lung adenocarcinomaEGFR
mutation as a molecularbiomarker for EGFR-TKIsLung cancers with an
EGFR mutation accountfor approximately 40% of adenocarcinomas
inEast Asians and approximately 15% of thosein Caucasians. Many in
vitro observations andretrospective and prospective studies
havereported that lung cancers with an EGFRmutation respond very
well to EGFR-TKIs,whereas those without EGFR mutations donot [8].
For chemotherapy-naive patients withlung cancer with EGFR
mutations, five PhaseIII trials have demonstrated that the rates
ofPFS of patients who were treated with EGFR-TKIs (gefitinib,
erlotinib, or afatinib) weresuperior to those of patients who
receivedplatinum-doublet chemotherapy [9-13].However, the question
of whether EGFR-TKIsprolong overall survival (OS) in lung
cancerpatients with EGFR mutations could not beanswered in these
trials because of the highcrossover rate between both arms. A
historicalcomparison between patients who were treatedbefore and
after approval of gefitinib in Japanhas given a strong indication
regarding thismatter [14]. OS was significantly longer amongthose
who were treated after gefitinib approvalcompared with that in
those who were treatedbefore gefitinib approval in patients withan
EGFR mutation (median survival time[MST] 27.2 months vs. 13.6
months; p
-
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 asmolecular biomarkers. A: The frequencies of these
oncogenic driver mutations are different betweenpatients with
differing pathological histology. Infrequent mutations that cause
adenocarcinoma includethose caused by HER2. BRAF. ROS. and MET. The
frequencies and suitable molecular target drugsfor each driver
oncogene are summarized in Tables 1 and 2. B: There is
heterogeneity within lungadenocarcinoma 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 withlow 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 oreriotinib are not necessarily mutually
exclusive. Next-generation ECFR-TKIs include irreversible ECFR-TKIs
and/or T790M-specific ECFR-TKIs.
Histologicalclassification
Molecular classification(biomarkers and candidates)
ECFRInfrequent
ALK I mutations
AdenocarcinomaMMMl
Ill 111 KRAS r i i n i n n i ~ r unknown
mH HI H DDR2 ffl ffl eCFR VIII
Squamous cell fffcarcinoma w j^i w w' f-^/.f~.^ ,, ,
ffl ffl U tu FCFR7 Unknown
Lung cancer patients Small cell carcinoma
Low efficacy togefitinib/erlotinib
Low IKB
T790MHI 111 lU 111 HI UJ Minor clone
Lung cancer patientswith EQFR mutation
Higher response togefitinib/erlotinib
M/C UIIUUIIlllllllllIllll Unknown
Candidates for future treatment
Low BIM ECFR-TKIs + BH3 mimetics
ECFR-TKIs + IKK inhibitor
Next-generation ECFR-TKIs
C719X or otherrare 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 inhibitorALK : anaplastic
lymphoma kinase; BH3: BCL-2 homology domain 3; BIM: BCL-2-like-i 1:
D0R2: discoidin domain receptor tyrosinekinase-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.
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94 Kenichi Suda and Tetsuya Mitsudomi
survival was observed in patients withoutEGFR mutations (MST
13.2 months vs. 10.4months; p=0.13). Similar results have alsobeen
obtained in patients with lung cancerin analyses that were
restricted to those withpost-surgical recurrences [15].
Biomarkers and candidates thatpredict resistance to
ECFR-TKIsUnfortunately, even in patients with EGFR-mutant lung
cancer, clinicians have noticedthat some of these patients have
poor responsesto treatment with gefitinib or erlotinib.
Initialreports attributed the difference in responseto the type of
EGFR mutation. Patients withthe two most common mutations, exon
19deletion and L858R point mutation, respondedvery well to
treatment with an EGFR-TKI;those with a G719X point mutation
respondedless well, whereas the presence of an exon20 insertion
mutation indicated intrinsicresistance to treatment [8]. In
addition, thepretreatment T790M gatekeeper mutation(which is
present in approximately 0.5% ofpatients with lung cancer with an
activatingEGFR mutation) [16] and loss of thephosphatase and tensin
homolog (PTEN)tumor suppressor gene [17] have also beenreported to
cause inherent resistance to theseEGFR-TKIs (Figure 1).
Furthermore, ina recent analysis using clinical specimensfrom
EGFR-mutam lung cancer patientswho showed inherent resistance, Yano
et al.observed that high levels of expression ofhepatocyte growth
factor (HGF; a ligand ofthe HGF receptor [MET] proto-oncogene)were
detected in 29% of tumors and MET gtncamplification in 4%,
suggesting that thesemolecules might be biomarkers for
intrinsicresistance to EGFR-TKIs in patients with lungcanccT with
EGFR mutations [18].
Biomarkers and condidates thotpredict low responses to
EGFR-TKIsAmong patients who respond to gefitinibor erlotinib, some
patients have a shorterlength of PFS. To explain this
phenomenon,Maheswaran et al. analyzed pretreatmenttumor specimens
for very minor clones ofthe T790M EGFR mutation using a high-
sensitivity method [19]. Interestingly, veryminor clones of the
T790M mutation weredetected in 38% of patients with lung cancerwith
an EGFR mutation, and correlated withreduced PFS following
treatment with EGFR-TKIs compared with patients who did not
haveminor clones of the T790M mutation. However,this is still
controversial because Fujita et al.have observed the opposite
result [20].
Molecular biomarkers other than EGFRhave also been found to
influence the responseto EGFR-TKI treatment. We observed
thatEGFR-TKI-treated patients with high levelsof expression of PTEN
showed favorablesurvival compared with those who had lowerlevels of
PTEN expression [21]. In addition,Bivona et al. identified that FAS
and nuclearfactor-KB (NF-KB) signaling mediated thesuppression of
cell death induced by EGFR-TKIs [22]. Following this observation,
theinvestigators analyzed the levels of expressionof NF-KB
inhibitor-a (NFKBIA; also knownas IKB) in patients with lung cancer
withEGFR mutations and found that low levels ofNFKBIA expression
(which induces a highactivation state of NF-KB) was predictive
ofworse PFS, whereas NFKBIA expression didnot predict PFS in those
who were treatedwith chemotherapy. Recently, Fabor et al. andNg et
al. have demonstrated that low levels ofexpression of
BCL-2-like-ll-EL (BIM-EL;one of three isoforms of the BIM protein),
andan intronic deletion polymorphism of BIMthat provides decreased
expression of BIM-EL, predict worse response to EGFR-TKItreatment
in patients with EGFR-mutatedlung cancers [23,24].
In the future, these molecular biomarkersthat predict inherent
resistance or low efficacyto EGFR-TKIs in patients with lung
cancerwith an EGFR mutation could be importantfor further
sub-classification of patientswith EGFR-mmam lung cancer for
furtherbiomarker-directed treatment.
Biomarkers post-acquisitionof resistance to first-generation
EGFR-TKIsDespite initial (potentially) dramaticresponses, almost
all patients with lung
-
Molecular Biomarkers for the Treatment of Lung Cancer 95
cancer with an EGFR mutation eventuallydevelop acquired
resistance to gefitinib orerlotinib. Molecular mechanisms
underlyingthis acquired resistance have been extensivelyanalyzed.
These mechanisms can be usefulbiomarkers for selecting the
appropriatetreatment for these patients after acquisitionof
resistance to first-generation EGFR-TKIs.
Acquisition of the T790M gatekeepermutation of the EGPR is the
most frequentlyacquired resistance mechanism [25,26]; therate of
development of this mutation has beenfound to be up to 68% using a
high-sensitivitydetection method [27]. To overcome resistancecaused
by the T790M mutation, second-generation EGER-TKIs that bind
irreversiblyto EGFR or third-generation EGFR-TKIsthat are designed
to inhibit mutant EGFR,including T790M but not wild-type EGFR,are
now under development. These novelEGFR-TKIs have been found to be
highlyeffective in preclinical models [28,29];however, afatinib (a
second-generationTKI) failed to improve OS compared withplacebo in
patients who experienced diseaseprogression following treatment
with gefitinibor erlotinib in a recent trial [30].
The second candidate of targetableacquired resistance is MET
activationby gene amplification [31,32] or by highexpression of the
ligand (HGF) [33]. Invitro models of acquired resistance causedby
MET activation are highly responsive tocombination therapy with an
EGFR-TKI anda MET-TKI [31,33,34].
There are several other candidates ofacquired resistance
mechanisms to EGFR-TKIs in patients with lung cancer with
EGFRmutation, such as PTEN downregulation,amplification of v-crk
sarcoma virus CTIOoncogene homolog (avian)-like (CRKL),activation
of NF-KB signaling; activationof the AXL receptor tyrosine
kinase(AXL), HER2 amplification, epithelial-to-mesenchymal
transition, or conversion toSCLC [35-37]. These molecular
mechanismsof acquired resistance might be goodmolecular biomarkers
for selecting treatmentto overcome resistance to
first-generationEGFR-TKIs in the near future.
/ILK^translocation and ALK-TKIsTranslocation and activation of
the anaplasticlymphoma kinase (ALK) proto-oncogenein lung
adenocarcinoma was first observedin 2007 [38,39]. Using transgenic
mousemodels, several ALK fusion genes (such asechinoderm
microtubule-associated proteinlike-4 [EML4]-ALK, kinesin family
member-5B [KIF5B]-ALK, or kinesin light chain-1[KLC1]-ALK) that
have been identified inpatients with adenocarcinoma have beenshown
to be oncogenic and highly sensitive toALK-TKIs [38,40,41].
Although lung cancerswith ALK translocations account for only 5%of
adenocarcinomas, development of the ALKinhibitor crizotinib was
focused on patientswith ALK fusion genes by applying lessonsthat
were learned from EGFR-TKIs [42]; thisresulted in rapid approval by
the US Foodand Drug Administration - only 4 years later- after the
discovery of ALK fusion genes inlung cancers. This is a typical
success story ofdrug development based on patient selectionusing a
molecular biomarker.
As with EGFR-TKIs, a retrospective studyhas also been performed
to demonstrate theability of crizotinib to prolong OS in
patientswith lung cancer with an ALK translocation.Shaw et al.
compared 30 ^LA^-translocation-positive patients who were given
crizotinib inthe second- or third-line setting with 23
ALK-translocation-positive controls who were givenother second-line
therapy, and identifiedsignificantly longer OS in the
crizotinib-treated group [43]. Currently, a Phase IIItrial
comparing crizotinib with platinum-doublet chemotherapy in the
first-line settingin patients with lung cancer with an
ALKtranslocation is underway (www.clinicaltrials.gov identifier:
NCT01154140). In addition,other ALK inhibitors are now
undergoingclinical development [44].
Oncogenic driver mutationsin adenocarcinoma: futurecandidate
biomarkersMutations in other driver oncogenes (suchas human EGFR-2
[HER2] [45,46], BRAF[47], and mitogen-activated protein
kinasekinase 1 [MEKl] [48]), other fusion genes
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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
CrizotinibVandetanib, 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
proteini
-
Molecular Biomarkers for the Treatment of Lung Cancer 97
Table 2. Oncogenic driver mutations as molecuiarBiomarkers
eCff iv i l l mutation
FCFR1 amplification
DDRZ mutation
MyCampiiflcation
Frequencies
5% in SqCLC
22% in SqCLC
3.8% in SqCLC
3-7% in SCLC
biomarkers in lungCandidate drugs
HKI-272
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 lungcancers are currently
underway [64]. Inaddition, a recent clinical trial suggestedthe
efficacy of a combination of selumetinib(a MEKl/2 inhibitor) plus
docetaxel [65], orsorafenib monotherapy [66], in patients withlung
cancer with a KRAS mutation.
Oncogenic driver mutations insquamous cell carcinomas and
SCLC:future candidate biomarkersFor the seeond and the third
mostcommon types of lung cancer (squamouscell carcinoma and SCLC,
respectively),no targeted therapies to inhibit driveroncoproteins
have been developed.However, several studies have suggestedthe
existence of driver mutations in thesecancers (Figure 1 and Table
2). The EGFRvariant III (vIII) mutation that lacks exon2-7 of its
extracellular domain has beendetected in 5% of lung squamous
cellcarcinomas [67]. EGFR vlll-driven murinetumors have been shown
to be sensitive toHKI-272, an irreversible BGFR-TKI [67].Recently,
two other driver mutations - focalamplification of the fibroblast
growth factorreceptor-l (FGFRl) gene, and a mutationin the gene
that encodes discoidin domainreceptor tyrosine kinase-2 (DDR2) -
havebeen reported in 22% and 3.8% of lungsquamous cell carcinoma
cases, respectively.Lung cancer cell lines harboring
FGFRlamplifications (such as H1581 and H520)were sensitive to a
non-isoform-specificFGFR inhibitor PD173074 [68]. Lungcancer cell
lines harboring DDR2 mutations(H2286 and HCC366) were also
sensitive tothe multi-target kinase inhibitor dasatinib.
In addition, a squamous cell lung cancerpatient who responded to
combinationtherapy with dasatinib and erlotinib wasreported to
harbor a DDR2 mutationbut not an EGFR mutation [69]. Clinicaltrials
for Z)Di?2-mutated lung cancers arecurrently underway.
In SCLC, MYC amplification reportedlyoccurs in 3-7% of tumors. A
recent studyidentified that Aurora kinase inhibitors(which inhibit
kinase activity of Aurorakinase B) are effective in SCLC cell
linesbearing MYC amplification [70].
These driver mutations in lung squamouscell carcinoma or in SCLC
might be used asbiomarkers in the near future.
Molecular biomarkers for drugs thatdo not target driver
mutationsConventional cytotoxic chemotherapies arestill the "gold
standard" for the treatment oflung cancers. For cytotoxic drugs,
althoughno molecular biomarkers have been acceptedby the scientific
community-at-large, theusefulness of several molecular
biomarkershave been suggested from in vitro data orfrom exploratory
analyses, and some ofthem are being evaluated in clinical
trials.Because many cytotoxic drugs kill cancercells by inducing
DNA damage, the levelsof expression of several DNA repair
genes,some of which have also been reported asprognostic markers,
are candidate biomarkers.For example, in the IALT-bio
(InternationalAdjuvant Lung Trial-bio) study, patientswith excision
repair cross-complementingrodent repair deficiency,
complementationgroup-1 (ERCC-l)-positive tumors
byimmunohistochemical analysis survived
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98 Kenichi Suda and Tetsuya Mitsudomi
longer (i.e. ERCC-1 acted as a prognosticmarker), whereas
platinum-based therapysignificantly prolonged survival
amongpatients with ERCC-1-negative tumors but notwith -positive
tumors (and thus it acted as apredictive biomarker for this
therapy) [71].
Expression of target genes has alsobeen reported as a biomarker
for cytotoxicchemotherapy. Thymidylate synthase (TS) isthe main
target of a multi-targeted antifolate,pemetrexed. In a preplanned
subset analysisof a Phase III trial, cisplatin plus
pemetrexedresulted in longer OS in patients with non-squamous
histology but shorter OS in thosewith squamous cell carcinoma
comparedwith cisplatin plus gemcitabine (cisplatinplus gemcitabine
showed similar OS in bothhistology groups) [72]. Lower TS
expressionin non-squamous histology carcinomacompared with that in
squamous cellcarcinoma is suggested to form the molecularbasis of
this result [73]. In vitro analysis,which found expression of TS to
be predictiveof pemetrexed chemosensitivity, furthersupports this
hypothesis [74]. Other candidatetarget genes as biomarkers are
summarized inTable 3 [75-78].
The addition of a third agent, amonoclonal antibody targeting
BGFR(cetuximab) or vascular endothelialgrowth factor (bevacizumab),
to platinumdoublet chemotherapy has been reportedto be effective in
some patients. Predictivebiomarkers have also been
extensivelyexamined for these antibody drugs. Inbiomarker analyses
using data from thePhase III FLEX (First-Line Erbituxin Lung
Cancer) study, high levels ofexpression of EGFR (as determined
byimmunohistochemistry) [79], but not EGERmutation, EGFR copy
number, KRASmutation, nor PTEN expression [80], wasreported as a
positive predictive biomarkerfor response to treatment with
cetuximab.For bevacizumab, no significant predictivebiomarker has
been discovered; high baselineplasma VEGF levels were reported
tocorrelate with higher response to treatmentincluding this
antibody, but did not predict asurvival benefit [78].
Recent and ongoing clinical trialsutilizing molecular
biomarkersPlatinum-doublet adjuvant chemotherapy,the current
standard of care for pathologicalstage II-III NSCLC patients after
"curative"resection, improves the 5-year survival rateby only 5.4%
compared with surgery alone[81]. Because pulmonary resection
providesabundant tumor tissues for molecularanalyses, several
molecular-biomarker-based clinical trials in the adjuvant
settinghave been performed or are ongoing (forfurther information
in this area, see thecurrent authors' recent review [82]). Someof
these trials have included EGFR statusas a molecular biomarker for
the selectionof adjuvant chemotherapy. Although theprematurely
terminated BR.19 trial couldnot show the efficacy of adjuvant
gefitinibtherapy compared with placebo even in asubset of patients
with EGER mutations[83], one retrospective study found thatadjuvant
EGFR-TKI was associated with alower risk of recurrence [84]. To
confirm therole of adjuvant EGFR-TKI prospectively inNSCLC patients
with an EGER mutation.Phase III trials that compare gefitinib
withcisplatin plus vinorelbine are now ongoing.In addition, to
confirm the efficacy ofbiomarker-tailored adjuvant therapy,
severalPhase III trials that compare customizedtreatment with
standard treatment are nowongoing. A specific example of such a
trial isthe TASTE (Tailored Post-Surgical Therapyin Early-Stage
NSCLC) study, in whichpatients are assigned to three groups in
thecustomized arm: eriotinib for those with anEGER mutation,
cisplatin plus pemetrexedfor those without an EGER mutation and
lowlevels of ERCC-1, and none for those withoutan EGER mutation and
high levels of ERCC-1, whereas all of the patients in the
standardarm receive cisplatin plus pemetrexed.
A biopsy-mandated, biomarker-based,adaptive-randomization
prospective studyhas also been performed for
unresectable,heavily-treated patients with NSCLC (theBATTLE
[Biomarker-Integrated Approachesof Targeted Therapy for Lung
CancerElimination] trial) [66]. Following an initial
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Molecular Biomarkers for the Treatment of Lung Cancer 99
Table 3. Candidate biomarkers for chemo-therapeutic drugs that
do not target drivermutations [71-77].ERCC-1High expression
BRCA-1Low expression
MSH-2Low expression
RRM-1High expression
TSHigh expressionLow expression
Betatubuiin iliLow expression
Resistance to platinum-based therapy
Sensitive to cisplatinResistance to paclitaxeland docetaxel
Resistance to cisplatin
Resistance to gemcitabine
Resistance to pemetrexedSensitive 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 randomizedto erlotinib, vandetanib, erlotinib
plusbexarotene, or sorafenib based on 11 relevantmolecular
biomarkers: mutational status ofEGFR, KRAS, and BRAF; fluorescence
insitu hybridization (FISH) analysis for EGFRand CCNDl; and
immunohistochemicalanalysis for VEGF, VEGFR-2, cyclin Dl,retinoid X
receptor-a (RXR-a), RXR-, andRXR-y. Overall results of the BATTLE
trialinclude a 46% 8-week disease control rate,suggesting the
feasibility of a new paradigmfor a molecular-biomarker-based
clinical trial.
Future directions andconcluding remarksAs described above, lung
cancerpatients with an EGFR mutation orALK translocation benefit
greatly fromindividualized molecularly targeted therapy.In
addition, biomarkers are also useful forrapid drug development and
successfulclinical trials. Establishment of detectionmethods and
the development of molecularlytargeted therapy to other driver
mutationsis, therefore, the next step in biomarkerapplication.
However, it is also true that a
subgroup defined by a single driver mutationis not uniform, as
shown by the heterogeneityof lung cancers with EGFR
mutations(Figure 1). In addition, it is unclear whethermolecular
biomarkers, usually quantitativebiomarkers, are useful for
determiningtreatment with cytotoxic chemotherapeuticdrugs or
antibody drugs. To ensure the mostappropriate treatment for all
patients withlung cancer, new biomarker exploration aswell as
method standardization and knownbiomarker evaluation by
investigators,and efforts to obtain tumor specimensfor biomarker
analyses by surgeons andphysicians, 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 fromAstraZeneca, Boehringer-lngelheim,
Chugai, Clovis, Kyowa HakkoKirin, Novartis, Pfizer, Roche, and
Synta.
Address for correspondence: Kenichi Suda, Department ofSurgery
and Science, Graduate School of Medical Sciences, KyushuUniversity,
3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8S82,Japan.Email:
ascarisisisrg2.med.kyushu-u.ac.jp
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