CHEST. Thyroid transcription factor 1 (TTF-1) is an important. Original Research

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1 CHEST Originl Reserch Clinicl Significnce of Thyroid Trnscription Fctor-1 in Advnced Lung Adenocrcinom Under Epiderml Growth Fctor Receptor Tyrosine Kinse Inhibitor Tretment Kuei-Pin Chung, MD; Yen-Tsung Hung, MD, MPH; Yih-Leong Chng, MD, PhD; Chong-Jen Yu, MD, PhD; Chih-Hsin Yng, MD, PhD; Yeun-Chung Chng, MD; Jin-Yun Shih, MD, PhD; nd Pn-Chyr Yng, MD, PhD, FCCP LUNG CANCER Bckground: Thyroid trnscription fctor 1 (TTF-1) positivity correltes with higher prevlence of epiderml growth fctor receptor (EGFR) muttion in lung denocrcinom. It is unknown whether TTF-1 expression ffects the clinicl outcome of ptients with dvnced lung denocrcinom, who hve received EGFR tyrosine kinse inhibitors (TKIs) during the tretment course. Methods: This study enrolled ptients with dvnced lung denocrcinom who hd results of EGFR muttion nlysis nd TTF-1 immunostining. The impct of TTF-1 expression on overll survivl (OS) nd progression-free survivl (PFS) under EGFR TKI tretment ws evluted. Multivrite nlyses were done to exmine the independent predictors of OS nd PFS. Results: Of 496 ptients with dvnced lung denocrcinom, 443 hd TTF-1-positive denocrcinom. Ptients with TTF-1-positive lung denocrcinom hd longer OS thn did those with TTF-1-negtive lung denocrcinom (medin survivl, 27.4 vs 11.8 months, P 5.001). In ptients with EGFR TKI tretment, those with TTF-1-positive lung denocrcinom nd mutnt EGFR hd longer OS. In ptients with EGFR muttion, those with TTF-1-positive lung denocrcinom hd longer PFS thn did those with TTF-1-negtive lung denocrcinom (medin survivl, 8.7 vs 5.7 months, P 5.043). Multivrite nlysis showed tht negtive TTF-1 expression is predictor for shorter OS, nd predictor for shorter PFS under EGFR TKI tretment. Conclusions: TTF-1 shows independent prognostic significnce in dvnced lung denocrcinom. Ptients with TTF-1-negtive lung denocrcinom hve not only shorter OS, but lso shorter PFS under EGFR TKI tretment, despite the existence of mutnt EGFR. Further studies re needed to investigte the optiml tretment of ptients with TTF-1-negtive lung denocrcinom. CHEST 2012; 141(2): Abbrevitions: ECOG 5 Estern Coopertive Oncology Group; EGFR 5 epiderml growth fctor receptor; EMT 5 epithelil-to-mesenchyml trnsition; IHC 5 immunohistochemistry; NSCLC 5 non-smll cell lung cncer; OS 5 overll survivl; PCR 5 polymerse chin rection; PFS 5 progression-free survivl; TKI 5 tyrosine kinse inhibitor; TTF-1 5 thyroid trnscription fctor 1 Thyroid trnscription fctor 1 (TTF-1) is n importnt trnscription fctor in lung morphogenesis nd regultes gene expression of type 2 pneumocytes nd Clr cells in the postntl lung. 1 It is n importnt mrker in the immunohistochemistry (IHC) pnel for the dignosis of pulmonry denocrcinom. 2,3 TTF-1-positive lung denocrcinom ws found to hve morphologic resemblnce to type 2 pneumocytes, Clr cells, nd noncilited bronchiolr cells. 4 Previous studies showed tht TTF-1 expression 420 is significnt prognostic fctor of better survivl in lung denocrcinom. 5-8 Furthermore, epiderml growth fctor receptor (EGFR) muttion is ssocited with TTF-1 expression in lung denocrcinom. 9,10 TTF-1-positive denocrcinom lso shows higher prevlence of negtive p53 stining, less frequent retinoblstom protein loss, nd preserved expression of p27. 4 Therefore, the expression of TTF-1 in lung denocrcinom is ssocited with different cncer genetics nd clinicl prognoses. Originl Reserch

2 EGFR muttion is the most importnt fctor for predicting the response of EGFR tyrosine kinse inhibitors (TKIs), such s gefitinib or erlotinib. Deletions in exon 19 nd L858R muttion in exon 21 re the most common muttions ssocited with the EGFR TKI response, wheres dupliction, insertion, or T790M muttion in exon 20 re ssocited with resistnce In ptients with dvnced non-smll cell lung cncer (NSCLC), EGFR muttion could lso confer survivl benefits under EGFR TKI tretment Although higher EGFR muttion rte ws found in TTF-1-positive denocrcinom, 17.5% of TTF-1- negtive denocrcinom still hd mutnt EGFR. 9 For lung denocrcinom with mutnt EGFR, the best tretment course of EGFR TKI between TTF-1-positive nd TTF-1-negtive denocrcinom is unknown. Previous studies bout the clinicl outcome between TTF-1-positive nd TTF-1-negtive lung denocrcinom hve enrolled ptients minly in n operble stge.5-7 In ddition, it is unknown whether TTF-1 expression ffects the tretment efficcy of EGFR TKI. We conducted study imed t evluting the prognostic significnce of TTF-1 expression in dvnced lung denocrcinom nd on the efficcy of EGFR TKI tretment. Study Popultion Mterils nd Methods Consecutive ptients with lung denocrcinom dignosed between Jnury 2004 nd December 2009 were identified using the dtbse of the Cncer Registry, Medicl Informtion Mngement Office of the Ntionl Tiwn University Hospitl, tertiry medicl center in northern Tiwn. Lung cncer histology ws clssified ccording to World Helth Orgniztion (Genev, Mnuscript received December 7, 2010; revision ccepted July 1, Affilitions: From the Deprtment of Lbortory Medicine (Dr Chung), the Deprtment of Pthology (Dr Y-L Chng), the Deprtment of Internl Medicine (Drs Yu, Shih, nd P-C Yng), nd the Deprtment of Medicl Imging (Dr Y-C Chng), Ntionl Tiwn University Hospitl, College of Medicine, Ntionl Tiwn University; Grdute Institute of Oncology (Dr C-H Yng), Cncer Reserch Center, Ntionl Tiwn University, Tipei, Tiwn; nd the Deprtments of Biosttistics nd Epidemiology (Dr Hung), School of Public Helth, Hrvrd University, Boston, MA. Funding/Support : This work ws supported by the Ntionl Science Council [Grnts B MY3 nd B MY3], Tiwn; nd Ntionl Tiwn University [Grnt 99C ], Tiwn. Correspondence to: Jin-Yun Shih, MD, PhD, Deprtment of Internl Medicine, Ntionl Tiwn University Hospitl nd Ntionl Tiwn University College of Medicine, No. 7, Chung- Shn S Rd, Tipei 100, Tiwn; e-mil: Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins ( site/misc/reprints.xhtml ). DOI: /chest Switzerlnd) pthology clssifiction. 20 Ptients were included if they hd (1) dequte tumor specimens for EGFR sequencing nlysis nd TTF-1 immunostining, nd (2) dvnced disese, which ws defined s stge IIIB with mlignnt pleurl effusion nd stge IV ccording to the sixth edition of the Americn Joint Committee on Cncer, or postopertive recurrence. 21 Tumor specimens, including primry lung tumors, mlignnt pleurl effusion cell blocks, nd distnt metstses, were obtined by surgicl or needle biopsy. Ptients were excluded if they hd combined tumor histology other thn denocrcinom (such s histologic fetures suggesting squmous cell crcinom), or history of second mlignncy other thn lung cncer. The clinicl dt of enrolled ptients retrieved from chrt review included ge (t dignosis or recurrence), sex, smoking history, weight loss ( 5%) on presenttion, Estern Coopertive Oncology Group (ECOG) performnce sttus, nd metsttic sites t dignosis or recurrence. The metsttic sites were determined by CT scns of the chest (from the neck to the level of the drenl glnds) nd brin, nd bone scn. When distnt metstses were not reveled by CT scns or bone scns, PET scn ws performed. If metstses were suspected by PET, dditionl imging studies (such s MRI), biopsies, or both were performed for confirmtion. All ptients received systemic chemotherpy or EGFR TKIs ccording to the decision of the ttending physicins nd the preference of the ptients. For ll ptients enrolled, we evluted the fctors tht ffected the overll survivl (OS), which ws mesured from the first dy of cncer tretment until deth or the lst follow-up on July 31, The study protocol ws pproved by the institutionl review bord of the Ntionl Tiwn University Hospitl, IRB pprovl # R. TTF-1, E-cdherin, nd Vimentin Expression TTF-1 expression in cncer cells hs been demonstrted with n IHC study, s reported previously. 2 From ech formlin-fixed, prffin-embedded tissue block, 4- m m-thick tissue sections were obtined, which were dewxed with xylene, followed by rehydrtion with grded series of ethnol. The sections were then immunostined with monoclonl ntibody to 8G7G3/1 TTF-1 (1:200; Dko Corportion), followed by het-induced epitope retrievl for 18 min in citrte buffer (ph 6.0). Thevidin-biotin method, with 3,39 -diminobenzidine s chromogen, ws used for ntigen locliztion. A positive externl control slide of TTF-1-positive lung denocrcinom nd n internl control of nonneoplstic type 2 pneumocytes were included in ech run. Cses with ny definite nucler stining were considered to be positive TTF-1 expression. In ddition, the membrnous expression of E-cdherin nd the cytoplsmic expression of vimentin were lso determined by IHC studies. Specific monoclonl ntibodies to E-cdherin (1:200; TKR Bio Incorportion) nd vimentin (1:50; Dko Corportion) were used. Tumor cells were considered positive for E-cdherin or vimentin expression if. 5% of cncer cells hd immunorectivity. Otherwise, negtive E-cdherin or vimentin expression in cncer cells ws considered. Muttion Anlysis of EGFR nd KRAS Muttion nlysis of the EGFR gene ws described previously Briefly, DNA ws derived from tumor smples embedded in prffin blocks using QIAmp DNA Mini Kit (Qigen). The tyrosine kinse domin of EGFR (exon 18-21) ws mplified by polymerse chin rection (PCR), nd the mplicons were purified nd sequenced by n utomtic ABI PRISM 3700 DNA nlyzer (Applied Biosystems). RNA ws extrcted from frozen tumor specimens using the RNesy Mini Kit (Qigen). Reverse trnscription-pcr ws used to mplify the four exons CHEST / 141 / 2 / FEBRUARY,

3 (exons 18-21) of the tyrosine kinse domin of the EGFR gene. The mplicons were then purified nd sequenced. KRAS muttion nlysis ws lso performed s described previously. 25 DNA from tumor specimens ws sequenced for exon 2 of the KRAS gene. Forwrd nd reverse sequencing rections were performed on n ABI 3700 genetic nlyzer (Applied Biosystems). All the sequencing rections were performed in both forwrd nd reverse directions using trcings from t lest two PCRs. EGFR TKI Tretment The tretment courses of ll study ptients were reviewed, nd those who hd received EGFR TKI were identified. Ptients who received TKI s mintennce therpy were excluded. We performed progression-free survivl (PFS) nd OS nlyses in the remining ptients with EGFR TKI tretment. PFS ws mesured from the first dy of TKI tretment until the first objective sign of disese progression or deth, whichever occurred first. For evlution of tretment response nd disese progression, chest rdiogrph ws tken every 2 to 3 weeks nd chest CT scn ws tken every 2 to 3 months. Sttisticl Anlysis Person s x 2 test or the Fisher exct test ws used to compre ctegoricl vribles between two groups s pproprite. Kpln- Meier curves with log-rnk tests were used to evlute the differences of OS nd PFS between different strtified ptient groups. Multivrite nlyses with Cox proportionl hzrd model were performed to clculte the hzrd rtios of deth nd of disese progression, with djustment for other potentil confounding fctors. Detils of the sttisticl method re described in e-appendix 1. A two-sided P,.05 ws considered sttisticlly significnt. The Kpln-Meier curves were plotted with SPSS softwre (version 17.0 for Windows; SPSS Inc). Other sttisticl nlyses were performed with SAS softwre (version 9.1; SAS Institute). Ptient Chrcteristics Results From 2004 to 2009, 2,298 ptients with lung denocrcinom were identified (737 ptients with stge IV denocrcinom nd 159 ptients with stge IIIB denocrcinom with mlignnt pleurl effusion). Five hundred forty-six ptients with dvnced-stge denocrcinom hd tumor specimens dequte for EGFR muttion nlysis nd TTF-1 immunostining. None of the ptients hd combined tumor histology other thn denocrcinom. Fifty ptients were excluded becuse of history of second mlignncy other thn lung cncer. The remining 496 ptients constituted the study popultion. Their clinicl chrcteristics re shown in Tble 1. Their men ge ws 62 yers (rnge, yers), nd 227 (46%) were men. The histology dignosis of denocrcinom ws estblished by surgicl specimens in 136 ptients, by smll biopsies in 205 ptients (156 by fine-needle biopsies nd 49 by bronchoscopy-guided biopsies), nd by pleurl effusion cell blocks in 155 ptients. From the study popultion, 443 (89%) hd TTF-1- positive lung denocrcinom. The clinicl chrcteristics, including ge, sex, smoking history, weight loss t presenttion, ECOG performnce sttus, disese stge (stge IV/IIIB or postopertive recurrence), number of metsttic sites, nd use of EGFR TKI during the tretment course, were not different between ptients with TTF-1-positive nd TTF-1- negtive tumors. Four hundred two ptients received EGFR TKI tretment. Among them, four ptients did not receive chemotherpy during the tretment course. The other 94 ptients without EGFR TKI tretment received chemotherpy. The medin OS of the entire group ws 26.7 months (95% CI, months). EGFR Muttion Pttern Ptients with TTF-1-positive tumors hd higher EGFR muttion rtes thn did those with TTF-1- negtive tumors (61.9% vs 32.1%, P,.001) (Tble 1 ). The EGFR muttion ptterns re shown in Tble 2 (e-tble 1). Of the 291 ptients with mutnt EGFR, 259 hd single EGFR muttion nd the remining 32 hd more thn one EGFR muttion. In ptients with single muttion, 117 hd deletion in exon 19 nd 113 hd n L858R muttion. In those with more thn one EGFR muttion (double or triple muttions), 14 hd muttions involving deletion in exon 19 or L858R. None of these 14 ptients hd T790M muttion, or dupliction or insertion in exon 20, with the L858R or exon 19 muttions. New Histology Clssifiction of Lung Adenocrcinom During the writing of this rticle, new clssifiction scheme of lung denocrcinom ws reported. 26 According to this new clssifiction scheme, 486 ptients hd definitive histology dignosis of denocrcinom, estblished by morphologic fetures under light microscopy. In the remining 10 ptients, IHC studies of the tumors showed positive TTF-1 expression, nd the histology dignosis ws NSCLC, fvoring denocrcinom. None of these 496 ptients hd histologic fetures of squmous cell crcinom. Of the 486 ptients with definitive dignosis of denocrcinom, 286 (58.8%) hd EGFR muttions. Of the 10 ptients with NSCLC fvoring denocrcinom, five (50%) hd EGFR muttions ( P by Fisher exct test, compred with those with definitive dignosis of denocrcinom). In ddition, three ptients hd histology of invsive mucinous denocrcinom ccording to the new clssifiction scheme. 422 Originl Reserch

4 Tble 1 Clinicl Chrcteristics of the Study Popultion Prmeters Totl (N 5 496) TTF-1 ( 1 ) (n 5 443) TTF-1 ( 2 ) (n 5 53) P Vlue Age y , 70 y Sex.275 Mle Femle Smoking history.488 Current or former smoker Never smoker Weight loss.533 Yes No ECOG.086, Stge.346 IV/IIIB Recurrence Metsttic sites b.163, TKI tretment.699 Yes No EGFR,.001 Mutnt Wild ECOG 5 Estern Coopertive Oncology Group; EGFR 5 epiderml growth fctor receptor; TKI 5 tyrosine kinse inhibitor; TTF 5 thyroid trnscription fctor 1. TTF-1(1 ) vs TTF-1( 2 ). b Includes mlignnt pleurl effusion, mlignnt pericrdil effusion, nd metstsis to lung, bone, liver, drenl glnd, soft tissue, brin, peritoneum, spleen, nd distnt lymph node. All these ptients hd TTF-1-negtive tumors, without EGFR muttions. TTF-1 Expression nd OS Ptients with TTF-1-positive lung denocrcinom hd longer medin survivl thn did those with TTF-1-negtive lung denocrcinom (medin survivl, 27.4 vs 11.8 months; P 5.001) ( Fig 1 ). To evlute the prognostic fctors in ll ptients enrolled (N 5496), multivrite nlysis for OS ws performed with the Cox proportionl model. The finl Cox proportionl model of OS is shown in Tble 3. Ptients with poor performnce sttus (ECOG 2) nd wide disese extent (number of metsttic sites 2) hd shorter OS. Ptients hd longer OS if they hd mutnt EGFR (hzrd rtio, 0.448; P,.001) or TTF-1 expression (hzrd rtio, 0.452; P,.001). Ptients who received EGFR TKI during the tretment course lso hd longer OS (hzrd rtio, 0.257; P,.001). In the entire study popultion, only four ptients did not receive chemotherpy during the tretment course. When chemotherpy tretment ws included in the Cox proportionl model, the hzrd rtio for TTF-1 expression did not chnge significntly (hzrd rtio, 0.456; P ) (e-tble 2). TTF-1 Expression nd Survivl Under EGFR TKI Tretment Four hundred two ptients received EGFR TKI during tretment. Fourteen ptients received EGFR TKI s mintennce therpy (13 ptients with TTF-1- positive tumors nd one ptient with TTF-1-negtive tumor), nd they were excluded from further nlyses. In the remining 388 ptients, we performed nlyses of OS nd PFS under EGFR TKI tretment. Two hundred fifty-one ptients received EGFR TKI s first-line tretment, 85 s second-line, nd 52 s third-line or subsequent lines. Their clinicl chrcteristics re shown in Tble 4. Ptients were strtified into four groups ccording to TTF-1 positivity nd EGFR muttion. The clinicl chrcteristics were not significntly different mong the four groups. Ptients with TTF-1-positive denocrcinom nd mutnt EGFR hd the longest OS (medin survivl, 30.1 months), wheres ptients with TTF-1-negtive denocrcinom nd mutnt EGFR hd medin OS of only 10.8 months ( P 5.004, compred with ptients with TTF-1-positive denocrcinom nd mutnt EGFR) ( Fig 2A ). Regrding PFS under EGFR TKI tretment, ptients with TTF-1-positive lung denocrcinom CHEST / 141 / 2 / FEBRUARY,

5 Tble 2 EGFR Muttion Ptterns in 291 Ptients With Mutnt EGFR EGFR Muttions TTF-1 ( 1 ) (n 5 274) TTF-1 ( 2 ) (n 5 17 ) Totl (n 5 291) Single muttion Deletion (42) 2 (12) 117 (40) L858R 106 (39) 7 (41) 113 (39) Others b 27 (10) 2 (12) 29 (10). 1 EGFR muttion (double or triple muttions) With deletion 19 c 2 (1) 0 (0) 2 (1) With L858R c 9 (3) 3 (18) 12 (4) Others d 15 (5) 3 (18) 18 (6) Dt re presented s No. (%). See Tble 1 for expnsion of bbrevitions. Becuse of rounding, the totl of the percentges does not equl 100. b Includes ll EGFR muttions other thn deletion in exon 19 nd L858R in exon 21. Refer to e-tble 1 for detiled EGFR muttion ptterns. c None of these ptients hd T790M or muttions in exon 20, with deletion in exon 19 or L858R muttion. d Includes ll other double or triple EGFR muttions not contining deletion in exon 19 or L858R muttion. Refer to e-tble 1 for detiled EGFR muttion ptterns. nd mutnt EGFR hd longer PFS thn did those with TTF-1-negtive lung denocrcinom nd mutnt EGFR (medin survivl, 8.7 vs 5.7 months; P 5.043) ( Fig 2B ). Multivrite nlysis for PFS ws performed with Cox proportionl model ( Tble 5 ). EGFR muttion ws the most significnt fctor ssocited with longer PFS under TKI tretment (hzrd rtio, 0.241; P,.001). Ptients with TTF-1-positive lung denocrcinom lso hd longer PFS (hzrd rtio, 0.524; P,.001). Ptients with poor performnce sttus Figure 1. Kpln-Meier curves of overll survivl (OS) in the entire study popultion (N 5 496). Kpln-Meier curves of OS were constructed with strtifiction by TTF-1. Ptients with TTF- 1-positive lung denocrcinom hd longer OS thn did those with TTF-1-negtive lung denocrcinom (MST, 27.4 vs 11.8 months, P 5.001). MST 5 medin survivl time; TTF-1 5 thyroid trnscription fctor-1. nd wide disese extent (number of metsttic sites 2) lso hd shorter PFS. In ddition, the clinicl settings in which EGFR TKIs were used (first-line, second-line, third-line or more) did not ffect PFS significntly. E-cdherin nd Vimentin Expression nd KRAS Muttion in TTF-1-negtive Adenocrcinom A previous study suggested tht TTF-1-positive denocrcinom might hve lower KRAS muttion rte thn tht of TTF-1-negtive denocrcinom. 9 TTF-1 expression ws lso shown to inhibit the trnsforming growth fctor- b-medited epithelilto-mesenchyml trnsition (EMT) in lung denocrcinom cells. 27 Moreover, poor clinicl outcome under EGFR TKI tretment ws found in NSCLCs with KRAS muttion or EMT ctivtion. 28,29 For TTF-1- negtive lung denocrcinom, it is unknown whether the worse clinicl outcome is due to EMT ctivtion or KRAS muttion. Therefore, we performed IHC studies for E-cdherin nd vimentin nd KRAS muttion nlysis in TTF-1-negtive lung denocrcinom. Of 53 ptients with TTF-1-negtive denocrcinom, 37 hd tumor specimens dequte for E-cdherin nd vimentin IHC studies. Thirty ptients hd denocrcinom with positive E-cdherin nd negtive vimentin expression. The remining seven ptients hd denocrcinom with negtive E-cdherin (n 5 4) or positive vimentin expression (n 5 3). Only one ptient mong these seven hd EGFR muttion (L858R). In ddition, 35 ptients hd dequte tumor specimens for KRAS muttion nlysis. Only three ptients hd KRAS muttion, nd ll of them hd wild EGFR. Discussion In ptients with dvnced lung denocrcinom, TTF-1 expression predicted longer OS independently. In ptients who hd received EGFR TKI during tretment course, those with TTF-1-positive lung denocrcinom nd mutnt EGFR hd longer OS thn did those with TTF-1-negtive lung denocrcinom, or TTF-1-positive lung denocrcinom but wild EGFR. In ptients with mutnt EGFR, those with TTF-1-positive lung denocrcinom hd longer PFS thn did those with TTF-1-negtive lung denocrcinom. The definition of positive TTF-1 expression under IHC study vries ccording to the study. Some studies hve defined positive TTF-1 expression s ny definite nucler stining, wheres other studies hve defined positive TTF-1 expression s tumors with. 5% or. 50% positivity. 5,7,9,30 However, one study showed tht the clinicl outcome between wekly TTF-1-positive nd strongly TTF-1-positive denocrcinom ws not different. 7 Therefore, in this study, we defined positive 424 Originl Reserch

6 Tble 3 Cox Proportionl Hzrd Model of Overll Survivl in All Ptients Enrolled in the Study (N 5 496) Covrite Estimte SE P Vlue Hzrd Rtio 95% CI Age 70 y ECOG , Stge IV/IIIB Metstses 2 b , Mutnt EGFR c TTF-1 expression , TKI tretment c , Strtified Cox proportionl hzrd model ws performed with strtifiction fctors of sex, smoking history, nd weight loss. See Tble 1 for expnsion of bbrevitions. Refers to postopertive recurrence. bno. metstses. 1; the sites of metstses include mlignnt pleurl effusion, mlignnt pericrdil effusion, nd metstsis to the lungs, bone, liver, drenl glnd, soft tissue, brin, peritoneum, spleen, nd distnt lymph node. c Time-dependent covrites of mutnt EGFR nd TKI tretment were included in the finl model. The estimte of the time-dependent covrite of mutnt EGFR (time by mutnt EGFR interction term) ws (SE, ; P ). Two time-dependent covrites of TKI tretment (time by TKI tretment nd time 2 by TKI tretment interction terms) were included. The estimte for time by TKI tretment interction term ws (SE, ; P ), wheres the estimte for time 2 by TKI tretment interction term ws (SE, ; P ). The result suggests tht the effects of mutnt EGFR nd TKI tretment decrese with time. TTF-1 expression s ny definite nucler stining in tumor cells. In vitro studies show tht the expression of TTF-1 in denocrcinom is relted to prolifertion nd survivl of cncer cells Furthermore, TTF-1 mplifiction, exmined by fluorescent in situ hybridiztion, occurs in 6% to 14% of lung denocrcinom. However, TTF-1 mplifiction does not correlte Tble 4 Clinicl Chrcteristics of Ptients With EGFR TKI Tretment (n 5 388) TTF-1 ( 1 ) TTF-1 ( 2 ) Prmeters Mutnt EGFR (n 5 234) Wild EGFR (n 5 111) Totl (n 5 345) P Vlue b Mutnt EGFR (n 5 15) Wild EGFR (n 5 28) Totl (n 5 43) P Vlueb P Vlue Age y , 70 y Sex.114 Mle Femle Smoking history.057 Current or former smoker Never smoker Weight loss.945 Yes No ECOG.075, Stge.347 IV/IIIB Recurrence Metsttic sites c.156, EGFR TKI tretment.432 First-line Second-line Third-line or more The tble does not include ptients who received EGFR TKI s mintennce therpy. See Tble 1 for expnsion of bbrevitions. TTF-1(1 ) vs TTF-1( 2 ). b Mutnt EGFR vs wild EGFR, in TTF-1( 1 ) nd TTF-1( 2 ) groups, respectively c Includes mlignnt pleurl effusion, mlignnt pericrdil effusion, nd metstsis to lung, bone, liver, drenl glnd, soft tissue, brin, peritoneum, spleen, nd distnt lymph node. CHEST / 141 / 2 / FEBRUARY,

7 Figure 2. Kpln-Meier curves of OS nd progression-free survivl in ptients who hd received EGFR TKI during tretment course (n 5 388). A, In 388 ptients who received EGFR TKI during tretment course, Kpln-Meier curves of OS were constructed with strtifiction by TTF-1 nd EGFR muttion. Ptients with TTF-1-positive lung denocrcinom nd mutnt EGFR hd longer survivl. B, Kpln-Meier curves of PFS were plotted with strtifiction by TTF-1 nd EGFR muttions. In ptients with muttions, those with TTF-1-positive denocrcinom hd longer survivl thn those with TTF-1-negtive denocrcinom (MST, 8.7 vs 5.7 months, P 5.043). EGFR = epiderml growth fctor receptor; TKI 5 tyrosine kinse inhibitor. See Figure 1 legend for expnsion of other bbrevitions. with TTF-1 expression. 7,33 In ptients with lung denocrcinom, those with TTF-1 mplifiction did not hve different clinicl outcome from those without TTF-1 mplifiction. 7,33 The study popultions were smll in these studies, nd further studies re needed to evlute the clinicl significnce of TTF-1 mplifiction in lung denocrcinom. Previous studies discussing TTF-1 expression nd clinicl outcome hve focused minly on operble stges. In one study, 83% of the study popultion hd dvnced lung denocrcinom. 5 Ptients with TTF-1-positive denocrcinom hd medin survivl of 14 months, wheres those with TTF-1-negtive denocrcinom hd medin survivl of only 5 months. However, in this study, ptients with TTF- 1-positive denocrcinom hd medin survivl of 27.4 months, wheres those with TTF-1-negtive denocrcinom hd medin survivl of 11.8 months. A high EGFR muttion rte (58.7%) ws found in the study popultion, nd most ptients (81.0%) received EGFR TKI during the tretment course. This my explin the survivl difference between the two studies. Additionlly, dvncements in chemotherpeutic gents my lso ccount for such differences. In ptients receiving EGFR TKI during the tretment course, this study shows tht ptients with TTF-1-positive denocrcinom nd mutnt EGFR hve longer survivl, compred with those with TTF-1-negtive denocrcinom, or those with TTF- 1-positive but wild EGFR. In ptients with mutnt EGFR, however, those with TTF-1-positive tumors hd longer PFS (8.7 months) thn did those with TTF-1-negtive tumors (5.7 months). According to recent phse 3 clinicl trils, in ptients with dvnced NSCLC nd sensitive EGFR muttions, PFS under EGFR TKIs is 9.2 to 14 months. 18,19,34 In our study, ptients with TTF-1-positive lung denocrcinom nd mutnt EGFR hd PFS under EGFR TKI similr to tht reported by previous clinicl trils. EMT is criticl step in cncer progression, invsion, nd metstses. 35,36 Lung cncer cells with EMT ctivtion not only lose epithelil mrkers (such s E-cdherin) but hve poor sensitivity to EGFR inhibition.37 Our recent study showed the expression of EMT regultor-slug correltes with the cquired resistnce to EGFR TKI. 38 A previous study showed tht TTF-1 expression inhibits the trnsforming growth fctor- b -medited EMT in lung denocrcinom cells. 27 However, only seven out of 37 ptients (18.9%) with TTF-1-negtive denocrcinom hd tumors with negtive E-cdherin or positive vimentin expression. Furthermore, KRAS muttion is n importnt mechnism tht cuses poor response to EGFR TKI tretment. In our study, only three of 35 ptients with TTF-1-negtive denocrcinom (8.6%) hd KRAS muttion. Therefore, the worse clinicl outcome in ptients with TTF-1-negtive denocrcinom could not be explined completely by EMT ctivtion or KRAS muttion. One recent study showed tht downregultion of TTF-1 in denocrcinom ws relted to loss of differentition nd incresed metsttic potentil. 39 The worse clinicl outcome could be cused by the ggressive biologic behvior of TTF-1-negtive denocrcinom. However, other mechnisms responsible might still exist, which need to be explored in future studies. There re some limittions to this study. First, there is no report on the response rte to EGFR TKI in TTF-1-positive nd TTF-1-negtive lung denocrcinom. However, PFS my be more importnt prmeter thn response rte in dily prctice. Second, 426 Originl Reserch

8 Tble 5 Cox Proportionl Hzrd Model of Progression-Free Survivl Under TKI Tretment (n 5 388) Covrite Estimte SE P Vlue Hzrd Rtio 95% CI Age 70 y Mle Smoking history Weight loss ECOG Stge IV/IIIB Metstses 2b Mutnt EGFR c , TTF-1 expression TKI tretment d Second-line Third-line or more See Tble 1 for expnsion of bbrevitions. Reference to postopertive recurrence. bno. metstses. 1; the sites of metstses include mlignnt pleurl effusion, mlignnt pericrdil effusion, nd metstsis to the lungs, bone, liver, drenl glnd, soft tissue, brin, peritoneum, spleen, nd distnt lymph node. c Time-dependent covrite of mutnt EGFR (time by mutnt EGFR interction term) ws included in the finl model, with the estimte s (SE, ; P ). The result suggests tht the effect of mutnt EGFR decreses with time. d Reference to first-line EGFR TKI tretment. in the PFS nlyses, EGFR TKIs were used t different times during the tretment course. Although ptients might receive EGFR TKIs s first-line, second-line, or third-line tretment, our previous study hs suggested tht PFS is not ffected by the timing of EGFR TKI tretment. 23 Moreover, from multivrite nlysis, the timing of EGFR TKI tretment (firstline, second-line, third-line or more) ws not significnt fctor ffecting PFS. Therefore, this did not hve significnt impct on our results. Finlly, becuse it is retrospective study, selection bis my exist, nd further prospective studies re needed to confirm such results nd to investigte whether the expression of TTF-1 ffects the clinicl outcome in lung denocrcinom. Conclusions In conclusion, TTF-1 not only is n importnt cell mrker in routine IHC pnel, but lso shows independent prognostic significnce in dvnced lung denocrcinom. Under EGFR TKI tretment, ptients with TTF-1-positive lung denocrcinom nd EGFR muttion hd longer OS. In ptients with EGFR muttion, those with TTF-1-negtive denocrcinom hd shorter PFS thn did those with TTF- 1-positive denocrcinom. Acknowledgments Author contributions: Dr Chung: contributed to the conception nd design of the study, finncil support, collection nd ssembly of dt, dt nlysis nd interprettion, mnuscript writing, nd finl pprovl of the mnuscript. Dr Hung: contributed to the collection nd ssembly of dt, dt nlysis nd interprettion, mnuscript writing, nd finl pprovl of the mnuscript. Dr Y-L Chng: contributed to the provision of study mterils nd recruitment of ptients, collection nd ssembly of dt, dt nlysis nd interprettion, nd finl pprovl of the mnuscript. Dr Yu: contributed to the conception nd design of the study, dministrtive support, provision of study mterils nd recruitment of ptients, nd finl pprovl of the mnuscript. Dr C-H Yng: contributed to the conception nd design of the study, dministrtive support, provision of study mterils nd recruitment of ptients, nd finl pprovl of the mnuscript. Dr Y-C Chng: contributed to the collection nd ssembly of dt, dt nlysis nd interprettion, nd finl pprovl of the mnuscript. Dr Shih: contributed to the conception nd design of the study, finncil support, provision of study mterils nd recruitment of ptients, collection nd ssembly of dt, dt nlysis nd interprettion, mnuscript writing, nd finl pprovl of the mnuscript. Dr P-C Yng: contributed to the conception nd design of the study, dministrtive support, provision of study mterils nd recruitment of ptients, mnuscript writing, nd finl pprovl of the mnuscript. Finncil/nonfinncil disclosures: The uthors hve reported to CHEST the following conflicts of interest: Dr Yu hs received honorri from AstrZenec nd Roche for speeches mde. Drs C-H Yng nd Shih hve received honorri from AstrZenec nd Roche for speeches nd d hoc dvisory committee prticiption, nd lso plyed n unpid dvisory role for Boehringer Ingelheim. Drs Chung, Hung, Y-L Chnge, Y-C Chng, nd P-C Yng hve reported tht no potentil conflicts of interest exist with ny compnies/orgniztions whose products or services my be discussed in this rticle. Role of sponsors : The sponsor hd no role in the design of the study, the collection nd nlysis of the dt, or in the preprtion of the mnuscript. Additionl informtion: The e-appendix nd e-tbles cn be found in the Online Supplement t org/content/141 /2 /420/suppl/DC1. References 1. Med Y, Dvé V, Whitsett JA. Trnscriptionl control of lung morphogenesis. Physiol Rev ;87(1): Chng YL, Lee YC, Lio WY, Wu CT. The utility nd limittion of thyroid trnscription fctor-1 protein in primry nd metsttic pulmonry neoplsms. Lung Cncer ;44(2): CHEST / 141 / 2 / FEBRUARY,

9 3. Lu SK, Luthringer DJ, Eisen RN. Thyroid trnscription fctor-1: review. Appl Immunohistochem Mol Morphol ;10 (2 ): Ytbe Y, Mitsudomi T, Tkhshi T. TTF-1 expression in pulmonry denocrcinoms. Am J Surg Pthol ;26 (6 ): Brlési F, Pinot D, Legoffic A, et l. Positive thyroid trnscription fctor 1 stining strongly correltes with survivl of ptients with denocrcinom of the lung. Br J Cncer ;93 (4 ): Angnostou VK, Syrigos KN, Bepler G, Homer RJ, Rimm DL. Thyroid trnscription fctor 1 is n independent prognostic fctor for ptients with stge I lung denocrcinom. J Clin Oncol ;27 (2 ): Brlett JA, Perner S, Ifrte AJ, et l. Clinicl significnce of TTF-1 protein expression nd TTF-1 gene mplifiction in lung denocrcinom. J Cell Mol Med ;13 (8B ): Tkeuchi T, Tomid S, Ytbe Y, et l. Expression profile-defined clssifiction of lung denocrcinom shows close reltionship with underlying mjor genetic chnges nd clinicopthologic behviors. J Clin Oncol ;24 (11 ): Ytbe Y, Kosk T, Tkhshi T, Mitsudomi T. EGFR muttion is specific for terminl respirtory unit type denocrcinom. Am J Surg Pthol ;29 (5 ): Tpi C, Svic S, Bihl M, et l. EGFR muttion nlysis in non-smll-cell lung cncer : experience from routine dignostics [in Germn]. Pthologe ;30 (5 ): Lynch TJ, Bell DW, Sordell R, et l. Activting muttions in the epiderml growth fctor receptor underlying responsiveness of non-smll-cell lung cncer to gefitinib. N Engl J Med ;350 (21 ): Po W, Miller VA, Politi KA, et l. Acquired resistnce of lung denocrcinoms to gefitinib or erlotinib is ssocited with second muttion in the EGFR kinse domin. PLoS Med ;2 (3 ):e Shih JY, Gow CH, Yng PC. EGFR muttion conferring primry resistnce to gefitinib in non-smll-cell lung cncer. N Engl J Med ;353 (2 ): Yng CH, Yu CJ, Shih JY, et l. Specific EGFR muttions predict tretment outcome of stge IIIB/IV ptients with chemotherpy-nive non-smll-cell lung cncer receiving first-line gefitinib monotherpy. J Clin Oncol ;26 (16 ): Wu JY, Wu SG, Yng CH, et l. Lung cncer with epiderml growth fctor receptor exon 20 muttions is ssocited with poor gefitinib tretment response. Clin Cncer Res ;14 (15 ): Mitsudomi T, Kosk T, Endoh H, et l. Muttions of the epiderml growth fctor receptor gene predict prolonged survivl fter gefitinib tretment in ptients with non-smll-cell lung cncer with postopertive recurrence. J Clin Oncol ;23 (11 ): Tkno T, Fukui T, Ohe Y, et l. EGFR muttions predict survivl benefit from gefitinib in ptients with dvnced lung denocrcinom: historicl comprison of ptients treted before nd fter gefitinib pprovl in Jpn. J Clin Oncol ;26 (34 ): Mitsudomi T, Morit S, Ytbe Y, et l ; West Jpn Oncology Group. Gefitinib versus cispltin plus docetxel in ptients with non-smll-cell lung cncer hrbouring muttions of the epiderml growth fctor receptor (WJTOG3405): n open lbel, rndomised phse 3 tril. Lncet Oncol ;11 (2 ): Memondo M, Inoue A, Kobyshi K, et l ; North-Est Jpn Study Group. Gefitinib or chemotherpy for non-smllcell lung cncer with mutted EGFR. N Engl J Med ; 362 (25 ): Trvis WD. Pthology nd Genetics of Tumours of the Lung, Pleur, Thymus nd Hert. Oxford, Englnd: Oxford University Press; Greene FL. AJCC Cncer Stging Mnul. New York, NY : Springer ; Shih JY, Gow CH, Yu CJ, et l. Epiderml growth fctor receptor muttions in needle biopsy/spirtion smples predict response to gefitinib therpy nd survivl of ptients with dvnced nonsmll cell lung cncer. Int J Cncer ;118 (4 ): Wu JY, Yu CJ, Yng CH, et l. First- or second-line therpy with gefitinib produces equl survivl in non-smll cell lung cncer. Am J Respir Crit Cre Med ; 178 ( 8 ): Wu SG, Gow CH, Yu CJ, et l. Frequent epiderml growth fctor receptor gene muttions in mlignnt pleurl effusion of lung denocrcinom. Eur Respir J ; 32 ( 4 ): Wu JY, Yng CH, Hsu YC, et l. Use of cetuximb fter filure of gefitinib in ptients with dvnced non-smll-cell lung cncer. Clin Lung Cncer ;11 (4 ): Trvis WD, Brmbill E, Noguchi M, et l. Interntionl ssocition for the study of lung cncer/mericn thorcic society/europen respirtory society interntionl multidisciplinry clssifiction of lung denocrcinom. J Thorc Oncol ;6 (2 ): Sito RA, Wtbe T, Horiguchi K, et l. Thyroid trnscription fctor-1 inhibits trnsforming growth fctor-bet-medited epithelil-to-mesenchyml trnsition in lung denocrcinom cells. Cncer Res ;69 (7 ): Riely GJ, Mrks J, Po W. KRAS muttions in non-smll cell lung cncer. Proc Am Thorc Soc ;6 (2 ): Yuch RL, Jnurio T, Eberhrd DA, et l. Epithelil versus mesenchyml phenotype determines in vitro sensitivity nd predicts clinicl ctivity of erlotinib in lung cncer ptients. Clin Cncer Res ;11 (24 pt 1 ): Tn D, Li Q, Deeb G, et l. Thyroid trnscription fctor-1 expression prevlence nd its clinicl implictions in non-smll cell lung cncer: high-throughput tissue microrry nd immunohistochemistry study. Hum Pthol ;34 (6 ): Tnk H, Yngisw K, Shinjo K, et l. Linege-specific dependency of lung denocrcinoms on the lung development regultor TTF-1. Cncer Res ;67 (13 ): Kwei KA, Kim YH, Girrd L, et l. Genomic profiling identifies TITF1 s linege-specific oncogene mplified in lung cncer. Oncogene ;27 (25 ): Weir BA, Woo MS, Getz G, et l. Chrcterizing the cncer genome in lung denocrcinom. Nture ;450 (7171 ): Rosell R, Morn T, Querlt C, et l ; Spnish Lung Cncer Group. Screening for epiderml growth fctor receptor muttions in lung cncer. N Engl J Med ;361 (10 ): Shih JY, Tsi MF, Chng TH, et l. Trnscription repressor slug promotes crcinom invsion nd predicts outcome of ptients with lung denocrcinom. Clin Cncer Res ; 11 (22 ): Yngw J, Wlser TC, Zhu LX, et l. Snil promotes CXCR2 lignd-dependent tumor progression in non-smll cell lung crcinom. Clin Cncer Res ;15 (22 ): Thomson S, Buck E, Petti F, et l. Epithelil to mesenchyml trnsition is determinnt of sensitivity of nonsmll-cell lung crcinom cell lines nd xenogrfts to epiderml growth fctor receptor inhibition. Cncer Res ; 65 ( 20 ): Chng TH, Tsi MF, Su KY, et l. Slug confers resistnce to the epiderml growth fctor receptor tyrosine kinse inhibitor. Am J Respir Crit Cre Med ;183 (8 ): Winslow MM, Dyton TL, Verhk RG, et l. Suppression of lung denocrcinom progression by Nkx2-1. Nture ;473 (7345 ): Originl Reserch

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