Lung cancer is the leading cause of cancer death worldwide, EGFR Mutation and Brain Metastasis in Pulmonary Adenocarcinomas

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1 Originl Article EGFR Muttion nd Brin Metstsis in Pulmonry Adenocrcinoms Dong-Yeop Shin, MD,* Im Il N, MD,* Cheol Hyeon Kim, MD, PhD, Sunhoo Prk, MD, PhD, HeeJong Bek, MD, PhD, nd Sung Hyun Yng, MD, PhD* Bckground: This study imed to explore the potentil ssocition of muttion in the epiderml growth fctor receptor (EGFR) with brin metstses in ptients with pulmonry denocrcinom. Methods: We nlyzed clinicl dt on 314 ptients who were tested for EGFR muttion nd underwent brin mgnetic resonnce imging t dignosis. The reltionship between EGFR muttion sttus nd brin metstses t the initil presenttion ws nlyzed. In ddition, prognostic significnce of EGFR muttionl sttus on the risk of brin metstsis ws evluted in subgroups of surgiclly treted ptients. Results: Of the 314 ptients, 138 ptients (43.9%) hd EGFR muttions. The frequency of EGFR muttion ws sttisticlly higher for ptients with brin metstses (64.7%, brin metstses; 39.8%, no metstses; 40.2%, extrcrnil metstses; p = 0.005). A strong ssocition between EGFR muttion sttus nd brin metstsis ws observed (djusted odds rtio = 3.83, p = 0.001), wheres no ssocition ws observed between EGFR muttion sttus nd extrcrnil metstses (djusted odds rtio = 1.73, p = 0.079). In ddition, the number of brin metstses ws significntly correlted with the EGFR muttion sttus (p = 0.029). Further nlysis of 133 ptients treted with surgicl resection showed tht EGFR muttion sttus ws poor prognostic fctor for the risk of brin metstsis (hzrd rtio = 4.49, p = 0.026) fter djustment for pthologic N stge. Conclusions: We found significnt ssocition between EGFR muttion nd risk of brin metstses t the time of dignosis nd follow-up fter curtive resection for pulmonry denocrcinom. This result indictes the distinct clinicl fetures of EGFR-mutted tumors in terms of brin metstses. Key Words: Epiderml growth fctor receptor muttion, Pulmonry denocrcinom, Brin metstsis, Crnil metstsis. (J Thorc Oncol. 2014;9: ) Lung cncer is the leding cuse of cncer deth worldwide, 1,2 nd extensive reserch on this cncer hs been *Deprtment of Internl Medicine, Division of Hemtology/Oncology Deprtment of Internl Medicine, Division of Pulmonology, Deprtment of Pthology, nd Deprtment of Thorcic Surgery, Kore Cncer Center Hospitl, Kore Institute of Rdiologicl nd Medicl Sciences, Seoul, Kore. Disclosure: The uthors declre no conflict of interest. Address for correspondence: Im Il N, MD, Deprtment of Internl Medicine, Kore Cncer Center Hospitl, 75 Nowon-gil, Nowon-gu, Seoul , Kore. E-mil: hmon@kcch.re.kr) Copyright 2013 by the Interntionl Assocition for the Study of Lung Cncer ISSN: /14/ conducted to dte. Recent progress in the field of medicl tretment of dvnced lung cncer hs been focusing on moleculr chnges. Genetic ltertion of the epiderml growth fctor receptor (EGFR), which is predominntly found in denocrcinoms, 3 is representtive mrker in determining the pproprite tretment for dvnced lung cncer. 3,4 The recognition of EGFR muttion indictes clinicl tretment with tyrosine kinse inhibitors such s gefitinib nd erlotinib. 5 7 Among distnt metstses, brin metstsis is one of the most devstting complictions of lung cncer thretening ffected ptients. 8 Although mgnetic resonnce imging (MRI) is used to detect brin metstses, its cost effectiveness remins uncertin. 9 Moreover, there is controversy over the use of routine brin MRI in stging symptomtic ptients with non smll-cell lung cncer (NSCLC), prticulrly when they hve erly thorcic diseses. 10,11 Thus, in studies of brin metstses, potentil bises rise from overlooking ptients with brin metstses. Extensive reserch hs proved the ssocition between the genetic ltertion of EGFR nd distnt metstses in vrious cncers such s those of the brest nd rectum In ptients with pulmonry denocrcinoms, different pulmonry metsttic ptterns of EGFR-mutted tumors were lso reported. 15 However, becuse of the limited dt vilble, it hs not been possible to determine different brin metstses ccording to EGFR muttion sttus in pulmonry denocrcinoms. Severl studies hve tried to identify the predictive fctors for brin metstsis in ptients with NSCLC. Crcinoembryonic ntigen, 16 size of primry tumor, nodl stge, 17 nd presence of bone metstses 18 hve been proposed s predictive fctors for the presence of brin metstsis in ptients with NSCLC. A histopthology of nonsqumous cell crcinom is lso known to be predictive fctor, which mens tht pulmonry denocrcinom hs higher tendency to metstsize to the brin thn squmous cell crcinom. 17 However, the clinicl implictions of EGFR muttion sttus in terms of brin metstsis in ptients with pulmonry denocrcinom hve not yet been exmined. In this study, we investigted the clinicl ssocition between EGFR muttion nd brin metstsis in ptients with pulmonry denocrcinom who were exmined by using brin MRI. Journl of Thorcic Oncology Volume 9, Number 2, Februry

2 Shin et l. Journl of Thorcic Oncology Volume 9, Number 2, Februry 2014 PATIENTS AND METHODS Ptients A totl of 314 ptients dignosed with denocrcinom of the lung were consecutively enrolled between October 2005 nd December 2011 t the Kore Cncer Center Hospitl. We evluted the ptients dt from chest computed tomogrphy (CT) scn, bone scn, nd MRI of brin, s routine stging workup, for which expenses were shred by ntionl helth insurnce. The tumor stge ws clssified using recently revised tumor, node, metstsis (TNM) system proposed by Americn Joint Committee on Cncer (8th edition). T nd N stge were determined on the bsis of the findings of CT with or without dditionl fiberoptic bronchoscopy. Medistinl lymph nodes lrger thn 1 cm on trnsxil CT imges were considered positive. Stge ws not bsed on the findings of dditionl positron emission tomogrphy scn becuse it ws not performed in ll ptients. Distnt metstses were ctegorized s metstsis to the brin nd those to extrcrnil sites only. Ptients with squmous cell nd denosqumous crcinom were excluded. Recurrence of brin metstses in ptients who hd been treted with curtive resection were suspected on the bsis of clinicl symptoms nd confirmed by results of brin MRI. EGFR Genotyping Genomic DNA ws extrcted from prffin-embedded tissues, s described previously. 19 In ptients whose only vilble tissue ws cytologic smple t initil dignosis, methnol-fixed cytologic specimens were used for DNA extrction. 20 EGFR muttion nlysis ws crried out by direct sequencing before Mrch 2009 (135 ptients), nd pyrosequencing ws performed for the detection of EGFR muttion fter Mrch 2009 (179 ptients), s described previously. 21 Sttisticl Methods Sttisticl nlysis of dt ws performed using STATA version 11 (Stt Corp, College Sttion, TX). The ssocitions between EGFR muttion sttus nd clinicl fetures, specificlly ge, sex, smoking, TNM stge, nd metsttic site, s well s brin metstsis, were nlyzed using logistic regression nlysis. Clinicl fctors known to be ssocited with EGFR muttion sttus in pulmonry denocrcinom nd stging fctors of TNM were included in the multivrite nlysis. The ssocitions between the spred pttern of brin metstses nd EGFR muttion sttus were lso evluted using Kruskl Wllis test. The prognostic implictions of EGFR muttion on the occurrence of brin metstsis in ptients who were treted with surgicl resection were nlyzed using competing risk regression nlysis of Fine nd Gry. 22 Deths without crnil disese were considered s competing events. A p vlue less thn 0.05 (two-sided) ws considered sttisticlly significnt. Ethics This study protocol ws reviewed nd pproved by the Institutionl Review Bord of the Kore Cncer Center Hospitl (Insititutionl Review Bord No: K ). The recommendtions of the Declrtion of Helsinki for biomedicl reserch involving humn subjects were followed. RESULTS Ptient Chrcteristics A totl of 314 ptients (151 men nd 163 women) with medin ge of 64 yers (rnge, yers) were consecutively enrolled in our study. Adenocrcinom ws the histologic subtype in ll ptients. Almost hlf of the ptients (153 ptients, 48.7%) hd metsttic disese. Among the 153 ptients with distnt metstses, 51 ptients (33.3%) hd crnil metstses nd 102 ptients (66.7%) hd only extrcrnil metstses (Tble 1). A totl of 138 ptients (43.9%) hd muttions, of which exon 19 deletion ws the most common (79 ptients, 57.2%), followed by L858R muttion in exon 21 (51 ptients, 37.0%). The other eight ptients (5.8%) hd G719X muttion in exon 18. EGFR Muttion nd Bseline Chrcteristics In univrite nlysis, EGFR muttion ws found more frequently in women (61.4% versus 25.2% [men], p < 0.001) nd never smokers (60.6% versus 26.6% [ smokers], p < 0.001). The difference in ge ccording to EGFR muttion (64 yers versus 61 yers [wild type], p = 0.12) ws not sttisticlly significnt. We further evluted the ssocition between stge nd EGFR muttion. A reverse correltion between dvnced nodl stge nd EGFR muttion ws observed (36.2% [N2 3] versus 47.9% [N0 1]). However, sttisticl significnce ws mrginl in univrite nlysis (p = 0.050). The frequency of EGFR muttion did not differ by T stge (44.7% [T1 2] versus 41.4% [T3 4], p = 0.63), wheres the size of primry tumor ws inversely correlted with EGFR muttion (3.0 cm versus 3.4 cm [wild type], p = 0.024) (Tble 1). Metsttic disese (M1) ws not ssocited with EGFR muttion in univrite nlysis (39.8% [M0] versus 48.4% [M1], p = 0.12). TABLE 1. Bseline Chrcteristics (N = 314) EGFR Muttion Positive (n,%) Negtive (n,%) p Vlue Age (medin, rnge), yers 63 (25 84) 61(35 82) 0.18 Sex, n (%) Mle 38 (25.2) 113(74.8) <0.001 Femle 100 (61.4) 63(38.7) T stge (44.7) 135 (55.3) (41.4) 41 (58.6) N stge (47.9) 109(52.2) (36.2) 67(63.8) Distnt metstsis No 64(39.75) 97(60.25) Crnil 33(64.7) 18(35.3) Extrcrnil 41(40.2) 61(59.8) Inclusion of 44 ptients with extrcrnil metstses. 196 Copyright 2013 by the Interntionl Assocition for the Study of Lung Cncer

3 Journl of Thorcic Oncology Volume 9, Number 2, Februry 2014 Brin Metstsis in EGFR-Mutted Lung Cncer EGFR Muttion nd Brin Metstsis in Multivrite Anlysis At the time of initil dignosis of pulmonry denocrcinom, the frequency of EGFR muttions ws sttisticlly different ccording to the site of metstses (39.8% [no metstses] versus 40.2% [extrcrnil metstses] versus 64.7% [brin metstses], p = 0.005). The percentge of EGFR muttions ws lso significntly different in subcohorts of metsttic disese (40.2% [extrcrnil metstses] versus 64.7% [brin metstses], p = 0.004). Next, we ssessed the significnce of EGFR muttion with respect to brin metstses by using the multivrite model. A strong ssocition between EGFR muttion sttus nd brin metstsis ws observed (djusted odd rtio = 3.83, 95% confidence intervl [CI]: , p = 0.001), wheres there ws no ssocition between EGFR muttion nd extrcrnil metstses (djusted odd rtio = 1.73, 95% CI: , p = 0.079) (Tble 2). In the finl model, nodl stge (p = 0.025) nd tumor size (p = 0.024) remined significnt fctors, wheres smoking history ws no longer significnt (p = 0.088). EGFR Muttion nd Physicl Fetures t Metsttic Brin Lesion To investigte the potentil difference in physicl fetures of brin metstses ccording EGFR muttion, we performed subgroup nlysis in ptients with brin metstses (n = 51). The number nd size of brin metstses strtified TABLE 2. Clinicl Fetures Relted to EGFR Muttion Sttus in Ptients with Lung Adenocrcinom Multivrite Odds Rtio (95% Confidence Intervl) p Vlue Sex 2.86 ( ) Smoking Size 0.54 ( ) 0.83 ( ) T (T3/4) 1.46 ( ) 0.30 N (N2/3) 0.50 ( ) M (M1) Crnil 3.83 ( ) Extrcrnil 1.73 ( ) Continuous vrible. TABLE 3. Chrcteristics of Brin Metstses ccording to EGFR Muttion Sttus in Ptients with Pulmonry Adenocrcinom with Brin Metstsis (n = 51) Brin Metstses EGFR Muttion Sttus Positive (n = 33) Negtive (n = 18) p Vlue Number (medin, rnge) 5 (1 57) 2 (1 21) Size b (medin, rnge) 1.2 ( ) 0.9 ( ) 0.44 Kruskl Wllis test. b Size of the lrgest brin metstsis in centimeters. by EGFR muttion sttus re described in detil in Tble 3. Multiple brin metstses ( 2 metsttic lesions) were more frequently detected in EGFR-mutted tumors thn in EGFR wild-type tumors (78.6% versus 47.8%, p = 0.022). In ddition, the number of brin metstses ccording to EGFR muttion sttus showed sttisticl significnce (p = 0.029). However, the size of the lrgest metsttic brin lesion ws not significntly different ccording to EGFR muttion sttus, in contrst with the primry tumor size (Tble 3). Risk of Brin Metstsis fter Surgicl Resection To evlute prognostic significnce of EGFR muttion sttus with respect to brin metstses, we performed subgroup nlysis for the risk of brin metstsis in ptients who were treted with curtive resection of pulmonry denocrcinom (133 ptients). The lst follow-up review of this group of ptients ws done on Jnury 2, The medin follow-up durtion in this cohort ws 28.6 months (rnge, ). The recurrent brin metstses suspected on the bsis of clinicl symptoms during follow-up period were confirmed by performing brin MRI. To rech concrete conclusion, the pthologic N stge ws included in the finl multivrite nlysis. Brin metstses were developed in totl of 10 ptients mong 133 ptients who were treted with curtive resection. Deths without crnil disese (n=17) were considered s competing events. Our result showed tht EGFR-mutnt tumor hd significntly higher risk of recurrence of brin metstsis (hzrd rtio = 4.49, 95% CI: , p = 0.026) djusted by pthologic N stge (0 1 versus 2, hzrd rtio =4.75, 95% CI: , p = 0.014) (Fig. 1). DISCUSSION In this study, we evluted different fetures of brin metstses ccording to EGFR muttion sttus. To exclude the impct of histology, this study ws confined to dt on pulmonry denocrcinom. Of note, the risk of brin metstses incresed in EGFR-mutted tumors t the time of dignosis s well s during disese course fter surgery. Compred with wild-type tumors, EGFR-mutted tumors showed wide spred of brin lesions. To dte, there hve been few studies tht focused on the implictions of EGFR muttion on brin metstsis in homogeneous popultion of pulmonry denocrcinoms. This is the first study to suggest tht EGFR muttion is significntly ssocited with higher likelihood of brin metstses in ptients with pulmonry denocrcinoms t initil presenttion. Some investigtors hve shown clinicl evidence for the impct of EGFR muttion on distnt metstsis. Preliminry results from Chinese study suggested different metsttic ptterns in the brin. 23 In contrst, in nother study evluting three different oncogenes (EGFR, V-Kirs2 Kirsten rt srcom virl oncogene homolog [KRAS], nd nplstic lymphom receptor tyrosine kinse [ALK]), 24 EGFR muttion ws not significntly ssocited with brin metstsis. 24 However, different dignostic timing of metsttic presenttion nd histologicl heterogeneity in the previous studies 23,24 should be considered. It seems difficult to drw Copyright 2013 by the Interntionl Assocition for the Study of Lung Cncer 197

4 Shin et l. Journl of Thorcic Oncology Volume 9, Number 2, Februry 2014 FIGURE 1. Cumultive risk of recurrence of brin metstsis ccording to EGFR muttion sttus fter curtive resection in ptients with pulmonry denocrcinom. EGFR, epiderml growth fctor receptor. conclusions from previous dt bout the clinicl impliction of EGFR muttion on brin metstses. 23,24 Further nlysis of dt from ptients with brin metstses showed tht EGFR muttion ws significntly ssocited with extended tumor spred in terms of the number of brin metstses. However, the size of brin metstses ws not ssocited with EGFR muttion sttus, neither were the specific subtypes of EGFR muttions correlted with the number nd size of brin metstses (dt not shown). In contrst with our study, Sekine et l. 25 proposed tht the miliry spred to the brin might be correlted with exon 19 deletion rther thn exon 21 point muttion. Compred with the previous study, 25 our study hd different ptient popultion. Our study popultion consisted of ptients with pulmonry denocrcinom, nd we collected dt from ptients who received routine brin MRI, minimizing potentil bis from using different methods for brin imging. Of interest, the incresed risk of brin metstses in EGFR-mutted tumors ws lso observed t the time of follow-up fter resection. It is well known tht tumors with denocrcinom histology, in generl, hve higher tendency of brin metstsis thn lung cncer involving other cell types such s squmous cell crcinom. 17,26 However, dt on the potentilly prognostic role of EGFR muttion with respect to recurrence in the brin in resected ptients re limited. Although the limittion of this study, its retrospective nture, cnnot exclude potentil bis during the disese course under tretment, we believe tht the prognostic impct of EGFR muttion on brin metstses is worth exmining in further studies. In our dt, ssocitions of EGFR muttions with primry tumor size nd nodl stge, in ddition to smoking history nd sex, were suggested. In previous study, EGFR muttions were predominntly seen in smller primry tumors. 27 The negtive correltion between EGFR muttion sttus nd dvnced nodl stge is lso consistent with findings from recent study. 28 Considering the result tht frequent metstses to the brin re expected in lrge primry tumors nd dvnced nodl stges, 17 the ssocition between brin metstses nd EGFR muttions cnnot be explined by tumor extent only. Rther, it is likely tht metsttic preference to the brin my result from distinct moleculr pthwy in EGFR-mutted tumors. The moleculr spect explining the link between EGFR muttion nd brin metstses is unknown. However, the dt from severl studies let us infer possible hypotheses explining why EGFR muttion hrboring pulmonry denocrcinoms esily metstsize to the brin. An experimentl study from Chin 29 showed tht EGFR inhibition significntly decresed brin metstses in brin-trophic clone of humn DMA-MB-231 brest crcinom cell line. Tht study iterted tht the ction of EGFR in brin metstsis might be through phosphoinositide 3-kinse/protein kinse B nd phospholipse C γ downstrem pthwys. Another report performed by Benedettini et l. 30 showed tht Met expression nd phosphoryltion induced by gefitinib tretment were lso ssocited with development of lte brin metstsis in ptients with NSCLC, indicting tht potentil role of nother genetic chnge such s Met ctivtion or modifiction of the downstrem signling pthwy below EGFR on brin metstses. Further clinicomoleculr studies need to performed to exmine this further. Our study hs severl limittions. First, the retrospective nture of our study ws one of the potentil pitflls. Second, we could not evlute other cliniclly importnt genetic chnges besides EGFR muttions, for exmple, KRAS muttion, Met mplifiction, or echinoderm microtubule-ssocited protein-like 4 nplstic lymphom kinse trnsloction. Despite these limittions, our study is vluble in view of new insights bout the clinicl ssocition between EGFR muttion sttus nd brin metstsis in pulmonry denocrcinom. Becuse of the devstting outcomes of brin metstses, 8 the results of our study theoreticlly support the ide tht physicins should py ttention to brin metstses, prticulrly in ptients with EGFR-mutted pulmonry denocrcinom. Considering the uncertinty of cost effectiveness of brin MRI, 9 EGFR muttions my be useful for erly detection of brin metstses. However, its predictive role should be determined through further studies. In conclusion, this study suggests n ssocition between EGFR muttion nd incresed risk of brin metstses t the time of dignosis nd during the disese course fter curtive resection. Despite its retrospective nture being limittion, this study is the first to indicte distinct clinicl fetures of EGFR-mutted tumors in terms of brin metstses. Moleculr studies should be conducted on this finding in the future. ACKNOWLEDGMENTS This work ws supported by Institute-Supported Reserch Project ppointed by Kore Cncer Center Hospitl. This study ws presented in prt t the 37th ESMO Congress, Vienn, Austri, 28 September to 2 October REFERENCES 1. Siegel R, Nishdhm D, Jeml A. Cncer sttistics, CA Cncer J Clin 2012;62: Copyright 2013 by the Interntionl Assocition for the Study of Lung Cncer

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