Case Report Ewha Med J 2014;37(1):46-51 http://dx.doi.org/10.12771/emj.2014.37.1.46 pissn 2234-3180 eissn 2234-2591 EGFR 돌연변이와 ROS1 전위를동시에가진폐선암환자의 Erlotinib 치료 1 예 김민환 1,2, 박예현 2, 박혜정 2, 지아영 2, 송창호 2, 진무년 2, 김영주 2, 김선욱 2, 이중희 2, 김인수 2, 김혜련 1,2, 김주항 1,2, 조병철 1,2 1 연세암센터종양내과, 2 연세대학교의과대학내과학교실 A Favorable Treatment Response of Erlotinib in Lung Adenocarcinoma with Concomitant Activating EGFR Mutation and ROS1 Rearrangement Min Hwan Kim 1,2, Yehyun Park 2, Hye Jung Park 2, Ah-young Ji 2, Changho Song 2, Moo-Nyun Jin 2, Young Ju Kim 2, Sun Wook Kim 2, Jung-Hee Lee 2, In-Soo Kim 2, Hye Ryun Kim 1,2, Joohang Kim 1,2, Byoung Chul Cho 1,2 1 Division of Medical Oncology, Yonsei Cancer Center, 2 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea The rearrangement of c-ros oncogene 1 (ROS1) has been recently identified as an important molecular target in non small cell lung cancer (NSCLC). ROS1 rearrangement and epidermal growth factor receptor (EGFR) mutation were mutually exclusive each other in previous studies, and the clinical implication of co-existence of the two genetic alterations has not been determined. We report a case of 46-year-old female never-smoker NSCLC patient whose tumor harbored ROS1 rearrangement and EGFR mutation concomitantly. She had undergone curative surgery for stage IIIA NSCLC, and the recurrence in left pleura and brain occurred at 2 years after the surgery. She received several lines of chemotherapy including docetaxel plus carboplatin, erlotinib, pemetrexed, and gemcitabine. Erlotinib therapy showed a favorable treatment response with progression-free survival of 9.5 months and partial response of tumor on radiologic evaluations. This case represents a successful erlotinib treatment in a NSCLC patient with concurrent ROS1 rearrangement and EGFR mutation. (Ewha Med J 2014;37(1):46-51) Received September 27, 2013, Accepted January 14, 2014 Corresponding author Byoung Chul Cho Division of Medical Oncology, Yonsei Cancer Center & Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: 82-2-2228-8126, Fax: 82-2-393-3562 E-mail: cbc1971@yuhs.ac Key Words c-ros oncogene 1; Epidermal growth factor receptor; Non-small-cell lung carcinoma; Erlotinib 서론폐암은전세계적으로가장흔한악성종양중의하나이며, 우리나라암관련사망의가장큰원인으로우리나라에서한해에 15,000 명이폐암으로사망한다 [1]. 폐암은조직형에따라소세포폐암과비소세포폐암으로구분되고, 최근비소세포폐암의종양발생기전에대한이해가증가되면서비소세포폐암은같은 조직형내에서도종양이가지고있는유전자형에따라세분화되고있다 [2]. 비소세포폐암의알려진중요한유전자변이로는 epidermal growth factor receptor (EGFR) 와 v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) 유전자의돌연변이가있으며, 최근에는 anaplastic lymphoma kinase (ALK) 유전자의전위가전체폐암의 4~6% 정도를차지하는중요한유전자변이로밝혀졌고 [3,4], 이에더하여 c-ros oncogene 1 (ROS1) 46 THE EWHA MEDICAL JOURNAL
Erlotinib in Lung Adenocarcinoma with EGFR Mutation and ROS1 Rearrangement 과 rearranged during transfection (RET) 유전자의전위도비소세포폐암발생에기여하는유전자변이임이밝혀지게되었다 [5-8]. ROS1 전위는전체비소세포폐암의 1~2% 에서보고되며, ROS1 전위양성환자에서 ALK 전위양성환자와마찬가지로 crizotinib 치료가우수한효과를나타내는것으로나타나 [7,9], ROS1 전위를가진비소세포폐암환자들의임상적의미를규명하고, 약제에대한반응성과저항기전을연구하는것이중요한과제가되고있다. EGFR, KRAS 돌연변이와 ALK, ROS1 전위는기존에는상호배타적으로나타나는것으로보고되었으나 [4,7,10], 최근드물게 EGFR 돌연변이와 ALK 전위가동시에나타난증례들이보고된바있으며 [11-14], 아직까지 ROS1 전위와 EGFR 돌연변이가동시에보고된예는없었다. 본증례는 EGFR 활성화돌연변이와 ROS1 유전자전위가동시에발견된동양인비흡연자재발성폐선암 (adenocarcinoma) 환자의치료경과를보고하고 erlotinib 치료가긴무진행생존기간과종양억제효과를보여주었음을보고하는바이다. 증례 46 세여자환자가오심, 구토, 식욕부진을호소하여본원에입원하였다. 흡연력및음주력이없었고, 과거력에서특이질병력은없었으나, 2004 년 9월에건강검진으로시행한흉부 X-ray 검사에서단일폐종괴가발견되어본원을방문하였고, 흉부전산화단층촬영 (computed tomography, CT) 에서좌폐상엽에 3.2 2.7 cm 크기의불규칙한모양의폐종괴소견과대동맥주위종격동림프절비대소견이확인되었다. 환자는기관지내시경및경기관지폐생검검사 (transbronchial lung biopsy) 를받았으며병리조직검사에서폐선암 (adenocarcinoma, acinar type) 으로진단되었다. 영상검사에서원격전이소견없어, 환자는 2004 년 9월 30 일좌상엽절제술및종격동림프절박리술을시행받았다. 수술후병리조직에서종양의장측늑막침범소견없으며, 기관지절제연의종양침범소견은없었다. 박리된 8개의림프절중대동맥주변의 2 개의종격동림프절에종양전이소견보여, 병리학적으로폐선암 pt2n2m0 stage IIIA 진단되었다. 환자는수술이후보조항암화학요법으로 vinorelbine+cisplatin 항암치료를 6회받았으며수술부위에방사선치료 (5,040 cgy, 28 회 ) 를받은이후질병재발소견없이외래추적관찰중이었다. 환자는 2006 년 5월부터오심, 구토, 식욕부진이악화되어본 Fig. 1. The treatment response of first-line docetaxel/carboplatin chemothearpy. (A) Chest computed tomography (CT) and brain magnetic resonance imaging of the patient at the initial diagnosis of non-smallcell lung cancer recurrence show newly developed left pleural metastasis and brain metastasis. Arrows indicate representative non-small cell lung cancer lesions, and names of the lesions are described in the right side of the figure (B) On the imagings after 4 cycles of docetaxel/carboplatin chemotherapy, partial response of lung lesions are noted on chest CT. THE EWHA MEDICAL JOURNAL 47
Kim MH, et al 원에입원하였으며, 기침, 가래, 복부불편감, 복통증상은없었고, 운동시호흡곤란을호소하였다. Eastern Cooperative Oncology Group (ECOG) 수행능력평가상 1점으로평가되었다. 이학적검사상혈압 105/60 mmhg, 맥박 92 회 / 분, 호흡수분당 20 회 / 분, 체온 37.5 o C이었고, 의식은명료하였으나전신외관에서만성병색소견보였다. 피부는건조하고따뜻하였으며비정상적인피부병변은발견되지않았다. 경부및액와촉진상비대한우측쇄골상림프절이촉지되었다. 흉부진찰에서흉곽은대칭적이었으나, 좌측폐야에호흡음이들리지않았으며심잡음은들리지않았다. 복부진찰에서복부는부드럽고편평하였으며, 장음은정상이었고, 압통은없었다. 양하지의함요부종소견은없었다. 입원시말초혈액검사에서백혈구 5,830/mm 3 ( 호중구 73.6%, 림프구 15.3%, 단핵구 7.2%, 호산구 1.4%), 혈색소 6.7 g/dl, 혈소판 437,000/mm 3 이었고, 혈액화학검사에서총단백 6.4 g/dl, 알부민 3.5 g/dl, AST 와 ALT 는각각 26 IU/L, 17 IU/L 이었고, 총빌리루빈 0.3 mg/dl, alkaline phophatase 77 mg/dl, BUN 7.9 mg/dl, 크레아티닌 0.7 mg/dl, carcinoembryonic antigen 382.61 ng/ml, CYFRA 21-1>5,000 ng/ml 였다. 혈액응고검사에서 PT 12.8 초, aptt 31.7 초였으며소변검사에서요당음성, 요단백음성이었다. 입원하여시행한흉부및복부 CT 검사에서다량의좌측흉수소견과우측쇄골상림프절및폐문부림프절전이소견보였고, 뇌자기공명영상 (magenetic resonance image, MRI) 검사에서오른쪽전두엽과왼쪽두정엽에뇌전이소견보였다 (Fig. 1). 전신뼈 스캔검사에서전이소견은없었다. 환자는입원이후빈혈에대한적혈구수혈과좌측흉관삽입술을시행받았으며, 입원 10 일째에뇌전이소견에대해감마나이프수술을시행받았다. 조직학적진단을위하여좌측늑막주변의폐결절에대해초음파유도하조직검사 (ultrasound guided gun biopsy) 를받았으며, 병리소견상재발성폐선암소견이확인되었다. 환자는 2006 년 6월 19 일부터 docetaxel+carboplatin (docetaxel 75 mg/m 2 +carboplatin area under the curve 5; 3주간간격 ) 병합항암화학치료를시행받고특이합병증없이퇴원하였다. 퇴원시이전좌상엽절제술조직에서 EGFR exon 18-21 유전자염기서열분석을시행하였으며 EGFR 유전자 19 번 exon 의 2236-2250 deletion 돌연변이소견을보였다 (Fig. 2). 환자는이후총 4회의 docetaxel/carboplatin 항암화학치료를시행받았으며, 4회항암치료이후시행한추적관찰 CT에서부분반응 (partial response) 소견을보였다 (Fig. 1). 이후추적관찰중 2006 년 12 월 6일에뇌 MRI 에서새롭게다발성뇌전이병변이발견되어환자는전뇌방사선치료 (10 회, 총 2,500 cgy) 를받았고, 2007 년 3월 22 일부터경구 erlotinib (150 mg 하루 1회, 매일투여 ) 치료를받았다. Erlotinib 2주기투여후추적영상검사에서부분반응소견을보였고 (Fig. 3), 환자는 2008 년 1월 5일까지 9.5개월동안진행소견없이경구 erlotinib 을투여받았다. 하지만환자는 2008 년 1월 5일우측옆구리통증발생하여다시본원입원하였고, 흉부 CT에서심낭삼출액소견이보이고, 복부 CT에서새로발생한후복막부위종괴로인하여우측요관폐색, 우측수신증, 공장폐색이발생한소견이보여, 전반적 Fig. 2. The molecular characterization results of the patient s tumor. (A) Exon 19 deletion is noted in nucleotide sequencing of epidermal growth factor receptor (EGFR gene; exons 18 through 21). (B) The c-ros oncogene 1 (ROS1) rearrangement is noted in fluorescent in situ hybridization (FISH) assay on the patient s tumor. ROS1 Break Apart Rearrangement FISH Probe (Abbott Molecular) was used, and FISH positivity for ROS1 rearrangement was defined as >15% of tumor cells with a split signal (orange and green probes, 1,000). 48 THE EWHA MEDICAL JOURNAL
Erlotinib in Lung Adenocarcinoma with EGFR Mutation and ROS1 Rearrangement 인질병진행이확인되었다. 환자는우측요관스텐트삽입술, 심낭천자술, 공장스텐트삽입술을받았으며, 이후증상호전되어항암치료약제변경하여 pemetrexed 단독치료 (500 mg/m 2, 3 주간격정맥주입 ) 를 2008 년 1월 30 일부터 2주기시행받았다. Pemetrexed 2주기투여후추적관찰 CT에서폐와복부병변은안정병변소견보였으나전신뼈스캔에서새롭게 4번흉추의뼈전이소견보였고, 등의통증이새로발생하여질병진행으로평가되었다. 환자는이후척추전이에대해고식적방사선치료시행받고 (10 회, 총 3,000 cgy), 2008 년 4월 17일부터 gemcitabine 단독치료를 ( 매주 1,000 mg/m 2 씩 3주간투여후 1주휴약 ) 8주기시행받았으나 2008 년 8월 18 일뇌 MRI 에서뇌전이진행소견이보였다. 환자는이후 irinotecan 항암화학치료 1주기시행받았 으나질병진행소견보여중단하였으며, 이전 erlotinib 치료반응을고려하여 EGFR-tyrosine kinase inhibitor (EGFR-TKI) 치료를재시도하기위해경구 gefitinib 치료 (250 mg 하루 1회, 매일투여 ) 를 2009 년 1월 8일부터 1월 21 일까지받았으나, 치료중통증및하지감각저하진행되어시행한척추 MRI 검사에서뼈전이진행을보였다. 동시에환자의전신상태도악화되어더항암치료를받지못하였고, 뇌전이로인한전신발작발생하여입원치료중 2009 년 3월 26 일사망하였다 (Fig. 4). 환자가사망한이후 ROS1 형광동소교잡반응검사 (fluorescence in situ hybridization, FISH) 를환자의수술조직에서시행하였으며, ROS1 유전자전위양성으로나와환자의수술조직에서 EGFR exon 19 번돌연변이와 ROS1 전위가동시에존재함이확인되었다 (Fig. 2). Fig. 3. The erlotinib treatment response. Comparision of chest computed tomography and brain magnetic resonance imaging of the patient (A) before and (B) after erlotinib treatment. Arrows indicate representative non-small cell lung cancer lesions, and names of the lesions are described in the right side of the (A) figure. After 2 cycles of erlotinib and whole brain radiotherapy (WBRT), the size of lung and brain metastasis are decreased Fig. 4. Treatment courses of the patient from the initial diagnosis of recurrent non-small-cell lung cancer. PD, progression of disease; SD, stable disease; PR, partial response; PFS, progression-free survival. THE EWHA MEDICAL JOURNAL 49
Kim MH, et al 고찰최근종양생물학에대한이해가증가되어종양형성에관여하는여러가지유전자가밝혀지고있으며, 특히 tyrosine kinase 단백질을암호화하는유전자들의돌연변이, 유전자증폭, 소실, 전위, 과발현등이여러암종에서암발생기전에중요한역할을하는것이알려지게되었다. ROS1 은 insulin receptor family 에속하는수용체 tyrosine kinase 로처음에는신경교세포종에서전위의존재가밝혀졌으며, 전위된유전자가종양발생능력을가짐이발견되었다 [11,15]. 이후 Rivoka 등 [16] 의연구를통해다양한비소세포폐암세포주에서도 ROS1 유전자전위가존재함이보고되었고, 비소세포폐암환자에서 ROS1 전위를검사하였을때약 1~3% 의비소세포폐암환자에서발견되며, ALK 전위와유사하게비흡연자, 젊은연령, 선암조직형환자에서높은빈도로나타남이보고되었다 [7,17]. 특히최근의임상연구에서 ROS1 유전자전위가있는비소세포폐암환자에서 ALK 저해제인 crizotinib 이현저한종양억제효과가있음이밝혀졌으며 [7,9], 그원인은 ALK 단백질과 ROS1 단백질이 kinase 부분의단백질서열에상당한유사성이있기때문으로생각된다. 점차로개인맞춤치료로발전되고있는비소세포폐암의치료에서 ROS1 전위는새롭게대두되고있는중요한바이오마커로중요한연구대상이되고있다. 최근연구들에따르면비소세포폐암의주요유전자형인 EGFR, KRAS 돌연변이와 ALK, ROS1 유전자전위는상호배타적으로발견되는것으로보고되고있으며 [4,7], 동시에두가지유전자변이가병합된경우는드물게보고되고있다 [11-14]. ROS1 나 ALK 전위를가진비소세포폐암은백금기반의항암화학치료에대해서는다른유전자형들과비슷한무진행생존기간과반응률을보이나, gefitinib 이나 erlotinib 과같은 EGFR-TKI 치료에는저항성이있는것으로보고되었다 [4,17]. 하지만 EGFR 돌연변이와 ALK 나 ROS1 유전자전위가동시에존재하는종양에서 EGFR-TKI 와다른항암치료제의반응은아직보고된예가많지않다. 현재까지동시에 EGFR 돌연변이와 ALK 유전자전위를보고한연구중 2 개의논문에서는좋은 gefitinib 치료반응을보고하였으며 [11,14], 반면다른논문에서는불량한치료반응을보고하여아직까지일관된결론은없는상태이다 [12]. 특히 EGFR 돌연변이와 ROS1 전위가같이동반된환자의 EGFR-TKI 치료증례는아직까지보고가없는상태이다. 본증례에서환자는 erlotinib 치료를받은이후종양의부분반응이일어났으며 9.5 개월간치료반응이유지되어단순 EGFR 돌연변이양성환자의 EGFR-TKI 반응과유사한좋은치료결과를보여주었다. 따라서본증례는 EGFR 돌연변이와 ROS1 유전자전위가동시에동반된환자에서도좋은 EGFR-TKI 치료반응이나타날수있음을시사하는첫예라고할수있다. 또한 ROS1 이나 ALK 전위를가진비소세포폐암은 pemetrexed 치료에대해우수한치료반응을나타내는것으로보고되었으며, 그기전은 ALK 전위양성종양에서 thymidylate synthase 의발현 이낮은것이이유로제시되고있다 [18-20]. 그러나본증례에서 는 pemetrexed 2 주기치료이후바로뼈전이가진행되어치료반 응이좋지않게나타났으며, 그원인은 EGFR 돌연변이가동반되 어종양의특성이달랐기때문일수도있고, 당시의환자전신상 태가불량하여항암치료가지연되어시행되었기때문에충분히 pemetrexed 치료의효과가나타나지않았을가능성도있을것으 로생각된다. 전이성및재발성비소세포폐암환자의전체생존기간은기존 의백금기반의세포독성항암치료를사용한연구에서는 8~10 개 월로보고되었으나 [9], 최근유전자형에맞는표적치료제를사용 한비소세포폐암환자들에서개선된예후가보고되고있다 [21]. EGFR-TKI 를시험한임상연구들에서 gefitinib 이나 erlotinib 을투 여받은 EGFR 돌연변이양성환자들의무진행생존기간은 6~9 개월, 반응률은 60~90% 로나타나며, 전체생존기간은 20~30 개월정도로나타났다 [21]. 또한 ALK 유전자전위양성환자에서 crizotinib 치료를시행한 3 상연구에서전체생존기간은기존보다 긴 20~23 개월정도로나타났으며, 후향적분석에서도 crizotinib 이기존치료에비해전체생존기간을연장한것으로보고되었다 [22,23]. 본증례의환자의경우백금기반항암화학치료, EGFR- TKI, pemetrexed, gemcitabine 치료등을통해재발이후약 2.8 년의긴전체생존기간이나타났으며, ROS1 을표적으로하는치 료까지시행되었다면더개선된생존기간을보였을가능성도있 다. 따라서본증례는재발성비소세포폐암치료에서 EGFR-TKI 와항암화학치료의임상적이득을보여주는예로생각된다. 본증례는비흡연자폐선암환자에서드물게 EGFR 돌연변이와 ROS1 전위가동시에나타났으며, erlotinib 치료가좋은치료결과 를나타내어약 2.8 년의전체생존기간을보여준사례를보고하는 바이다. 본증례는비소세포폐암환자의치료를계획하고약제반 응을예측하는데있어서 EGFR, KRAS, ALK, ROS1 과같은바이 오마커의탐색이매우중요한역할을함을시사한다. 참고문헌 1. Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, Lee JS. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat 2013;45:1-14. 2. Oxnard GR, Binder A, Janne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 2013;31:1097-1104. 3. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-566. 4. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients 50 THE EWHA MEDICAL JOURNAL
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