Targeted Therapy for Breast Cancer 113 있고, 이 HER2 단백이과발현되어있는유방암환자가그렇지않은환자보다예후가불량한것으로보고되었고 [3] 이에대한표적치료제의가능성이꾸준히제시되어오던중, 1998 년에 HER2 단백의 extracelluar

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1 112 Hanyang Medical Reviews Vol. 32, No. 2, 유방암의표적치료 Targeted Therapy for Breast Cancer 오호석울산의대강릉아산병원내과학교실 Ho-Suk Oh, M.D., Ph.D. Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea 책임저자주소 : 오호석, , 강원도강릉시사천면방동길 38 강릉아산병원내과 Tel: , Fax: hosukoh@hanmail.net The last decade has shown hopeful progress in breast cancer chemotherapy, especially, targeted therapy. Therefore, emphasis of this review has been placed on targeted drugs, mechanism of action and its use in clinical practice. Key Words: Breast Neoplasms; Molecular Targeted Therapy; Trastuzumab 투고일 : 2012 년 3 월 22 일, 심사일 : 2012 년 3 월 31 일, 게재확정일 : 2012 년 5 월 8 일 서론 Abstract Breast cancer is the most common cancer in women in the U.S. and Western Europe and second most common cancer in women in Korea. Targeted therapies for breast cancer are evolving rapidly. Amplification of the human epidermal growth factor receptor 2 (HER2)/ neu gene occurs in approximately 20% of invasive ductal carcinomas of the breast. Amplification of the HER2/neu gene results in protein overexpression and poor prognosis. The first HER2-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 protein. Trastuzumab therapy prolongs the survival of patients with metastatic HER2 overexpressing breast cancer and shows dramatic improvements in disease-free survival when used in the adjuvant therapy setting. Other targeted therapies, such as lapatinib, a dual HER1 and HER2 inhibitor, bevacizumab, a monoclonal antibody targeting angiogenesis, have been developed in phase III clinical trials. 세계암통계인 GLOBOCAN (Global cancer statistics) 2008에의하면유방암은세계여성암중발생률 1위로, 새로발생한여성암의 23% 여성암사망의 14% 를차지한다 [1] 년에보고된국가암등록사업연례보고서에따르면, 2009년우리나라에서발생한유방암은약 13,400 건으로인구 10만명당 54명의유방암이발생하여전체여성암의 19.8% 를차지하였고갑상샘암에이어두번째로흔한여성암으로최근 20 년동안빈도가증가되고있다 [2]. 유방암은새로진단받은환자의 30-40% 에서진단시이미액와림프절에전이가있고이경우근치적수술을하더라도종양의크기에따라 5년생존율이 50% 이하로될수있다. 따라서수술후보조치료가재발률감소와생존율향상에중요한역할을한다. 전이성유방암은항암화학요법의발전에의해생존기간이많이증가하여일종의만성질환으로인식되고있으며삶의질도치료의발전과더불어향상되고있다. 유방암환자의치료를결정할때이미문헌에보고된의학적근거를치료의기본으로하여유방암의분자생물학적특징을고려해야한다. 가장중요한것은호르몬수용체의발현과 human epidermal growth factor receptor 2 (HER2) 단백의과발현여부를확인하는것이며이에따라보조항암화학요법및전이암의항암화학요법이결정된다. 특히유방암환자의대략 20% 에서 HER2 단백이과발현되는것으로알려져

2 Targeted Therapy for Breast Cancer 113 있고, 이 HER2 단백이과발현되어있는유방암환자가그렇지않은환자보다예후가불량한것으로보고되었고 [3] 이에대한표적치료제의가능성이꾸준히제시되어오던중, 1998 년에 HER2 단백의 extracelluar domain 부위를표적으로하는 humanized monoclonal antibody인 trastuzumab이개발되어전이성유방암에서 HER2 과발현된경우기존의항암제단독군보다치료성적의향상이보고되었다 [4]. 이러한표적치료제의개발은유방암치료의큰전환점이되었고치료의가장중요한부분중의하나이다. 본원고에서는유방암에서의표적치료제를이용한치료의최근발전을전이성유방암치료와보조항암화학요법으로나누어서살펴보기로하겠다. 본론 1. HER2 과발현전이성유방암환자의표적치료표적치료제는기존사용해오던세포독성 (cytotoxic) 항암제와는치료기전에차이가있다. 세포독성항암제는빠르게분열하는세포의 DNA 나 microtubule 등에작용하므로정상세포에대한독성을피할수없지만표적치료제는분자표적을이용하여암세포만선별적으로공격한다. 표적치료제의분자표적으로는혈관신생, 세포사멸, 세포의신호전달경로, 세포주기조절인자등이있으며다양한표적을대상으로한표적치료제가개발되고있다. 표적치료제의치료효과는대개세포의증식을억제하는작용을하므로장기간단독으로사용하거나다른세포독성항암제와병용하여사용하는것이일반적이다. 유방암에서 HER2 과발현은세포의생존, 증식, 혈관생성, 침습, 및전이를촉진하는역할을하는것으로알려졌다 [5]. 또한유방암에서전통적인전신항암화학요법에내성을보여불량한예후를예견해왔기때문에종양치료의표적이되었다. 따라서전이성유방암환자의항암화학요법을결정하기전반드시 HER2 수용체에대한검사를해야하며 HER2 과발현은 immunohistochemical (IHC) stain (3+) 인경우나 HER2 IHC (2+) 인경우는 fluorescence in-situ hybridization (FISH) 이나 silver in-situ hybridization (SISH) 을이용하여과발현여부를평가한다. 1) Trastuzumab Trastuzumab은 1998년에 HER2 단백의 extracelluar do main 부위를표적으로하는 humanized monoclonal antibody로개발되어처음으로 FDA 승인을받았다. Trastuzumab 이 HER2 단백에작용하는기전은명확하게알려져있지는않지만첫째는세포내신호전달경로를억제하는것과 [6] 세포내 G1/S 세포주기억제가일어나게되는데이로인하여적은수의암세포에서만세포사멸이발생하지만세포독성항암제와병용투여할경우세포사멸이크게증가하는것으로알려져있다 [7]. 둘째는면역체계의활성화로종양억제반응을유도한다는것을마우스를이용한연구결과를통하여간접적으로입증하였다 [8]. Trastuzumab은과거에세포독성항암화학요법을받지않은 HER2 과발현환자에서단일약제로사용시 30% 정도의반응률이보고되었고전이성유방암에서사전에항암화학요법을받은환자의경우 15% 정도의반응률을보였으며 taxane, doxorubicin/cyclophosphamide 병용투여시에는전체생존기간, 반응률, 진행까지의기간모두향상을보였다. 투여하는방법은 1주간격으로투여하는방법과 3주간격으로투여 (8 mg/kg를 loading 한후 3주마다 6 mg/kg 투여 ) 하는방법이있는데효과는비슷하며환자편의를고려하여 3주간격으로투여하는경우가많다. 부작용으로는미열, 오한, 피로감같은전신증상이주로첫번째투여시에생겼으며심각한부작용은드물었다. 그러나 anthracyclin 제제와의병용투여시심독성이유의하게증가하는것을관찰할수있어가능하면병용투여는권고되지않는다 [9-11]. 병용하여투여하는항암제는주로 paclitaxel과 docetaxel 등의 taxane 제제가권장되며그외에도 vinorelbine, capecitabine, cisplatin, gemcitabin 등이보고되고있다. 또한한가지항암제를병용하는것보다 paclitaxel/carboplatin이나 platinum salts/ docetaxel 등과병용하는것이우월한효과를보여주고있어 1차치료제로권유되기도하지만상대적으로독성도흔하여환자의상태에따라투여를신중히고려할필요가있다 [12]. 우리나라의경우보험기준의제한도있어 paclitaxel 혹은 docetaxel 복합요법을 HER2 과발현된전이성유방암환자에서우선적으로고려한다. 항호르몬요법과병용투여는항호르몬제재인 anastrozole을단독투여보다병용요법이반응률과진행까지의기간이모두향상되었으나항암제와의병

3 114 Hanyang Medical Reviews Vol. 32, No. 2, 2012 용투여시에비해성적이저조하므로 1차투여로권고하지는않는다 [13]. Trastzumab 투여기간은유방암의진행이일어날때까지지속적으로투여하는것이추천되고있으며진행이된이후에도다른항암제와복합적으로사용하는것이좋다는증거들도있다. 2) Lapatinib Lapatinib은 HER1과 HER2 수용체의 intracellular tyrosine kinase inhibitor (TKI) 로알려져있는경구용약제이다 [14]. Trastuzumab과마찬가지로단독투여보다는항암제와의병용요법이더효과적이다. 이전에 anthracyclin, taxane 및 trastuzumab에노출된환자를대상으로한 3상연구에서 capecitabine 과 lapatinib의병용요법이 capecitabine 단독과비교시진행까지의중앙값및전체반응률이모두병용요법이우월하다고보고되었다 [15]. 호르몬수용체양성이며폐경환자에서는항호르몬제재인 letrozole 에 lapatitnib을추가하는병용요법이 letrozole 단독에비해우월함이입증되어사용되기시작하였다 [16]. Lapatinib의주된부작용으로는설사, 피부발진, 구역, 피로등이고 grade 4의독성은없었다. 환자를대상으로한 2상연구에서 26.9% 의반응률을보였다 [18]. 5) Neratinib Neratinib은 lapatinib과유사하게경구로투여가능한 tyrosine kinase inhibitor이지만 HER1과 HER2를억제하는작용이외에도 HER4까지억제하는작용이있다. 2상임상연구에서 trastuzumab에노출된전이성유방암환자에서 26% 의반응률을 trastuzumab에노출되지않은환자에서는 56% 의반응률을보였다고보고하였다 [19]. 2. HER2 과발현이없는전이성유방암환자의표적치료유방암에서의표적치료는주로 HER2 과발현된환자를대상으로이루어져왔다. 그러나 HER2 과발현이없는 80% 의환자를대상으로한표적치료도지속적으로연구되고있다. 대표적인것이신생혈관억제제인 Bevacizumab을이용한치료와 Poly adenosine diphosphate ribose polymerases (PARP) 억제제를이용한치료등이있다. 3) Pertuzumab 1) Bevacizumab Pertuzumab은 humanized monoclonal antibody 로 HER2의다른항원기에작용하여 HER2 와 HER3의 dimerization을억제하는기전을갖고있다. CLEOPATRA 연구에서 docetaxel과 trastuzumab군에비해 docetaxel과 trastuzumab및 pertuzumab을투여한군에서무진행생존기간중앙값이 12.4 개월에서 18.5 개월로연장되는결과를보여주었다 [17]. 4) Trastuzumab-DC1 (T-DM1) 항암제가정상세포에는작용하지않고종양세포에만특이적으로작용하는 antibody drug conjugate (ADC) 로서최초로개발된약물이다. Maytansine으로부터유도된 tubulin polymerization inhibitor 인 DM1 약물을 trastuzumab과결합시킨 conjugate 로서두약물을합쳐서 T-DM1 이라고명명되었다. Trastuzumab과 lapatinib으로치료받은후병이진행된 종양의성장에는신생혈관형성이관여하므로종양세포는혈관신생을촉진시킨다. 이과정에서필요한물질이 vascular endothelial growth factor (VEGF) 이며 VEGF 수용체는정상혈관보다는종양혈관에과발현된다. Bevacizumab은 recombinant humanized murine monoclonal antibody 로 VEGF와결합하여수용체에결합하지못하게함으로신생혈관형성을억제해항암효과를나타낸다. 이전에항암화학요법을받았던전이성유방암환자를대상으로한 3상연구에서 bevacizumab과 capecitabine을병용투여한경우 capecitabine 단독보다반응률의향상은보였으나무진행생존기간과전체생존기간의연장은없었다 [20]. 반면에일주간격으로투여하는 paclitaxel과 bevacizumab을병용한경우일주간격으로투여하는 paclitaxel 단독보다전체반응률과무진행생존기간의향상을가져왔다 [21]. 그러나이연구에서일주간격으로투여하는 paclitaxel의반응률이다른연구에비해낮은것이문제점으로지적되며 bevacizumab을

4 Targeted Therapy for Breast Cancer 115 사용한군에서고혈압, 출혈, grade 3-4의단백뇨와신경병증등이관찰되었다. 아쉽게도아직까지 bevacizumab 의효과를예측할수있는인자가밝혀지지않았다. 그러나호르몬수용체와 HER2 모두음성인경우병용요법으로치료의이득을얻을가능성이있어추가적인 bevacizumab 을병용하여투여하는연구가진행되고있다. 2) PARP 억제제 보조항암화학요법으로서의표적치료에대한효과가입증된연구결과는없지만수술전선행항암화학요법시 taxane 계열항암제에 bevacizumab 을병용하여사용한군이단독혹은 capecitabine 혹은 gemcitabine을병용한군보다병리학적완전관해율이높다는보고를하였다 [26]. 다만부작용으로고혈압, 점막염, 수족구증후군, 좌심실기능부전과수술부위합병증등이 bevacizumab을사용하지않은군에비해높게보고되었으므로사용시부작용을고려해야한다. PARP는손상된 DNA의회복에서중요한역할을담당하는데 DNA 회복기전에돌연변이가생긴암세포에서 PARP 를억제하므로세포사멸을유도할수있다. 호르몬수용체와 HER2 모두음성인전이성유방암에서 PARP 억제제를 gemcitabine 과 carboplatin에추가하여투여하였을때무진행생존기간을유의하게연장시킨다는초기연구결과와달리 2011 년 American Society of Clinical Oncology (ASCO) 에발표된최근결과는 PARP 억제제의이익을증명하지못하였다 [22-23]. 그러나이연구에서 DNA 회복장애가있는환자만포함된것이아니므로추후의연구결과들을지켜볼필요가있다. 3. 보조항암화학요법에사용되는표적치료보조항암화학요법에서의표적치료는전이성유방암환자에서치료효과를확인한 trastuzumab 사용이가장중요하다. HER2 과발현되는수술이가능한조기유방암환자를대상으로보조항암화학요법을시행한군과보조항암화학요법시행후 trastuzumab 투여를한군과비교연구를한결과 Herceptin Adjuvant (HERA) 연구에서 trastuzumab을 1 년간투여한군에서재발률을 36% 감소시켰으며 2년간투여한군에서는사망률을 34% 감소시키는결과를보고하였다 [24]. 그러나 trastuzumab의가장적절한투여기간은정확하지않다. HERA 연구로서는 2년투여가바람직하지만다른연구에서단지 9주간투여하고도비슷한결과를보였기때문이다 [25]. 따라서 2006년 National Comprehensive Cancer Network (NCCN) guideline에서는 anthracycline 계열보조항암화학요법을마친후 1년정도의기간동안 trastuzumab 사용을권고하고있다. HER2가과발현되지않는수술가능한조기유방암의경우 결론유방암환자발생의증가와함께유방암의항암화학요법도지속적으로발전되고체계화되었다. 유방암의수술후재발이줄어들고전이성유방암환자의생존기간이늘어나고전이성유방암환자가만성질환환자처럼여겨지기도한다. 이러한성과의한부분을담당한것이표적치료제이다. 예후가나쁜인자로알려졌던 HER2 과발현환자에서 trastuzumab을시작으로하는표적치료가시작되고 trastuzumab에저항하는유방암에대한 HER2를표적으로하는다른표적치료제들이개발되었으며 HER2 음성인환자를대상으로한표적치료제의연구도활발히진행되고있다. 이러한연구들이지속적으로발전되어더욱유방암환자의생존기간과삶의질향상을기대한다. References 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61: The Korea Central Cancer Registry. Annual report of cancer statistics in Korea in Goyang: National Cancer Center; Report No Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235: Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a

5 116 Hanyang Medical Reviews Vol. 32, No. 2, 2012 monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344: Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5: Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, et al. Ligand-independent HER2/ HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC Cancer Cell 2009;15: Le XF, Pruefer F, Bast RC, Jr. HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27kip1 via multiple signaling pathways. Cell Cycle 2005;4: Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 2000;6: Bullock K, Blackwell K. Clinical efficacy of taxanetrastuzumab combination regimens for HER-2-positive metastatic breast cancer. Oncologist 2008;13: Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20: Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2- overexpressing metastatic breast cancer. J Clin Oncol 2002;20: Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2- overexpressing metastatic breast cancer. J Clin Oncol 2006;24: Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009;27: Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26: Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008;112: Schwartzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist 2010;15: Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366: Burris HA, 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, et al. Phase II study of the antibody drug conjugate trastuzumab-dm1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;29: Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2010;28: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23: Miller KD, Wang M, Gralow J, Dickler M, Cobleigh MA, Perez EA, et al. 28th Annual San Antonio Breast Cancer Symposium - Abstracts: General Sessions. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastic breast cancer: a trial coordinated by the Eastern Cooperative Group (E2100). Breast Cancer Res Treat 2005;94:S6.

6 Targeted Therapy for Breast Cancer O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011;364: Plummer R. Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer? Breast Cancer Res 2011;13: Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:

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