Woo J and Lim W 본론유방암에서사용되는내분비요법은에스트로겐의작용을방해하거나에스트로겐의생산을막음으로써 ER 양성인종양의성장을저해하는치료방법이다. 이는에스트로겐이유방종양의발달과성장에관여하는주된호르몬이기때문이다. 에스트로겐의작용을방해하는약제에는선택적에스트로겐수용체

Review Article Ewha Med J 2014;37(2):83-91 http://dx.doi.org/10.12771/emj.2014.37.2.83 pissn 2234-3180 eissn 2234-2591 유방암특집 유방암의내분비요법 우주현, 임우성 이화여자대학교의학전문대학원외과학교실 Endocrine Therapy for Breast Cancer Joohyun Woo, Woosung Lim Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea Breast cancer is the second most common cancer in Korean women and its mortality rate has increased steadily. Although breast cancer is heterogeneous tumor, hormone receptor-positive tumors comprise about 75 percent of all breast cancers. Therefore endocrine therapy that works by targeting estrogen receptor is a pivotal treatment for breast cancers. There are selective estrogen receptor modulators, such as tamoxifen and raloxifene, aromatase inhibitors, such as anastrozole, letrozole and exemestane, fulvestrant and luteinizing hormone-releasing hormone agonists used in endocrine therapy. Endocrine therapy is effective in treating early breast cancer as an adjuvant therapy and metastatic breast cancer as a palliative therapy. Also in women who are at high risk for breast cancer, tamoxifen or raloxifene can prevent breast cancer. Studies for neoadjuvant endocrine therapy are emerging. Considering side effects of each drug and overcoming drug resistance are needed to maximize effectiveness of treatment and advance endocrine therapy. (Ewha Med J 2014;37(2):83-91) Received August 1, 2014 Accepted August 29, 2014 Corresponding author Woosung Lim Department of Surgery, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, 1071 Anyancheon-ro, Yangcheon-gu, Seoul 158-710, Korea Tel: 82-10-2570-8980, Fax: 82-2-2644-7984 E-mail: limw@ewha.ac.kr Key Words Breast neoplasms; Drug therapy; Antineoplastic agents, hormonal 서론유방암은미국에서 2009 년여성 10 만명당약 65 명의발생률을보이고, 전체여성암의 27% 를차지하는가장흔한암이다 [1]. 한국에서는 2011 년중앙암등록본부통계자료에의하면여성 10 만명당 50 명의발생률을보이고, 전체여성암의 14.8% 를차지하는두번째로가장흔한암이다. 특히, 한국유방암의사망률은미국, 유럽등과비교해볼때발생률과사망률은낮지만, 다른국가에서그수준이점차감소하는반면한국의유방암의발생률및사망률은꾸준히증가하고있으며사망률의경우, 중앙암등록본부에따르면 2000 년 10 만명당 4.8명에서 2011 년 10 만명당 7.9명으로 2배가까이증가하였다 [2]. 유방암은여러가지서로다른특성들이혼재되어있는 (heterogenous) 것이대표적인특징이고, 분자생물학적특성에따라네가지아형 (subtype) 으로구분되며각아형에따라표적으로하는치료에대한반응이나그에따른예후에차이를보인다. 유방암의아형중에스트로겐수용체 (estrogen receptor, ER) 나프로게스테론수용체 (progesterone receptor, PR) 와같은호르몬수용체양성인유방암이가장흔하다. 50 세이하의침윤성유방암의 2/3가호르몬수용체양성이고 50 세이상의경우약 80% 에서 ER 양성을나타낸다 [2]. 따라서내분비요법은화학요법과더불어유방암치료의중심축을이루는치료방법이다. 이종설에서는대규모연구들의최신결과들을바탕으로유방암치료에현재사용되고있는내분비요법에대하여이해하고앞으로내분비요법발전에필요한연구의방향을찾아보고자한다. 83

Woo J and Lim W 본론유방암에서사용되는내분비요법은에스트로겐의작용을방해하거나에스트로겐의생산을막음으로써 ER 양성인종양의성장을저해하는치료방법이다. 이는에스트로겐이유방종양의발달과성장에관여하는주된호르몬이기때문이다. 에스트로겐의작용을방해하는약제에는선택적에스트로겐수용체조절제 (selective estrogen receptor modulator, SERM) 가있다. SERM 에는 tamoxifen, raloxifene, toremifene 등이있고, 이약제들은유방에서대부분 ER 에대해에스트로겐과경쟁적으로결합하여에스트로겐길항제 (estrogen antagonist) 역할을한다 [3]. Tamoxifen 은다른 SERM 과비교할때가장효과적인것으로보고되어일차적으로사용되는약물로서부분적비스테로이드에스트로겐길항제 (nonsteroidal estrogen agonist) 에스트라디올 (estradiol) 의제 2형경쟁적억제제이다 [4]. 에스트로겐의작용을방해하는기전의다른약제로는 fulvestrant 가있다. Fulvestrant 는가장최근에개발된내분비요법약제로서에스트로겐유사작용이없는스테로이드성 ER 순수길항제이며진행성유방암의 2차적인내분비요법에선택적으로사용될수있다 [5,6]. Fulvestrant 는세포내의 ER에결합하여 ER 의분해를가속화시킴으로써효과를나타낸다. 에스트로겐의생산을막는약제로는 aromatase 억제제 (aromatase inhibitor, AI) 가대표적이다 [7]. 이약제는부신피질의스테로이드형성에는영향을주지않으면서생식샘, 유방종양, 지방, 근육, 뇌등에존재하는에스트로겐생합성에필수적효소인 aromatase 를억제함으로써혈중에스트라디올의농도를낮춘다. AI 에는 1세대 aminoglutethimide, 2세대 formestane, fadrozole, 3세대 anastrozole, letrozole, exemestane 이있다 [8]. Aminoglutethimide 와 formestane 및 fadrozole 은부신부전 (adrenal insufficiency) 이나알도스테론억제를일으키는등의부작용이보고되어현재는 3세대 AI 만이사용되고있다 [8]. 이약제들은 aromatase 와의상호작용유형에차이를보이는데, anastrozole 과 letrozole 은비스테로이드성제제로가역적반응을하지만, exmestane 은스테로이드성제제로비가역적인반응을한다 [4]. 폐경후유방암환자에서는난소의기능이저하된상태이기때문에 aromatase 를억제함으로써에스트로겐의생산을억제할수있지만, 폐경전유방암환자에서는난소의기능이활발하여 AI 로는효과적으로에스트로겐의생산을억제하기어렵다. 따라서에스트로겐의주생산을담당하고있는난소의기능을억제함으로써혈중에스트로겐의농도를낮출수있다. 영구적으로난소의기능을억제하는방법에는난소절제술이나방사선요법이있고, 황체형성호르몬분비호르몬 (luteinizing hormone-releasing hormone, LHRH) 작용제인 goserelin 은난소가에스트로겐을생산하도록자극하는, 뇌하수체로부터나오는신호를방해함으로써일시적인난소기능억제효과를일으킨다 [9]. 1. 보조내분비요법보조요법은조기유방암에서수술후치유의가능성을높이기위해시행하는치료를뜻한다. 그중내분비요법은 ER 을표적으로하며 PR 은그자체가치료의표적은아니지만 ER 과함께내분비요법에대한반응을예측할수있는중요한예측인자이면서예후인자이기도하다 [2]. ER 양성유방암의 50% 는 PR 양성을보이고, ER 과 PR 이모두양성인유방암은내분비요법에약 75% 의반응률을보이는반면 ER 양성 /PR 음성인유방암은 1/3이하의반응률을보인다 [10]. Tamoxifen 은폐경전, 폐경후 ER 양성유방암에서표준보조요법으로사용되고있으며 ER 과결합하게되면세포주기중 G1 Fig. 1. (A) Pre- and (B) posttreatment breast magnetic resonance imaging (MRI) in a patient who received neoadjuvant endocrine therapy. A 72-year-old woman was diagnosed with breast cancer on April, 2013. A left subareolar mass was confirmed as invasive ductal carcinoma by core needle biopsy and immunohistochemistry revealed that the tumor was estrogen receptor- and progesterone receptor-positive, and C-erbB2- negative breast cancer. She was treated with letrozole for 6 months. MRI shows the clinical response of neoadjuvant endocrine therapy. The size of primary tumor partially decreased from 4.2 cm to 3.0 cm on MRI after neoadjuvant endocrine therapy for 6 months (arrows). Also metastatic lymph node in left axilla disappeared (not shown). 84

Endocrine Therapy for Breast Cancer 기 ( 제 1 휴지기 ) 의순환을막게되어종양의성장을억제하고, 세포자멸사를유도한다 [11]. Early Breast Cancer Trialists Collaborative Group (EBCTCG) 에서 194 개의무작위연구들을메타분석한결과, ER 양성유방암에서 5년간의 tamoxifen 보조요법을통해매년유방암사망률을 31% 줄일수있었고, 이러한효과는항암제사용, 나이, PR 상태, 림프절전이상태와관계없이나타났다 (Table 1)[12]. 또한반대쪽유방암발생률이 ER 양성혹은 ER 불명유방암환자에서통계학적으로유의하게 1/3 감소하였다 [12]. 또한지연된 tamoxifen 보조요법도치료효과가있는데, 494 명이유방암환자를대상으로한연구에서최초치료시점으로부터 2년이상 tamoxifen 보조요법을받지않았던 ER 혹은 PR 양성환자에서늦게라도 tamoxifen 을복용했을때유방암의재발률과사망률이유의하게감소함을보여주었다 [13]. Tamoxifen 을 1~2년간투약했을때보다 5년간투약하는것이유방암재발및사망률을줄일수있고, ER 양성이고림프절전이가없는유방암환자에서 5년이상 tamoxifen 을복용했을때추가적인이득은없었으나 [12,14] Adjuvant Tamoxifen Longer Against Shorter (ATLAS) 연구결과에따르면 10 년동안 tamoxifen 을복용했을때 5년복용했을때보다재발률, 사망률이낮아졌지만 tamoxifen 으로인한폐색전증과자궁내막암의발생률이유의하게상승하였다 [15]. 또한 ER 불명환자를포함한 ER 양성환자 6,934 명을대상으로 tamoxifen 5년치료군과 10 년치료군을비교하는 adjuvant tamoxifen treatment offers more (attom) 연구가진행중에있으며그결과를기다려보아야하겠다 Tamoxifen 이 ER 양성유방암의표준내분비보조요법으로서치료효과가인정되었지만, 폐경전환자에서는폐경후환자에서와는다르게골소실 (bone loss) 을증가시킨다는단점이있다. 보조화학요법과같은유방암의표준치료가골소실을증가시켜골다공증의위험도를높일수있고특히, 폐경전유방암환자에서는보조화학요법과더불어생식샘자극호르몬자극호르몬 (gonadotropin-releasing hormone, GnRH) 작용제투여, 수술적난소절제등으로인한난소기능의억제되어조기폐경과빠른골소실을초래한다 [4,16]. Tamoxifen 은뼈에서에스트로겐작용제역할을하기때문에내인 (endogenous) 에스트로겐농도가낮은폐경후환자에서는치료기간동안골소실을유의하게감소시키지만 [17-21], 폐경전환자의내인에스트로겐농도에서는 tamoxifen 의시상하부-뇌하수체축에서난포자극호르몬 (follicle-stimulating hormone, FSH) 의농도를낮춤으로써난소로부터생성되는내인에스트로겐농도를낮추는에스트로겐길항제로서의효과자체가골밀도감소시키게된다 [22-24]. 따라서폐경전환자중화학요법후무월경이온환자들에서 tamoxifen 을사용했을때, 화학요법후에도무월경이오지않은환자들에서 tamoxifen 을사용했을때보다골감소가더심하게나타났고, 무월경이온환자들에 Table 1. A summary of research studies on adjuvant tamoxifen Study Design Subject Treatment Results NSABP, 2001 [14] 1,172 patients Node ( ) 7-yr follow-up EBCTCG, 2005 [12] Meta-analysis, 71 trials 15-yr follow-up ATLAS, 2013 [15] 6,846 patients Early breast cancer attom (ongoing) 6,934 patients ER unknown 4.2-yr follow-up Tamoxifen 5 yr placebo vs. Tamoxifen 5 yr Tamoxifen Tamoxifen 1 2 yr Tamoxifen 10 yr Tamoxifen 10 yr For tamoxifen more than 5 yr: No additional benefit For tamoxifen 5 yr: Improvement in survival Breast cancer mortality 31% /yr regardless of age, menopause, chemotherapy and node metastasis For tamoxifen 10 yr: Recurrence Breast cancer mortality Overall mortality Pulmonary embolism (HR, 1.87) Endometrial cancer (HR, 1.74) Ischemic heart disease (HR, 0.76) NSABP, National Surgical Adjuvant Breast and Bowel Project; ER, estrogen receptor; EBCTCG, Early Breast Cancer Trialists Collaborative Group; ATLAS, Adjuvant Tamoxifen Longer Against Shorter; attom, adjuvant Tamoxifen Treatment offers more. 85

Woo J and Lim W 서 tamoxifen 을사용한군과 tamoxifen 을사용하지않은군을비교하였을때 tamoxifen 을사용한군에서골감소를줄일수있었다 [22, 23]. 폐경전 ER 양성유방암환자에서 LHRH 작용제단독요법은 cyclosphosphamide, methotrexate, fluorouracil 병합해서투여하는 CMF 화학요법과비슷한전체생존율및무병생존율을보였고, tamoxifen 단독요법과도비슷한무병생존율이보고된바있다 [25]. LHRH 작용제와 tamoxifen 의병합요법은 LHRH 작용제단독요법보다효과적이지만 tamoxifen 단독요법이나 LHRH 작용제와 AI 의병합요법과비교는논쟁의여지가있다. 또한 LHRH 작용제와화학요법을병행하는것, 작용제와 tamoxifen 그리고화학요법을병행하는것이화학요법단독치료에비해전체생존율및무병생존율이향상되는경향을보여주었지만아직까지 LHRH 작용제는현재의화학요법및 tamoxifen 의병합요법에더하여필수적인표준치료로인정되지는않고있다 [9]. AI 가폐경후여성에서 tamoxifen 에비해전체생존율은비슷 하나무병생존율을약간더높일수있다고보고됨에따라폐경후여성에서표준내분비요법으로사용되며이는보조화학요법후폐경이온경우에도마찬가지이다 (Table 2)[26]. 메타분석에따르면, 2~3년동안 tamoxifen 을투약한후 AI 로변경하여 2~3년간투약을한환자들에서 5년간 tamoxifen 을투약한환자들에비해유방암사망률이의미있게감소하였다 [27]. 그러나 tamoxifen 에서 AI 로변경하여투약한경우보다는 AI 단독으로 5년간투여했을때가치료성적이더좋았으며오히려 tamoxifen 을사용하는초기에재발이많이발생하였다 [28]. 또한 tamoxifen 을 5년사용한후 AI 를 5년추가로사용한것이 tamoxifen 만을 5년사용했을때보다재발률과사망률이의미있게낮았다 [29]. AI 를사용한경우 tamoxifen 을사용한경우에비해자궁내막암, 혈전색전증이적게발생하였으나, 관절통및골절이더많이발생하였다 [26,30]. 따라서 AI 를사용하는동안골밀도에대한평가가필요하며골절의위험도에따라적절한치료가필요하다 [31-33]. Table 2. A summary of research studies on adjuvant aromatase inhibitor Study Design Subject Treatment Results IBCSG BIG 1-98, 2007 [65] IBCSG BIG 1-98, 2009 [28] Phase III Phase III 4,922 Patients Early breast cancer 51-mo follow-up 6,182 Patients Early breast cancer 71-mo follow-up ATAC, 2010 [26] 5,216 Patients Early breast cancer ER/PR (+) 120-mo follow-up EBCTCG, 2010 [12] Meta-analysis 9,856 Patients 5.8-yr follow-up 9,015 Patients 3.9-yr follow-up after switching MA.17, 2012 [29] Phase III 5,170 Patients ER/PR (+) 64-yr follow-up Letrozole 5 yr vs. Tamoxifen 5 yr Letrozole 5 yr vs. Letrozole 2 yr tamoxifen 3 yr vs. Tamoxifen 2 yr letrozole 3 yr Anastrozole 5 yr vs. Anastrozole+tamoxifen 5 yr AI 5 yr vs. Tamoxifen 5 yr Tamoxifen 2 3 yr tamoxifen vs. Tamoxifen 2 3 y AI Tamoxifen 5 yr AI for 5 yr vs. Tamoxifen 5 yr placebo 5 yr For letrozole: Recurrence 18% For switching: Not more effective Letrozole vs. tamoxifen: No difference in mortality For anastrozole 5 yr: Recurrence 14% No difference in mortality For AI 5 yr: Recurrence 2.9% For switching: Recurrence 3.1% Breast cancer mortality 0.7% For adding AI 5 yr: Disease free survival (HR, 0.58) Overall survival (HR, 0.76) IBCSG, International Breast Cancer Study Group; BIG, Breast International Group; ER, estrogen receptor; ATAC, arimidex, tamoxifen, alone or in combination; PR, progesterone receptor; EBCTCG, Early Breast Cancer Trialists Collaborative Group; AI, aromatase inhibitor. 86

Endocrine Therapy for Breast Cancer 2. 완화내분비요법 (palliative endocrine therapy) AI 는 ER 양성의전이성유방암의일차치료로 tamoxifen 보다다소우월한성적을보여준다. 1990 년대까지폐경후 ER 양성전이성유방암환자에서 tamoxifen 이표준적치료로사용되었으나여러가지무작위연구및메타분석을통해 AI 가생존율에서우월한성적을보여줌으로써현재진행성유방암의표준적치료는 AI 이다 [4,34]. 서로다른 AI 간의교차내성이발생하지않기때문에실제임상에서는한가지 AI 치료에실패한경우다른 AI 를사용하고있으며, 아직 3가지의 3세대 AI 중어떤것이어떤상태에서더효과적인가에대해서는연구가필요하다 [35]. Fulvestrant 는비스테로이드성 AI 치료에실패한폐경후 ER 양성유방암에서스테로이드성 AI 와비교했을때비슷한효과를보여주었고, fulvestrant 월 1회의 250 mg치료를시작할때, 부하용량 (loading dose) 으로서 fulvestrant 500 mg 근육주사 (intramuscular injection) 후 2주간격으로 250 mg씩 2회피하주사함으로써항정상태 (steady state) 에도달함을확인하였다 [36]. 또한폐경 후국소진행성혹은전이성유방암환자에서첫번째내분비요법으로서 fulvestrant 500 mg을매달투여하였을때 anastrozole 보다질병진행시간 (time to progression) 이유의하게길었고부작용에서는의미있는차이를보이지않았다 [37]. 3. 신보강내분비요법 (neoadjuvant endocrine therapy) 신보강내분비요법은신보강화학요법과같이완전관해혹은부분관해를통하여종양의크기를줄임으로써수술이불가능한상태의종양을수술이가능한상태로만들거나, 유방보존술을시행하기에종양의크기가큰유방암에대하여유방보존술의가능성을높일수있는이점이있다 [38]. 이러한수술전시행하는전신적요법 (systemic therapy) 은궁극적으로는재발률을감소시키고생존율을향상시키는것을목표로하지만전체생존율및무병생존율은수술후시행하는전신적요법과비슷한것으로보고되고있다 [39,40]. 신보강내분비요법의전반적인임상적반응률은 13.5~100%, 초음파를통한영상학적반응률은 20~91.7% 였 Table 3. A summary of research studies on neoadjuvant endocrine therapy Study Design Subject Treatment Eiermann et al., 2001 [44] Multicenter 337 Patients ER/PR (+) IMPACT, 2005 [46] 330 Patients Operable Locally advanced PROACT, 2006 [43] ACOSOG Z1031, 2011 [47] STAGE, 2012 [45] Randomzed Double -blind Multicenter Phase II Phase III Multicenter 451 Patients ER/PR (+) Operable Locally advanced 377 Patients Clinical stage II-III 197 Patients Premenopausal HER2 (-) Operable Letrozole Tamoxifen For 4 mo Tamoxifen Anastrozole Tamoxifen+anastrozole For 3 mo Tamoxifen Anastrozole For 1 mo Exemestane Letrozole Anastrozole For 16 18 wk Goserelin+anastrozole Goserelin+tamoxifen For 6 mo Clinical response (%) 55 36 P<0.001 36 37 39 46.2 50.0 62.9 74.8 69.1 For all patients: No differences in surgical results, PEPI score and Ki- 67 suppression Breast-conserving rate (%) 45 35 P=0.022 22 46 26 P=0.03 30.8 43.0 P=0.04 70.4 50.5 P=0.004 ER, estrogen receptor; PR, progesterone receptor; IMPACT, immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen; PROACT, pre-operative "arimidex" compared to tamoxifen; ACOSOG, American college of surgeons oncology group; PEPI, Preoperative endocrine prognostic index. 87

Woo J and Lim W 고, ER 양성유방암에서신보강화학요법과통계학적으로비슷한반응률을보였다 (Fig. 1) [38,41,42]. 대부분의연구가 AI 중 letrozole 을대상으로시행되었는데, 임상적및영상학적반응률에서 letrozole 이 tamoxifen 과비슷하거나약간더효과적인결과를보였으며, 신보강내분비요법후수술이불가능에서가능한상태로바뀌었거나유방전절제술에서유방보존술이가능한상태로바뀌었다고판단되는환자들이 letrozole 을사용한군에서의미있게많았다 (Table 3) [43-46]. AI 간의비교연구에서는 letrozole 이 anastrozole 이나 exemestane 보다반응률은가장좋고, 유방보존술비율은가장낮았으나통계학적의미는없었다 [47]. 수술이어려운고령의유방암환자에서 tamoxifen 을사용하였을때수술을한환자들과비교하여전체생존율에차이가없다고보고되면서대부분의신보강내분비요법에대한연구는호르몬수용체양성인폐경후유방암환자를대상으로 tamoxifen 및 AI 를사용했을때의결과를보고하였다 [48]. 한편, 호르몬수용체양성인폐경전유방암환자에서 tamoxifen 치료와함께난소기능억제치료를선택적으로시행하는것이표준치료지침으로제시됨에따라 LHRH 작용제인 goserelin 을통한가역적인난소절제 (reversible ovarian ablation) 치료를 letrozole 과병행하는연구가시행되었다 [49]. 그결과, 보조내분비요법에서와는다르게신보강내분비요법에서는폐경전유방암환자에서 24 주간 goserelin 과 anastrozole 을함께투여한군에서 goserelin 과 tamoxifen 을함께투여한군보다반응률이의미있게더좋았다 [45,50]. 아직은신보강내분비요법이흔히고려되는치료방법은아니며, 현재 ER 양성유방암환자를대상으로신보강내분비요법과신보강화학요법을비교하는연구가진행중이다. 향후 ER 발현정도, 조직학적유형에따른신보강내분비요법의효과, 가장효율적인치료기간등에대한연구가필요할것으로생각된다. 호르몬수용체양성유방암에서신보강화학요법과비교하여신보강내분비요법이적어도비슷한효과를보인다면치료로인한독성을고려하였을때호르몬수용체양성인환자들에있어서선택적으로고려될수있을것이다. 4. 화학예방 (chemoprevention) 내분비요법은유방암을예방하거나전암 (precancer) 을치료하기위해서시행될수있다. 암형성 (carcinogenesis) 은수년에걸쳐진행되는과정으로, 현재까지유방에서는비정형증식증에서관내암으로진행하는데에 14~18 년이걸리고, 그이후 6~10 년후침습암으로진행되는것으로알려져있다 [51]. 밝혀져있는유방암에영향을주는환경및식이위험인자 (risk factor) 는대부분에스트로겐에의노출과관련되어있다 [52,53]. 난소절제술등의수술적시도및 ER, aromatase, 싸이토카인 (cytokine) 등을표적으로한약리적시도를통해내분비요법이유방암에대한에스트로겐의영향을없애고, 종양의진행을막을수있음을보여준바있다 [34,54]. ER-α 신호 (signaling) 는에스트로겐의존성 (estrogen-dependent) 유방암의발생및진행에필수적이다 [55]. 따라서 ER-α 를표적으로하는 tamoxifen 은고위험여성에서 ER 양성유방암의발생을의미있게줄여줄수있다. 게일모형 (Gail model) 에따른고위험군여성 13,207 명을대상으로한 National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 연구에서 5년동안 tamoxifen 을투약하였을때위약군에비하여침습성유방암발생이 43%, 비침습성유방암발생이 37% 감소하는것으로나타났다 [56]. 이러한 tamoxifen 의화학예방효과는 ER 양성침습성유방암에서만나타났고, ER 음성유방암의발생률을감소시켜주지는못하였다 [56]. 7,152 명의고위험군여성을대상으로한 International Breast Cancer Intervention Study (IBIS-1) 에서역시 5년간 tamoxifen 을투약한군에서유방암의위험도가 1/3로감소하는유사한결과를보여주었다 [57]. Exemestane 과 letrozole 는 ER 양성인고위험폐경후유방암환자에서재발을막을수있는약물이지만, 화학예방을위한 AI 의효과는아직완전히밝혀지지않았다 [58]. Tamoxifen 이유방조직과뇌에서 ER 의길항제로작용하지만, 지질대사, 혈관계통, 혈액응고기전, 자궁, 뼈에대해서는에스트로겐과같은작용을한다 [3,17,59,60]. Tamoxifen 을복용함으로써골다공증으로인한골절의발생이감소하는것으로나타났으나, 자궁내막암의위험도는 2.0~3.3 배증가하는것으로보고되었고이는 50 세이상의여성에서더욱두드러졌다 [56,57,61]. 또한 tamoxifen 투약군에서폐색전증, 심부정맥혈전증, 뇌졸중과같은혈전색전증관련질환과백내장의위험도가증가하였으나허혈성심장병의위험도는위약군과차이가없었으며, 이러한질환발생률의증가혹은감소는각연구마다통계학적의미가다르게나타났다 [56,57,61]. 메타분석에서모든사망원인을포함한전체사망률은 tamoxifen 을복용한군과위약군간에차이가없었다 [57]. 결론내분비요법은화학요법에비해상대적으로약물로인한이환율 (morbidity) 이낮으면서도재발률및유방암으로인한사망률을감소시킬수있기때문에 ER 양성유방암의중요한치료방법이다. 현재폐경여부에상관없이유방암의고위험군에서 tamoxifen 이화학예방을위해사용되고있고, 폐경후유방암고위험여성에서는 raloxifene 또한유방암발생의위험도를줄일수있다 [62]. 보조요법으로서폐경전 ER 양성유방암환자에서는 tamoxifen 5년요법이표준치료이며 LHRH 작용제가선택적으로병용될수있다. 또한 tamoxifen 으로치료를시작한경우에도치 88

Endocrine Therapy for Breast Cancer 료중폐경여부를확인하여 2~3 년후 AI 로변경하여 2~3 년투 여하는것이효과적이다. 폐경후 ER 양성유방암환자에서는 AI 5 년치료가가장효과적인표준보조치료이며, 진행성유방암에 서도 AI 는효과가있다. 각내분비요법약제의부작용을고려하 여약제를선택및변경해야하며 tamoxifen 으로 5 년치료를한경 우 AI 를이어서사용하는연장요법도고려될수있겠다. 한편신보 강요법으로서의내분비요법에대한임상적연구또한활발히이루 어지고있어적용범위가더욱확대될것으로생각된다. 또한내 분비요법은수술이나화학요법을시행하기어려운환자에서대안 적치료로고려될수있다 [63,64]. 그러나대부분의환자에서내 분비요법중에다양한경로의저항성이발생하는것이가장큰문 제이며이는유방암을치료하기위해앞으로극복해야할과제이 다 [63,64]. 참고문헌 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-249. 2. The Korean Breast Cancer Society. The breast. Seoul: Koonja; 2013. 3. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-year follow-up of theroyal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 2007;99:283-290. 4. Lumachi F, Luisetto G, Basso SM, Basso U, Brunello A, Camozzi V. Endocrine therapy of breast cancer. Curr Med Chem 2011;18:513-522. 5. Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers. Br J Cancer 2002;87:1354-1359. 6. Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000;7:17-28. 7. Puhalla S, Brufsky A, Davidson N. Adjuvant endocrine therapy for premenopausal women with breast cancer. Breast 2009;18 Suppl 3:S122-S130. 8. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:2431-2442. 9. Goel S, Sharma R, Hamilton A, Beith J. LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev 2009:CD004562. 10. Donegan WL, Spratt JS. Cancer of the breast. Philadephia: Saunders; 2002. 11. Osborne CK, Boldt DH, Clark GM, Trent JM. Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res 1983;43:3583-3585. 12. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-1717. 13. Delozier T, Switsers O, Genot JY, Ollivier JM, Hery M, Namer M, et al. Delayed adjuvant tamoxifen: ten-year results of a collaborative randomized controlled trial in early breast cancer (TAM- 02 trial). Ann Oncol 2000;11:515-519. 14. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001;93:684-690. 15. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805-816. 16. Ramaswamy B, Shapiro CL. Osteopenia and osteoporosis in women with breast cancer. Semin Oncol 2003;30:763-775. 17. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992;326:852-856. 18. Ward RL, Morgan G, Dalley D, Kelly PJ. Tamoxifen reduces bone turnover and prevents lumbar spine and proximal femoral bone loss in early postmenopausal women. Bone Miner 1993;22:87-94. 19. Saarto T, Blomqvist C, Valimaki M, Makela P, Sarna S, Elomaa I. Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens. Br J Cancer 1997;75:602-605. 20. Marttunen MB, Hietanen P, Tiitinen A, Ylikorkala O. Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 1998;83:1158-1162. 21. Grey AB, Stapleton JP, Evans MC, Tatnell MA, Ames RW, Reid IR. The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med 1995;99:636-641. 22. Vehmanen L, Elomaa I, Blomqvist C, Saarto T. Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol 2006;24:675-680. 23. Ellmen J, Hakulinen P, Partanen A, Hayes DF. Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res Treat 2003;82:103-111. 24. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996;14:78-84. 25. Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002;20:4628-4635. 89

Woo J and Lim W 26. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:1135-1141. 27. Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, et al. Metaanalysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28:509-518. 28. BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thurlimann B, Paridaens R, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 2009;361:766-776. 29. Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol 2012;30:718-721. 30. Lonning PE, Geisler J. Indications and limitations of thirdgeneration aromatase inhibitors. Expert Opin Investig Drugs 2008;17:723-739. 31. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092. 32. McCloskey E. Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 2006;42:1044-1051. 33. Hadji P, Ziller M, Albert US, Kalder M. Assessment of fracture risk in women with breast cancer using current vs emerging guidelines. Br J Cancer 2010;102:645-650. 34. Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev 2009:CD003370. 35. Lonning PE. Lack of complete cross-resistance between different aromatase inhibitors; a real finding in search for an explanation? Eur J Cancer 2009;45:527-535. 36. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al., randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008;26:1664-1670. 37. Robertson JF, Llombart-Cussac A, Rolski J, Feltl D, Dewar J, Macpherson E, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009;27:4530-4535. 38. Charehbili A, Fontein DB, Kroep JR, Liefers GJ, Mieog JS, Nortier JW, et al. Neoadjuvant hormonal therapy for endocrine sensitive breast cancer: a systematic review. Cancer Treat Rev 2014;40:86-92. 39. Mieog JS, van der Hage JA, van de Velde CJ. Neoadjuvant chemotherapy for operable breast cancer. Br J Surg 2007;94:1189-1200. 40. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97:188-194. 41. Alba E, Calvo L, Albanell J, De la Haba JR, Arcusa Lanza A, Chacon JI, et al. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-ii study. Ann Oncol 2012;23:3069-3074. 42. Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007;110:244-254. 43. Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptorpositive breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. Cancer 2006;106:2095-2103. 44. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized doubleblind multicenter study. Ann Oncol 2001;12:1527-1532. 45. Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, et al. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol 2012;13:345-352. 46. Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108-5116. 47. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, et al. phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--acosog Z1031. J Clin Oncol 2011;29:2342-2349. 48. Hind D, Wyld L, Beverley CB, Reed MW. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev 2006:CD004272. 49. Kataja V, Castiglione M; ESMO Guidelines Working Group. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20 Suppl 4:10-14. 50. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679-691. 51. O'Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg AJ, Hong WK, Fabian CJ, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 2002;8:314-346. 52. Lumachi F, Ermani M, Basso SM, Lonardi S, Tosoni A, Brandes AA. Breast cancer risk in symptomatic women spontaneously undergoing clinical breast examination. Anticancer Res 90

Endocrine Therapy for Breast Cancer 2003;23:3565-3568. 53. Thomsen A, Kolesar JM. Chemoprevention of breast cancer. Am J Health Syst Pharm 2008;65:2221-2228. 54. Lumachi F, Basso SM, Orlando R. Cytokines, thyroid diseases and thyroid cancer. Cytokine 2010;50:229-233. 55. Tomita S, Zhang Z, Nakano M, Ibusuki M, Kawazoe T, Yamamoto Y, et al. Estrogen receptor alpha gene ESR1 amplification may predict endocrine therapy responsiveness in breast cancer patients. Cancer Sci 2009;100:1012-1017. 56. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005;97:1652-1662. 57. Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002;360:817-824. 58. Dunn BK, Ryan A. Phase 3 trials of aromatase inhibitors for breast cancer prevention: following in the path of the selective estrogen receptor modulators. Ann N Y Acad Sci 2009;1155:141-161. 59. O'Regan RM, Jordan VC. The evolution of tamoxifen therapy in breast cancer: selective oestrogen-receptor modulators and downregulators. Lancet Oncol 2002;3:207-214. 60. Love RR, Wiebe DA, Newcomb PA, Cameron L, Leventhal H, Jordan VC, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 1991;115:860-864. 61. Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003;361:296-300. 62. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-2741. 63. Larionov AA, Miller WR. Challenges in defining predictive markers for response to endocrine therapy in breast cancer. Future Oncol 2009;5:1415-1428. 64. Basso U, Fratino L, Brunello A, Lumachi F, De Salvo GL, Lonardi S, et al. Which benefit from adding gemcitabine to vinorelbine in elderly (>or=70 years) women with metastatic breast cancer? Early interruption of a phase II study. Ann Oncol 2007;18:58-63. 65. Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 2007;25:486-492. 91