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1 ORGINAL ARTICLE 유방암환자의보조적항암화학요법 Department of Surgery, Ajou University School of Medicine, M.D. 아주대학교병원외과학교실정용식 초록유방암은다학제적치료를통해가장큰효과를볼수있는대표적인악성종양이며수술후의보조적항암화학요법은환자의생존율을높일수있는효과적인방법으로서지금까지많은약제들이등장하였고그보다더많은조합들이임상시험에이용되었다. 여러문헌에따르면수술후보조적항암화학요법에의한사망률의감소는일반적으로 25~30% 정도로추정되는것으로생각되며, 대표적요법으로는 anthracycline 기반요법, taxane 첨가요법, 표적치료를이용한보조요법등이대표적이있다. 그러나아직까지도항암화학요법의최적의스케줄이나용량, 그리고대상환자의선정등에대해서는확실히밝혀지지않은부분이있으며이에대한계속적인연구가필요한것이사실이다. 이글에서는현재널리사용되고있는대표적인약제와조합들에대해서정리하여보았다. 중심단어 : 유방암, 보조항암화학요법 책임저자 : 정용식경기도수원시영통구원천동산 5번지아주대학교의과대학외과학교실 Tel : , Fax : , drjys@ajou.ac.kr 접수일 : 2008년 10 월 15 일 ; 게재승인일 : 2008년 11 월 12 일 서론유방암의치료에있어서보조적항암화학요법은필수적인요소중의하나로받아들여지고있으며 1970년대최초의표준복합요법인 CMF(cyclophosphamide,methotrexate, 5-fluorouracil) 요법이개발된이래로많은약제들과조합들이임상치료에이용되고있다. Early Breast Cancer Trialists' Collaborative Group(EBCTCG) 의메타분석 (meta-analysis) 에따르면수술후보조적항암화학요법에의한사망률의감소는 50세이하의환자에있어서 38% 정도로추정된다고보고하였으나과연어떤약제와조합이가장효율적인가에대해서한마디로결론을내리는것은쉽지않은일이다. 1) 또한지난 30년의연구를통해유방암의생물학적특성에따라다양한치료가가능하다는것이밝혀졌으며현재여성호르몬수용체의발현여부, HER2 유전자과발현등의특성에따라전신적약물치료의조합은더욱복잡해지고있다. 이에현재널리사용되고있는대표적인항암화학요법약제와조합들에대해서임상시험들의결과를중심으로정리하여보았으며투여용량과스케줄에대한연구들의결과와표적치료제를이용한임상연구에대해서언급하고자한다. 본론 1. 대상환자의선정일반적으로수술후보조적항암화학요법의시행은종양과관련된요인과환자의요인에의해결정된다. 다시말해서종양의재발위험도와환자의전신상태가시행여부를결정하는가장중요한요인이라할수있다. 일반적으로임파선에전이가있는유방암의경우항암화학요법이필수적인것으로생각되어지나 2 cm 이하의임파선전이가없는종양에대해서는지역이나권고안에따라다른의견이존재한다. 가장대표적인항암화학요법권고안은 NCCN(National Comprehensive Cancer Network), St Gallen, NIH(National Institutes of Health) 의권고안등이며, NCCN의경우 1 cm 이상의유방암에대해보조적항암요법을권하는데비해 St. Gallen 권고안의경우항암화학요법에대해신중한입장을보이고있다 (Table 1). 최근에는환자의유전자발현을이용한예후의예측이임상에서적용되고있으며임상에서사용할수있는검사는 Oncotype DX TM 와 Mammaprint TM 가대표적이다 (Table 2). 30

2 Korean Journal of Clinical Oncology winter 2008 ; Vol.4, NO.2: Table 1. Comparison of Recommendation of Adjuvant Chemotherapy According to Consensus Group NCCN St. Gallen Last updated Adjuvant chemotherapy Tumor size Recommended >1 cm > 2cm Optional cm 0-2cm Hormone receptor status No regard to status Negative Adjuvant trastuzumab HER2 Positive Positive NCCN=National Comprehensive Cancer Network; HER2=human epidermal growth factor receptor2. Oncotype DX TM 는 21개의유전자검사결과에따라재발점수 (recurrence Score, RS) 를산출하며점수에따라 high, internediate, low group으로분류되며 NSABP-14, 20 등의연구대상환자중호르몬수용체양성, 임파선전이음성인환자를대상으로재분석하였을때 high risk군에서는항암화학요법을하는것이생존율향상에도움이되는것으로밝혀졌으며 low risk군에서는추가적인항암화학요법이도움이되지않는것으로보고하였다. 2) Oncotype DX TM 의경우 2006년 FDA의승인을받았으며 2007년 American Society of Clinical Oncology(ASCO) 에서조기유방암에서항암화학요법의시행여부를판단할수있는검사로추천이되었다. 3) Mammaprint TM 역시유전자검사를통해재발의가능성을예측하는검사로 Oncotype DX TM 가파라핀고정조직을이용한반면 mammaprint TM 는고정되지않은조직을이용해 DNA microarray 방식으로 70개의유전자의발현을검사하여 high risk, low risk군으로분류하게된다. 이러한유전자검사들을통해항암화학요법이필요한대상환자를선별하여불필요한항암화학요법을줄일수있을것으로기대가된다. 여러후향적연구를통해가능성을입증하였으며현재대규모전향적임상시험인 TAILORx 연구 (Oncotype DX TM ) 나 MINDACT 연구 (Mammaprint TM ) 가진행중이다. 2. 항암화학요법의선택 1) CMF and Anthracycline 1976년 CMF를이용한보조적항암화학요법이임파선전이가있는유방암환자의재발률을낮춘다는알려진이래로가장효율적인조합을찾기위한노력이지속적으로이루어져왔다. 4) Bonadonna 등에따르면치료후 20년추적관찰결과에서 CMF는재발위험은 35%, 사망위험은 24% 감소시키는것으로보고되었으며, 5) anthracycline과 taxane 등장이전까지 CMF 요법은유방암의표준화학요법으로널리사용되어져왔다. CMF 요법은이후등장하는새로운항암화학요법연구의대조군으로서이용되었으며, anthracycline 기반의요법등장이후두요법간의효과에대한임상연구가오랫동안지속되었다. 1990년 NSABP B-15의연구에서임파선전이가있는유방암환자를대상으로하여 4주기의 Doxorubicine-Cyclophosphamide(AC) 사용이전체생존율과무병생존율에있어서 6차례의 CMF를사용한것과차이가없음을보고한이후 anthracycline을기반으로하는다양한조합이선보였다. NSABP B-23에서는임파선전이음성환자를대상으로하여같은디자인의연구를시행한결과역시차이가없음을보고하였다. 조금더강력한 anthracycline기반의요법인 6주기의 FAC 요법과 6주기의 CMF 요법을비교한연구에서임파선음성인유방암환자인경우 CMF 에비해전체생존율과무병생존율의향상을보여주었으나임파선양성군을대상으로한연구에서는두군간의차이가없었다. 6,7) 또다른 anthracycline 약제인 epirubicine을기반으로한 FEC 6주기와 CMF 6주기를비교한연구에서는액와부임파선전이여부에상관없이 FEC 요법이전체생존율과무병생존율에서다소우월한결과를보여주었으며 epirubicin과 CMF를순차적으로투여한군과 CMF만을사용한군을비교한연구에서도 epirubicin을추가한군에서월등한성적을보여주었다. 8~10) 현재까지의연구결과를볼때 4주기의 AC요법은 6주기의 CMF와동등하며 6주기의 FAC, FEC 요법은 6주기의 CMF 요법에비해다소우월한것으로보여진다. 따라서미국의경우 NSABP B-15의결과를바탕으로 CMF 에비해짧은투여기간을가지는 AC 4주기요법이선호되었으며캐나다나유럽의경우, Table 2. Gene expression profiling models in breast cancer Model Number of gene Tissue Assay Availability Prospective study MammprintTM 70 Fresh frozen Microarray FDA approved MINDACT Oncotype DXTM 21 Paraffin embedded RT-PCR FDA approved TAILORx Gene expression grade index 97 Fresh frozen Microarray Rotterdam signature 76 Fresh frozen Microarray Two gene ratio 2 Paraffin embedded RT-PCR MINDACT=Microarray in Node-Negative Disease May Avoid Chemotherapy; TAILORx=Trial Assigning Individualized Options for Treatment (Rx). 31

3 CMF에비해우월한효과를보인 FAC, FEC 6 주기요법이선호되었다. Anthracycline이가지는심독성및약제저항성에대한논란에도불구하고 anthracycline은아직까지대다수의술후보조요법의조합에포함되어있어 (AC, EC, FAC, FEC, A-CMF, E-CMF 등 ) 유방암의기본적인보조요법으로사용되고있으며 CMF 요법또한저위험군환자나고령의환자, 심장질환등이있는경우유용하게선택되고있다. 2) Taxanes Taxanes 계열의약제들은 microtubule에결합하여세포증식을억제하는약물로전이성유방암에서의우수한효과를바탕으로보조요법에서도사용되기시작하였다. anthracycline과교차내성이없고부작용이겹치지않아 anthracycline과의병용요법으로널리사용되고있으며투여순서에따라 anthracycline과순차적으로투여하는방법과동시에투여하는방법으로분류할수있다 (Table 3). Cancer and Leukemia Group B(CALGB) trial 9344는 taxane을이용한최초의보조요법임상시험으로, AC 4 주기군과 AC 4 주기후 paclitaxel 4주기를추가한군을비교하였을때재발및사망이 17%(p=0.0023), 18%(p=0.0064) 감소하였으며이를통해임파선양성인유방암에서보조요법으로 FDA 승인을받게되었다. 11) NSABP B-28, GEICAM 9906 연구에서도 paclitaxel 추가 군에서유의한무병생존율의향상을보고하였으나이러한연구들은대조군에비해 taxane 추가군의항암제투여횟수자체가많았으므로생존율의향상이 taxane의추가때문인지투여횟수자체가늘어났기때문인지가불분명하다는논란이제기되었다. 12,13) PACS01 연구는 FEC 6주기를대조군으로하고 FEC 3주기후 docetaxel 3주기투여한군을비교하였으며 docetaxel군에서전체생존율과무병생존율이향상됨을보고하였다. 14) Breast Cancer International Group(BCIRG) 001 trial 은 docetaxel을보조요법으로이용한첫번째임상시험이었으며 TAC 6 cycle 요법과 FAC 6 cycle 요법을비교하였으며 doctaxel을포함한경우재발위험은 28%(p=0.001), 사망은 30%(p=0.008) 감소하는것으로보고하였다. 하지만 docetaxel군의 24.7% 에서발열을동반한호중구감소증이보고되었으며현재 ASCO 권고안에서는 TAC 요법사용시예방적인과립구집락자극인자 (G-CSF) 의사용을권하고있다. 15) Estern Cooperative Oncology Group(ECOG) trial 2197의경우 taxane 추가군과대조군간에유의한차이를보여주지못하였으며이는연구에사용된 docetaxel의용량이낮았던점 (60 mg/m2) 과임파절음성인고위험군환자가과반수포함된점이영향을미쳤을것으로생각된다. Anthracycline과병용요법시순차적투여방법과동시에투여방법에대한비교 (BIG 02-98) 에서순차적으로 docetaxel을 Table 3. Main Characteristics and Results of Clinical Trials with Taxanes Study Patient Regimen DFS OS Sequential administration CALGB ,121, N+ 4*AC(60,75,90/600) q3w 70% vs 65% 80% vs 77% 4*AC 4*P(175) q3w HR:0.83, p= HR:0.82, p= NSABP B 28 3,060, N+ 4*AC(60/600) q3w 76% vs 72% 85% vs 85% 4*AC 4*P(225) q3w HR:0.83, p=0.006 HR:0.93, p=0.46 GEICAM ,248, N+ 6*FEC(600/90/600) q3w 85% vs 79% 95% vs 92% 3*FEC HR:0.63, p= HR:0.74, p=0.137 q3w 8*P(100)q1w PACS 01 1,999, N+ 6*FEC(500/100/500) q3w 78% vs 73% 91% vs 87% 3*FEC 3* T(100) q3w HR 0.82, p=0.012 HR:0.73 p=0.017 Concomitant administration BCIRG 001 1,491 N+6*TAC(75/50/500) q3w 75% vs 68% 87% vs 81% 6*FAC(500/50/500)q3w HR 0.72, p=0.001 HR:0.70 p=0.008 ECOG ,952 4* AT (60/60) q 3w 87% vs 87% NR N+/- 4* AC (60/600) q 3w HR:1.08, p=0.43 HR:1.09, p=0.48 CALGB=Cancer and Leukemia Group B; NASBP=National Breast and Bowel Project; GEICAM=Grupo Espanol de Investigacion en Cancer de Mama; PACS=French Protocol Adjuvant dans le Cancer du Sein; BCIRG=Breast Cancer International Research Group; ECOG=Eastern Cooperative Oncology Group; P=Paclitaxel; T=Docetaxel. 32

4 Korean Journal of Clinical Oncology winter 2008 ; Vol.4, NO.2: 투여한경우가동시투여에비해무병생존율및전체생존율이높은것으로보고되었으나사망한환자의수가예상보다적었으므로투여방법에대한추가적인연구는필요할것으로생각된다. 16) 현재까지의연구결과를볼때보조요법으로 taxane을사용하는것은생존율의향상에도움이되는것으로보여지며호르몬수용체의발현여부나 HER2 유전자의발현여부, taxane의종류나투여방법 ( 순차적투여혹은동시투여 ), 전이된임파선의개수에상관없이 anthracycline 단독사용에비해우수한성적을보이고있다. 그러나임파선전이가없는환자에대해서는아직까지성적향상에대한증거가부족하므로현재는임파선양성인유방암의표준요법으로 taxane 계열의약제들이이용되고있다. 3) Anthracycline의사용에대한논란앞서언급했듯이 anthracycline은유방암의보조요법에있어서가장많이포함되는약제이나현재주목받고있는여러연구에서는 anthracycline을제외한다른유용한요법을찾기위한시도가계속되고있다. 이러한배경에는 anthracycline이갖고있는비가역적인심독성이문제가되기때문이다. 또한최근사용되는표적치료제인 trastuzumab 역시심독성이문제가되며이전에 anthracycline을사용한환자에있어서더욱심각한부작용을초래할수있으므로 anthracycline을가능하다면배제해야할필요성이생긴것이한가지이유라생각되며최근의연구에서 anthracycline에대한반응이 topoisomerase llα의발현과관련이있는것으로밝혀지면서더욱논란이되고있다. BCIRG 006연구에서 AC 4 주기후 docetaxel 4 주기와 trastuzumab을 1년간사용한군 (AC-T+H) 과 6주기의 docetaxel과 carboplatin에 trastuzumab을사용한군 (TCH) 을비교하였을때생존율의차이가없다고보고하여 anthracycline의사용이필수적이아님을시사하였다. 또한 topoisomerase llα가발현이된환자의경우생존율이높았으며이런경우기존의 AC+docetaxel군과 trastuzumab을추가한군 (AC+TH, TCH) 사이에생존율의차이를보이지않을정도로 anthracycline에대한반응이좋은것으로나타났다. 17) 다른연구에서도 topoisomerase llα의발현과 anthracycline의반응성에대해서는일치되는결과를보고하고있어 anthracycline의사용하는데있어서 topoisomerase llα가중요한역할을하는것은분명하나전체유방암환자를놓고보았을때대략 10% 정도에서만 topoisomerase llα가발현이되는것으로알려져있고또 HER2 음성인환자에서는 topoisomerase llα의발현이거의없는것으로알려져앞으로 anthracycline을대체할수조합에관심이모여지고있다. US oncology 9735 trial은 AC 4 주기와 TC(docetaxel+cyclophosphamide) 4 주기를비교한연구로 7년간추적관찰결과무병생존율이 75% vs 81%, 전체생존율이 82% vs 87% 로 TC군에서통계적으로유의하게높은것으로나타났다. 이러한결과는환자의나이나 HER2 유전자의발현여부에상관없이일치되게나타남에따라보조요법으로의 anthracycline이꼭필요한가에대한의문을제기하였다. 18) 또한대상환자의 50% 정도가임파선전이가없는환자로구성되어있어임파선음성유방암환자에서의 taxane의효과에대해서도기대감을높였으며 4 주기의 TC 투여로비교적낮은부작용을유발한다는등의장점이있어조기유방암에서 anthracycline 기반의항암요법의대안으로기대받고있다. 현재같은 US Oncology Group에서 TC 6cycle과 TAC 6cycle에대해서임상연구를진행하고있으며연구결과가나오면보조요법에서 anthracycline의유용성에대한결론에좀더접근할수있을것으로기대된다. 3. Modification of dose and schedule, Dose intensity and Dose density 보조요법의효과를높이기위해적용되는방법에는크게두가지가있으며하나는투여용량을늘리는방법 (dose intensity) 이있고또하나는투여간격을줄이는방법 (dose density) 이있다. 앞서언급한 CALGB 9344의경우두가지연구목적을가지고진행되었다. 첫번째는 paclitaxel의추가에따른차이를보는것이었으며, 두번째는각각다른 doxorubicin의용량을투여했을때의차이를보기위한것이었다. 11) 연구결과 doxorubicin 의용량을 60/70/95 mg/m2로다르게투여한군을비교하였을때치료성적에차이가없는것으로나타났으며 NSABP B-22, B-25 연구의경우에서도 AC 요법사용시 cyclophosphamide 의용량을 2400/4800/9600 mg/m 2 으로다르게투여하여비교하였을때치료성적에영향이없는것으로보고하였다. 19,20) 고용량항암화학요법 (high dose chemotherapy) 의경우에도 2007년 San Antonio Breast Symposium에서발표된보조요법영역에서의 15개의임상시험결과분석을볼때기존의일반적항암화학요법에비해성적의향상은없으며부작용은높은것으로보고되어현재임상적으로는사용되지않고있다. 결국표준용량이어느정도인지정확히알수는없으나여러임상시험을기준으로추정된용량을사용하는것이적절하며그보다낮은용량에서는낮은효과를보이나용량을높인다고해서치료효과가같이높아지는것은아닌것으로판단된다. 용량밀도 (dose density) 의경우표준용량을짧은간격으로투여하여암세포가항암제에노출되는시간을극대화하는방법으로서, 투여간격에발생할수있는종양세포의재생을최소화할 33

5 수있을것으로기대되어관심을받고있다. 21,22) CALGB 9741 trial에서 AC->paclitaxel, A-T-C 3주간격표준요법과같은조합을 2주간격으로한용량밀도요법을비교하였으며표준요법에비해전체생존율 (RR = 0.69; p =.013) 과무병생존율 (RR = 0.74;p =.010) 이유의하게향상됨을보고하였다. 23) FEC를이용한용량밀도임상연구 (GONO-MIG1, Grouppo Oncologico Nord- Quest-Mamme Inter Grouppo Group) 에서는표준 FEC 와차이가없는결과를보여주었으나세부분석에서는 50세이하의젊은여성과호르몬수용체음성인군에서용량밀도군의생존율이높게나타났다. 24) 여러연구에서용량밀도요법이희망적인결과를보고하고있으나과연어느조합이또어떤환자들이용량밀도요법에적합할것인가에대해서는연구가더필요할것으로생각되며투여의간격을어느정도로하는것이적절한지에대해서도추가적연구가필요하다. 현재 AC-T, TAC 등의조합이용량밀도요법에서조금더좋은결과를보여주고있어임상적으로많이적용이되고있으나효과와부작용등을고려하여선택할필요가있어보인다. 4. Target therapy: HER2 directed treatment 일반적으로유방암환자의 20~30% 에서 HER2 과발현이관찰되고있으며이는종양의증식과변형등에영향을주어예후인자로써예전부터사용되어왔다. 25) Trastuzumab은 HER2의단클론항체를이용한첫번째약제로 1998년전이성유방암의치료제로 FDA 의승인을받았다. 보조요법 과관련된임상시험으로는 NSABP B-31, NCCTG(North Central Cancer Treatment Group) N9831, Herceptin Adjuvant (HERA) study가가장규모가크며 FinHER study(finland Herceptin study), BCIRG 006 study 등이유명하다. 26~28) NSABP B-31의경우 AC-weekly paclitaxel 12주에 trastuzumab을동시사용하였으며 NCCTG의경우앞의두조합에 AC-weekly Paclitaxel-Herceptin 순으로순차적으로사용한군이추가되었다 (Table 4). FInHER 연구의경우 trastuzumab 의투여기간이 9주기로다른연구에비해서짧은것이특징이며 BCIRG006의경우 TCH(Docetaxel+Carboplatin+Herceptin) 조합이포함된것이특징이다. 모든연구에서 HER2 과발현군의경우 trastuzumab이포함되었을때무병생존율혹은전체생존율의향상을보임에따라 NCCN이나 St Gallen의권고안에도 HER2 유전자가발현된유방암의수술후보조요법에 trastuzumab이포함되었다. 현재까지 trastuzumab의표준투여기간은밝혀지지않았으며기존의연구결과를바탕으로 1년동안의투여가권장되고있다. 다만 trastuzumab이가진심독성등을고려할때적정투여기간에대한연구가좀더진행되어야할것으로생각된다. 비록소규모의임상연구이나 FinHER study에서 9주간의요법으로무병생존율이향상되었음은짧은기간의 trastuzumab 투여역시효과가있음을시사하는결과로주목을끌고있으며현재 trastuzumab 9주투여와 51주투여에대한임상연구가핀란드그룹에서진행중이며, 6개월투여와 12개월투여를비교하는임상연구역시미국과유럽에서각각진행중이다. Table 4. Clinical Trials Using Trastuzumab in Adjuvant Treatment Study Regimen n of Median Trastuzumab schedule patient F/U HERA* Arm A: CT observation 1,698 loading dose of 8 mg Arm B: CT H*12 mos 1,703 2 year 6 mg/kg every 3 weeks Arm C: CT H* 24 mos 1,689 NCCTG Arm A: AC P 807 loading dose 4 mg N9831 Arm B: AC P+H year 2 mg weekly for 51weeks Arm C: AC P H 981 NSABP Arm A: AC P year loading dose 4 mg B31 Arm B: AC P+H 864 weekly 2 mg for 51weeks BCIRG Arm A: AC D 1,073 loading dose 4 mg 006 Arm B: AC +H 1,074 3 year 2 mg weekly for 12 weeks Arm C: D+Carb+H 1,075 followed 6 mg every 3 weeks for 14 cycle FinHER Arm A: D or V CEF year loading dose 4 mg Arm B: D or V+H CEF mg weekly for 9 weeks. *HERA trial allowed the administration of several alternative chemotherapy regimens; chemotherapy was anthracycline based in 94% of patients; 26% received a taxane a AC=doxorubicin and cyclophosphamide; BCIRG=Breast Cancer International Group; Carbo=carboplatin; CEF=cyclophosphamide, epirubicin, and fluorouracil; CT=chemotherapy; D=docetaxel; FinHER=Finland Herceptinstudy; H=trastuzumab; HERA=HerceptinAdjuvant trial; NCCTG=North Central Cancer Treatment Group; P=paclitaxel; NSABP=National Surgical Adjuvant Breast and Bowel Project; V=vinorelbine. 34

6 Korean Journal of Clinical Oncology winter 2008 ; Vol.4, NO.2: 다른표적치료제인 Lapatinib (ALTTO study;adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation Study), Bevacizumab (BEATRICE Study: A Study of Bevacizumab Adjuvant Therapy in Triple Negative Breast Cancer) 등에대한연구역시현재진행중이며다양한표적치료제에대한연구결과에따라술후보조요법의방법에도변화가있을것으로기대가된다. 결론유방암영역에서보조적항암화학요법이치료성적의향상을이끈것은분명하나적절한조합이나용량, 스케줄등에대해서는아직까지많은부분이모르는채로남아있다. 지금까지의항암화학요법의투여가대략적인위험도의감소목적으로투여되어왔으나앞으로의방향은최소한의부작용으로최대한의효과를볼수있는방향으로전개될것이다. 여러종양단백질에대한표적치료제들이개발되어임상연구가진행중이며그결과에따라향후적은부작용으로높은치료결과를기대할수있게되었다. 또한환자의유전자정보를이용한예후의예측과선별적인항암화학요법의시행도조만간가능할것으로예상된다. 과거에논의되었던소위 'Gold standard' 요법은무엇인가에대한논쟁은더이상큰의미가없으며개별적환자에대한치료반응의예측과가장효과적인치료제의선택이향후항암화학요법치료의가장중요한요소가될것으로예상된다. REFERENCES 1. Early Breast Cancer Trialists' Collaborative Group. 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: Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen treated, node-negative breast cancer. N Engl J Med 2004;351: Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007;25: Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294: Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332: Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8: Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, et al. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM Group. Ann Oncol 2003;14: Coombes RC, Bliss JM, Wils J, Morvan F, Espie M, Amadori D, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol 1996;14: Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 1998;16: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, et al. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 2006;355: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005;23: Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, et al. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst 2008;100: Roche H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 Trial. J Clin Oncol 2006;24:

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Lee A and Moon BI 행성유방암을수술이가능하게할경우, 수술종양의크기를감소시켜유방보존술의가능성을증가시킬경우, 환자의사정으로당장수술이불가능할경우등에서신보강화학요법을시행할수있다. 이러한점이외에도항암제에대한종양의감수성정도를평가할수있으며, 항암제에대한종양의반응정도를평

Lee A and Moon BI 행성유방암을수술이가능하게할경우, 수술종양의크기를감소시켜유방보존술의가능성을증가시킬경우, 환자의사정으로당장수술이불가능할경우등에서신보강화학요법을시행할수있다. 이러한점이외에도항암제에대한종양의감수성정도를평가할수있으며, 항암제에대한종양의반응정도를평 Review Article Ewha Med J 204;37(2):-82 http://dx.doi.org/0.277/emj.204.37.2. pissn 2234-380 eissn 2234-259 유방암특집 유방암의항암치료 이안복, 문병인 이화여자대학교의학전문대학원외과학교실 Chemotherapy in Breast Cancer Anbok Lee, Byung-In