<30312EC6AFC1FD30342DC1A4B0E6C7D82E687770>

Transcription

1 대한내과학회지 : 제 77 권제 1 호 2009 특집 (Special Review) - 진행성악성종양별맞춤항암요법의최신지견 진행성유방암의맞춤항암요법의최신지견 울산대학교의과대학내과학교실 정경해 Personalized therapy for advanced breast cancer using molecular signatures Kyung Hae Jung, M.D., Ph.D. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea In Korea, breast cancer is the second common cancer in women and many patients suffer from metastatic disease after surgery and adjuvant therapy. Metastatic breast cancer is unlikely to be cured, but it is possible to choose therapeutic options according to clinical factors and tumor biology to avoid unnecessary toxicity and improve efficacy. Hormone receptors and HER2 status are the most important predictive factors and should be evaluated in all breast cancers. Hormonal treatment is preferred for initial treatment of hormone receptor positive metastatic breast cancer due to its more favorable side effect profile. Tamoxifen has been the mainstay of hormonal treatment. However, new aromatase inhibitors challenge tamoxifen as the first line therapy in postmenopausal women. Trastuzumab with conventional chemotherapy is the standard of care in patients with strong overexpression of HER2 and lapatinib is active after trastuzumab failure. (Korean J Med 77:26-34, 2009) Key Words: Breast cancer; Metastasis; Therapy; Hormone; HER2 서론유방암은우리나라여성암중갑상샘암에이어흔히발생하는종양으로전체유방암환자중 5% 미만에서전이성유방암으로처음진단받지만, 근치적치료를받은환자중약 40% 에서재발하며뼈, 간, 폐, 림프절, 늑막등에주로전이를하게된다. 전이성유방암은다른고형암에비해비교적항암요법에반응이좋고중앙생존기간도약 2~3년으로길지만완치는어렵다. 생물학적특성또한매우다양하여진단후수개월만생존하는가하면, 5~10% 의환자가 5년이상생존하고, 2~5% 는그이상생존한다. 따라서전이성유방암의치료목표는환자와종양의특성을고려하여, 치료의부작용을최소화하면서암을안정시키거나무진행생존기간과전체생존기간을연장시키고암으로인한증상을완화하고 삶의질을향상시키는것이다. 현재임상에서사용되는전이성유방암의치료에는호르몬치료, 항HER2 요법및세포독성항암화학요법이있는데, 재발한환자의임상적상태와암의특성에따라각치료방법에대한반응을예측하고치료법의독성을고려하는것은첫치료법과이후치료의적절한순서와시기를결정하는데도움을준다. 호르몬수용체와 HER2 과발현여부는치료에대한반응예측에가장중요한인자이며, 이로써개개환자에게맞춤치료를통한치료효과의상승및독성을최소화하는것이가능하다. 유방암병력이있는환자에서임상적으로의심이되는병변모두가유방암의전이를의미하지는않으며, 다른양성질환이나이차암일수있다. 특히폐의고립결절 (solitary nodule) 은흡연력이있으면약 50% 까지원발폐암의가능성이

2 - Kyung Hae Jung. Personalized therapy for advanced breast cancer using molecular signatures - 있으므로조직검사로확인하는것이중요하다 1). 또한원발유방암과재발한유방암에서호르몬수용체와 HER2의불일치가 20~40% 에서발견되고, 20% 의환자에서치료방침이달라지므로유방암의재발이의심되는경우다시전이병변의조직검사로확인할것을추천하고있다 2). 호르몬수용체 (estrogen receptor 또는 progesterone receptor) 가양성이면음성에비하여예후가좋으며호르몬치료에잘반응하나, 호르몬수용체음성이거나호르몬치료에반응하지않는경우항암화학요법이우선적으로사용된다. 호르몬치료는반응을보인환자에서반응지속기간이길고다른호르몬치료에반응할확률이높고약제의부작용이비교적경미한반면, 항암화학요법은높은반응을빨리유도할수있으나치료에따른부작용이호르몬치료보다심하다는단점을갖는다. 그러므로호르몬치료에반응할환자에게항암화학요법을시행하면불필요한부작용을경험하게되는반면, 호르몬치료에반응하지않을환자에게그치료를시행하면그동안질병이진행되어나중에항암화학요법을받을수있는기회를잃을수있으므로, 치료를시작하기전에이상의인자들을충분히고려하여적절한치료법을선택하여야한다. 또한 HER2가과발현된경우일반적으로예후가좋지않으나, 항HER2 치료에잘반응하는것으로알려져있으므 로, 치료를시작하기전호르몬수용체와 HER2 과발현여부를확인하는것은매우중요하다. 이외질병의진행속도나생존기간을예측하는데중요한임상적요소로진단후재발까지의기간, 전이부위의수, 내장의침범유무를꼽을수있다. 예로전이가뼈, 연조직이나림프절에제한된경우장기무진행생존을기대할수있으나, 간또는림프상 (lymphangitic) 폐전이가있으면예후가좋지않아호르몬수용체가양성이더라도항암화학요법을먼저고려한다. 이상을바탕으로전이성유방암환자의예후는표 1과같이저위험군과고위험군으로나눌수있으며, 전신적치료선택의일반적기준 ( 표 2) 과순서 ( 그림 1) 를제시하였다. 아직까지진행성유방암에서항암화학요법에대한치료효과를예측할수있고임상에적용가능한분자생물학적지표는없으므로, 본장에서는임상에서사용이허가된호르몬치료와항HER2 치료를중심으로기술하겠다. 호르몬치료 1896년 Beatson이폐경전유방암환자에서난소적출술후유방암의진행이억제되는것을보고하면서 3), 난소호르 Table 1. Classification of breast cancer according to risks Low risk High risk Hormone receptor Positive Negative HER2 expression Negative Positive Disease-free interval > 2 years < 2 years Tumor growth Slow Fast Tumor burden Limited Extensive Metastatic sites Soft tissue, bone Viscera Table 2. Treatment options according to disease status Treatment Characteristics of disease Endocrine therapy ER+/PR+ Long time to recurrence Non-visceral disease Response to prior endocrine therapy Chemotherapy ER-/PR- Short time to recurrence Rapidly progressing visceral disease Lack of response to endocrine therapy Anti-HER2 therapy HER2+ ER, estrogen receptor; PR, progesterone receptor

3 - 대한내과학회지 : 제 77 권제 1 호통권제 587 호 Advanced breast cancer ER/PR positive ; Endocrine therapy ER/PR negative; Chemotherapy Refractory to endocrine therapy Figure 1. Treatment of advanced breast cancer HER2 positive; Chemotherapy + Trastuzumab HER2 negative; Chemotherapy Table 3. Endocrine agents for advanced breast cancer Premenopausal Antiestrogens SERMs (Tamoxifen) Estrogen-deprivation therapy: Ovarian ablation Oophorectomy LHRH agonist Sex steroid therapies Progestins High-dose estrogens Postmenopausal Antiestrogens SERMs (Tamoxifen, Toremifene) Fulvestrant Estrogen-deprivation therapy: Aromatase inhibitors (AI) Anastrozole Letrozole Exemestane Sex steroid therapies Progestins High-dose estrogens 몬생성을억제함으로써유방암치료를할수있다는가능성이처음제시되었다. 이후에스트로겐이유방암발생에중요한역할을한다는것을발견되고이를억제또는차단함으로써치료효과를기대할수있다는것이알게됨에따라암치료중최초의맞춤치료가가능하게되었다. 호르몬치료에대한반응을예측하는데가장중요한인자는종양세포에서의호르몬수용체의존재유무와발현정도로, 에스트로겐수용체 (estrogen receptor, ER) 와프로게스테론수용체 (progesterone receptor, PR) 가모두양성인환자의경우약 70% 의환자에서호르몬치료에반응하고, 두개중한개만양성인경우는약 40% 에서반응을하는반면, ER과 PR 의발현이없는경우는 10% 미만에서만반응을하므로호르몬치료를시작하는것은적절하지못하다 4,5). 처음호르몬치료에반응하였다가진행하게되는경우다른종류의호르몬치료에반응할수있으므로, 순차적으로호르몬치료를시도할수있다. 호르몬치료는표 3과같이크게세가지로나눌수있다. 첫째는항에스트겐약제로, tamoxifen, toremifene과같은선택 적에스트로겐수용체조절인자 (Selective Estrogen Receptor Modulator, SERM) 와 fulvestrant와같은스테로이드계항에스트로겐이있다. 둘째로에스트로겐을박탈 (deprivation) 하는방법인데아로마타제억제제 (Aromatase Inhibitor, AI) 로에스트로겐의말초변환을억제하거나, 수술, 방사선치료또는 goserelin 과같은 LH-RH 작용제 (leutinizing hormone-releasing hormone agonist, LHRH agonist) 로난소기능을차단하거나억제하는방법 (ovarian ablation/suppression) 이있으며, 셋째로성호르몬치료법으로 progestin 이나고용량에스트로겐의사용이여기에해당한다. 폐경전여성에서는난소에서주로에스트로겐이생성되고난소외조직에서말초변환에의해 androstenedione과테스토스테론이아주소량 estrone 과 estradiol로변환되지만, 폐경후여성에서는대부분말초변환에의해에스트로겐이생성되고난소에서생성되는에스트로겐이거의없다. 그러므로폐경전과폐경후여성에서호르몬치료는다르며, 폐경전여성에서는 ER을차단하거나난소기능을차단 / 억제하고, 폐경후여성에서는 ER을차단하거나 AI를사용하는것이

4 - 정경해. 진행성유방암의맞춤항암요법의최신지견 - 바람직하다. 폐경후여성에서 tamoxifen이호르몬치료의일차요법제로여겨져왔으나, 최근 AI와새로운항에스트로겐이개발되면서호르몬치료의근간이바뀌었다. 1세대아로마타제억제제인 aminoglutethimide의부작용을최소화하고효과를높인 3세대 AI에는비스테로이드계 AI인 anastrozole, letrozole과스테로이드계 AI인 exemestane 이있다. Tamoxifen 사용후 12개월이내재발되거나치료중진행된전이성유방암환자를대상으로 AI와 megesterol acetate 또는 aminoglutethimide를비교한대부분의 3상연구에따르면 6-8), AI 치료군에서진행까지의기간이연장되고일부에서생존기간의연장도관찰된다. 호르몬수용체양성이거나호르몬수용체상태를알수없는환자를대상으로 AI를 1차치료제로 tamoxifen과비교한연구들을메타분석한결과에따르면 9), 반응률, 진행까지의기간과전체생존기간모두 AI군에서높아, 폐경후여성에서 AI가 1차치료제로서자리잡게되었다. Tamoxifen 의부작용은주로 50세이상에서많이관찰되는데, 폐색전증, 심부정맥혈전증, 뇌경색, 백내장과자궁내막암같은중대한부작용과안면홍조, 구역및질분비가흔하다 10). 반면 AI는안면홍조, 관절통을비롯한근골격계증상이흔하고, 자궁내막암이나혈전증의빈도는 tamoxifen보다유의하게낮다. AI를복용하면작지만골다공증과골절의위험이증가하므로정기적인골밀도측정과치료가필요하지만 11), 지질대사의변화로인한심혈관계위험을증가시키는가는아직판정을내리기어렵다 12). 이상과같이 AI가효과면에서 tamoxifen보다우월하고부작용도 tamoxifen에비해수용할만하므로이전에호르몬치료를받은적이없는환자나 tamoxifen 보조요법중재발하였거나, tamoxifen 혹은 AI 보조요법종료 1년후재발한호르몬수용체양성폐경후여성에서일차치료제로인정되고있다. Fulvestrant는순수한항에스트로겐제제로에스트로겐과경쟁적으로 ER과결합하여 ER의이합체형성과 DNA와의결합을방해하고 ER을하향조절한다. 보조요법이나일차치료제로 tamoxifen을사용한후에진행된폐경후유방암환자를대상으로이차치료로서 anastrozole 과 fulvestrant를비교한연구에서 13) 두약제간에임상효과의차이는없었다. 나아가호르몬수용체양성인폐경후전이성유방암에서 fulvestrant와 tamoxifen을일차치료제로서비교한 3상연구에서효과차이는없었다 14). 두약제간의부작용은비슷하지만, fulvestrant 치료군에서안면홍조의빈도가의미있게낮았다. 그러므로 AI 보조요법중이나종료 1년내에재발하였다면 tamoxifen이나 fulvestrant를일차치료제로사용할수있다. AI와 tamoxifen 모두에질병이진행한다면, fulvestrant, exemestane ( 이전에사용하지않은경우 ) 과 megestrol acetate를사용할수있다. 혈전이나심혈관계위험인자가없고조절되지않는고칼슘혈증이없다면조심스럽게에스트로겐치료도고려할수있다. 폐경전여성의 1차치료법으로는 tamoxifen, 난소기능억제 ( 난소적출술, LHRH 작용제 ) 와이둘의병합을꼽을수있다. 호르몬수용체양성인폐경전여성에서 tamoxifen은표준요법으로알려져왔다. LHRH 작용제는호르몬수용체양성인전이성유방암환자에서난소적출술과비교하여반응률, 무진행생존기간과전체생존기간의차이는없으며 15), 수술에비해안면홍조와종양플레어 (flare) 가흔하지만 LHRH 작용제사용을중단했을때난소기능이가역적으로회복되고부작용빈도가낮은장점이있다. LHRH 작용제와 tamoxifen을함께사용함으로써에스트로겐을완전차단하고자하는시도들이이루어졌는데, 호르몬수용체양성인전이성유방암환자들을대상으로 LHRH 작용제와 tamoxifen 의병합은 LHRH 작용제단독에비해임상반응률이높고무진행생존기간과전체생존기간을향상시키므로 16) 폐경전호르몬수용체양성인유방암환자에서일차치료로서추천된다. 그러나그차이가크지않으므로 tamoxifen을먼저사용하고암이진행하면 LHRH 작용제를순차적으로사용하는것도타당하다. 한편, 폐경전여성에서 LHRH 작용제만사용한것과 LHRH 작용제로난소기능을억제한후 AI를사용하는방법중어느것이우월한가에대해서는아직알려지지않았으므로, 임상에서두약제를병합하여사용하는것은추천되지않는다. 이견이있기는하지만, 몇몇자료에의하면 HER2 양성이면호르몬수용체양성이더라도호르몬치료에대한반응이떨어질수있다. 전임상연구에서 HER2와 ER 신호전달경로는서로영향을끼치므로 (cross-talk), ER양성유방암세포에 HER2를과발현시키면에스트로겐에비의존적인성장을하고 tamoxifen에내성을보인다 17). 전이성유방암환자에서 HER2 과발현은호르몬치료반응에영향을미치는데, 한메타분석에의하면 18) HER2 음성인환자에비해 HER2 양성인환자에서 tamoxifen이나다른호르몬치료에실패할가능성이높았다. 그러나상반된연구들도많아 HER2 과발현여부로호르몬치료를결정하는것은추천되지않으며, 호르몬치

5 - The Korean Journal of Medicine: Vol. 77, No. 1, 료는호르몬수용체유무에따라결정해야한다 19). ER+/PR+ 인종양의 20~25% 는호르몬치료에처음부터반응하지않고 20), 처음에반응을보인경우도결국에는거의대부분에서호르몬치료에내성을획득하게된다. Tamoxifen 내성에대한원인으로 ERα와 ERβ의다양한발현, 종양에따라다른 coactvator와 corepressor와결합, spliced ER mrna 변종이나 EGFR이나 HER2 의활성화에따른 ER 발현저하등이거론되고있으나이들을임상에서이용하는것은어렵다. 한편 CYP2D6의 *4, *5, *10과 *41 대립유전자 (allele) 를갖거나 CYP2D6 억제제인 SSRI (serotonin receptor reuptake inhibitor) 를복용하면 tamoxifen보다 100배강력한 endoxifen으로의변환이억제되고, 전이성유방암에서예후가나쁜것으로알려져있다 21). CYP2D6 유전자형을검사할수있는 AmpliChip 이미국에서인정되어사용이가능하지만, 이를기준으로 tamoxifen과 AI를선택하는것은아직표준으로받아들여지지않는다. 단 tamoxifen을복용할때 CYP2D6 억제제인 fluoxetine이나 paroxetine과같은 SSRI의사용을피하는것이추천된다. 항HER2 치료분자생물학적이해가깊어지면서종양의발생, 성장과전이과정에서결정적인역할을하는분자표적을겨냥하여암을치료하고자하는목적으로약이개발되기시작했다. HER2 (HER-2/neu, HER-2, c-erb-b2) 와유방암과의연관성이알려지면서, 세포막표면의 HER2와강하게결합하여 HER2 유전자신호를차단하는재조합인간화단일클론항체인 trastuzumab과 HER2의세포내티로신키나제를불활성화시키는소분자약제인 lapatinib이개발되어임상에서사용되고있다. HER2는염색체 17q21에위치한 c-erbb2 유전자에의해코딩되는 185 Kd의세포막에위치한표면단백으로, 전체유방암환자의약 20~25% 에서 HER2 유전자의증폭또는단백질의과발현 ( 이상 HER2 양성 ) 이발견되며, 유방암환자의치료를결정하는데매우중요한요소이다. 또한 HER2 양성인경우그렇지않은경우에비해예후가좋지않은것으로알려져있고, 치료에대한반응을예측하는데도움을준다. 지금까지미국 FDA 인증을받은 HER2 과발현을판단하는방법에는 HER2 단백질과발현을살피는면역조직화학염색법 (IHC, immunohistochemical staining) 과형광제자리부합법 (FISH, fluorescent in situ hybridization) 과색소원제자리부합법 (CISH, chromogenic in situ hybridization) 으로 HER2 유전자 증폭을평가를하는것이있다 22). IHC는이미익숙하게널리쓰여지던방법으로가격이저렴하고형광현미경과같은장비가필요하지않아가장널리이용되고있다. FISH는내부대조 (internal control) 가있고직접 DNA를타겟으로하며, CISH는 IHC와 FISH의장점을가지고있어 2008년사용이인정되었다. FISH에서유전자증폭이확인되었거나 IHC 3+ 이면 HER2가과발현되었다고판정하며, IHC 2+ 인경우에는 FISH로 HER2 유전자증폭을확인하는것이필요하다. 우리나라에서는 IHC로먼저검사한후 IHC 2+ 일때 FISH 검사하는것을권하고있다. 미국임상종양학회 (ASCO) 의지침에따르면 23) 중앙검사실결과와각병원간의검사결과가약 20% 에서일치하지않으므로, 검사인증을받은기관에서 HER2 검사를시행하도록권고하고있다. 앞서언급한바와같이원발종양과전이성유방암간에 HER2 과발현의불일치가관찰되고이들중상당수에서 HER2 음성종양이 HER2 가과발현되는방향으로변화하므로 24,25), 가급적새로운전이성종양에서 HER2를다시검사하는것이추천된다. HER2 양성이면 trastuzumab 이나 lapatinib 같은항HER2치료로득을얻을가능성이매우높다. Trastuzumab 초기연구에서 HER2 2+ 나 3+ 인환자들만이연구대상이었는데, trastuzumab 은 IHC 3+ 이거나 FISH에서유전자복제수가높은환자들에서효과가있었으며 26,27), IHC 2+ 인환자의약 24% 에서만 FISH로유전자증폭이발견되므로 28), IHC 3+ 이거나 FISH로핵당 HER2 유전자수가 6을초과하거나, HER2 유전자신호대 17번염색체신호의비가 2.2를초과하는경우항HER2 치료를권한다. HER2 발현이낮거나정상인환자중 neuregulin이과발현되면 trastuzumab 치료로생존기간이향상된다는소규모연구결과가있으나 29), 일반적으로 HER2 음성이면 trastuzumab 에효과가없으므로사용하지말아야한다 30). Trastuzumab 은 HER2 양성이고항암제에내성을보인전이성유방암환자에서반응률 15%, 중앙생존기간 13개월이었으며 26), 1차치료제로서반응률은 26% (IHC 3+ 인경우 35%) 로단일제제로서의유용성을제시되었다 27). Trastuzumab은처음 4 mg/kg를준뒤매주 2 mg/kg을투여하는방법이나 8 mg/kg을준뒤 3주간격으로 6 mg/kg을투여하는방법모두우수하지만, 후자가환자에게더편리하다. Slamon 등의연구에서 31) HER2를과발현하는전이성유방암환자를대상으로표준항암화학요법만을시행한군과 trastuzumab 을추가한군을비교한결과병용요법군에서반응률 (50% 대 32%, p<0.001), 무진행생존기간 (7.4개월대 4.6개월, p<0.001)

6 - Kyung Hae Jung. Personalized therapy for advanced breast cancer using molecular signatures - 과전체생존기간 (25.1개월대 20.3개월, p=0.046) 이모두유의하게우월하였고, 특히 HER2 2+ 보다 HER2 3+ 인환자에서더우수하였다. Docetaxel과 trastuzumab 병용군을 docetaxel 단독과비교한 2상연구에서도병용군의성적이모두우수하여 taxane을포함하는항암화학요법과 trastuzumab 을병용하여사용하는것이 HER2 양성전이성유방암의표준치료로인정된다. 이외많은다른연구들에서 capecitabine, vinorelbine, gemcitabine, cisplatin 등과 trastuzumab 의병합치료가 1차또는 2차치료로서효과가있음이보고되었다. 그러나 taxane과 trastuzumab 에 platinum을추가하는유용성은아직검증되지않았다. 최근 trastuzumab 과항암제병용요법에도불구하고질병이진행한경우 capecitabine 단독으로전환하는것보다 trastuzumab 을 capecitabine과함께지속적으로병용하는것이우수하다는보고가있어이를고려할만하다 32). Trastuzumab 은항암제의독성을악화시키지않으며부작용이경미하지만, 좌심실박출률감소와심부전과같은심장독성이발생할수있다. 단독또는 taxane과병용시심부전빈도는 4% 이내이고대개내과적치료에가역적이지만, anthracycline과함께사용하면위험이더증가하므로병용을피하여야한다. 현재까지 trastuzumab 치료후심장독성을예견할수있는혈액이나조직학적지표는알려져있지않으며, 이전 anthracycline의사용, 당뇨, 관상동맥질환, 고혈압, 및심부전이있는경우가위험인자라고알려져있으므로이들환자에서 trastuzumab 의사용에주의를요한다 22). 그러나 HER2 양성인모든환자에서 trastuzumab 치료가효과적이지않은데, PTEN의상실, IGF-1R 의과발현, trastuzumab과의결합부위인 HER2의세포막외부분이잘린 p95her2 등이내성기전으로제시되고있다 22). Lapatinib은표피세포성장인자수용체 (EGFR, epidermal growth factor receptor) 와 HER2 두수용체의티로신키나제 ATP 결합부위에경쟁적으로결합하여신호전달을가역적으로차단하는저분자량약물로, trastuzumab 치료후진행된유방암에서 lapatinib을단독투여시반응률은 5% 였다. 그러나, lapatinib은 EGFR 양성일지라도 HER2 음성이면효과가없으므로사용하지말아야한다 33,34). Anthracycline과 taxane, trastuzumab 에불응한유방암환자를대상으로 capecitabine 을단독또는 lapatinib과병용치료를비교한 3상연구에의하면 lapatinib 병용군에서진행까지의기간이의미있게증가되어 (8.4개월대 4.4개월, p<0.001), 사용승인이되었다. 주로나타나는부작용은설사 (3도이상 10% 미만 ) 35), 발진, 오심및피로감등이며, 단지 1.6% 에서만좌심실박출률감소가관찰 되었다 36). Trastuzumab 이혈액뇌장벽을통과하지못하는것에비해, lapatinib은 trastuzumab 과방사선치료후뇌전이가악화된환자의 6% 에서뇌전이의반응을보여뇌전이가있는유방암환자에게고무적이지만연구가더필요하다 37). HER2 양성유방암세포주에서 lapatinib과 trastuzumab 은서로상승효과가있고두약제사이에교차내성이없는데, trastuzumab 치료중진행된 HER2 양성유방암환자에서 trastuzumab 과 lapatinib 병용요법을 lapatinib 단독과비교한연구에따르면 38), 병합요법에서무진행생존기간이 12주대 8.4주로증가하여 (p=0.029), 표적치료제간의병합도가능하다. 또한 HER2와 ER을동시에발현하는유방암세포에서 trastuzumab 이항호르몬제에대한저항성을복원시키는데, AI와 trastuzumab 또는 lapatinib과병용하는것도전망이밝다. HER2 단백질의세포외부분인혈청 c-ecd 수치로 trastuzumab이나 lapatinib의효과를예측하지못하므로 ASCO 패널은종양표지자로사용하는것을추천하지않는다 19). 조기유방암에서는 HER2와 anthracyclin같은항암제효과가서로관련된다는보고들이있어 ASCO 지침에서는 HER2 양성인조기유방암에서 anthracycline의사용을추천하고있으나, 전이성유방암에서 HER2 상태와 anthracycline이나 taxane의효과와의관계는불명확하므로 HER2 과발현여부로항암제를선택하는것은추천되지않는다 19). 전망앞서언급한약제이외에도분자표적에기초한약제들이개발되어사용되거나임상연구중에있다. Bevacizumab은혈관내피세포성장인자와직접결합하는단일클론항체로신생혈관형성을방해하여종양성장을억제한다. 전이성유방암환자에서 paclitaxel 또는 docetaxel과의병합하면전체생존기간을향상시키지는못하지만반응률과진행까지의기간을향상시켜사용이허가되었다 39,40). 고혈압, 단백뇨, 혈전, 두통, 출혈등의부작용이관찰되지만, 효과를예측할수있는인자는밝혀지지않았다. 올해미국임상종양학회에서삼중음성또는 BRCA 돌연변이가있는유방암환자에서 poly ADP-ribose polymerase (PARP) 억제제가효과가있다는보고가있었고, 이외항HER2제 (pazopanib), trastuzumab-dm1, 비가역적인 EFGR계억제제 (HKI-272), mtor 억제제 (everolimus, temsirolimus), 다중표적치료제 (sunitinib, sorafenib, pazopanib), src 억제제 (dasatinib) 등이유방암환자를대상으로활

7 - 대한내과학회지 : 제 77 권제 1 호통권제 587 호 발히연구되고있어향후이들의결과가기대된다. 그러나아직도임상에서바로사용이가능한항암화학요법효과를예측할수있는지표는마땅치않다. 유전자발현에따른분자생물학적분류를통해임상적으로의미있는아형으로나눌수있으며 41), 이미조기유방암에서유전자발현양상에따라재발위험을예측하고치료방향을결정하는데이용되고있지만, 전이성유방암에서유전자발현과치료계획수립에대해서는앞으로많은연구가필요하다. 요 유방암은우리나라여성에서두번째로흔히발생하는암으로근치적치료후많은환자에서재발한다. 전이성유방암은비교적항암요법에반응이좋고중앙생존기간도약 2~3년으로길지만완치는어렵다. 현재임상에서사용되는전이성유방암의치료에는호르몬치료, 항HER2 요법및항암화학요법이있는데, 재발한환자의임상적상태와암의특성에따라각치료방법에대한반응을예측하고치료법의독성을고려함으로써, 치료의부작용은최소화하면서생존기간을향상시키고삶의질을향상시킬수있다. 호르몬수용체와 HER2 과발현여부는치료에대한반응예측에가장중요한인자로원발성유방암은물론전이암에서다시검사하는것이추천된다. 호르몬치료는부작용이적어호르몬수용체양성인환자에서일차치료로추천된다. 그간 tamoxifen 이호르몬치료의근간을이루었으나, 최근폐경후여성에서 3세대아로마타제억제제의우수성이입증되면서더선호되고있다. 호르몬치료에반응한환자는다음호르몬치료에반응할확률이높으며호르몬치료에반응하지않는환자, 호르몬수용체음성인환자와급격히진행하는전이성유방암에서는항암화학요법이추천된다. Trastuzumab 은전이성 HER2 양성환자의일차치료제로항암제와병용하는것이표준치료이며, lapatinib은 trastuzumab 치료에실패한환자에서효과가입증되어사용되고있다. 약 중심단어 : 유방암 ; 전이 ; 치료 ; 호르몬 ; HER2 REFERENCES 1) Wilkins EW, Jr., Head JM, Burke JF. Pulmonary resection for metastatic neoplasms in the lung. Experience at the Massachusetts General Hospital. Am J Surg 135: , ) Simmons C, Miller N, Geddie W, Gianfelice D, Oldfield M, Dranitsaris G, Clemons MJ. Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol, ) Beatson G. On the treatment of inoperable carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 2:104, ) Bloom ND, Tobin EH, Schreibman B, Degenshein GA. The role of progesterone receptors in the management of advanced breast cancer. Cancer 45: , ) Osborne CK, Yochmowitz MG, Knight WA, 3rd, McGuire WL. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46: , ) Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer 83: , ) Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: , ) Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi F, Bodrogi I, Ludwig H, Reichardt P, O Higgins N, Romieu G, Friederich P, Lassus M. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol 9: , ) Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 98: , ) Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, Bevers TB, Kavanah MT, Atkins JN, Margolese RG, Runowicz CD, James JM, Ford LG, Wolmark N. 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 97: , ) Mouridsen HT. Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women. Curr Med Res Opin 22: , ) Lenihan DJ, Esteva FJ. Multidisciplinary strategy for managing cardiovascular risks when treating patients with early breast cancer. Oncologist 13: ,

8 - 정경해. 진행성유방암의맞춤항암요법의최신지견 - 13) Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer 104: , ) Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 22: , ) Taylor CW, Green S, Dalton WS, Martino S, Rector D, Ingle JN, Robert NJ, Budd GT, Paradelo JC, Natale RB, Bearden JD, Mailliard JA, Osborne CK. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 16: , ) Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 19: , ) Liu Y, el-ashry D, Chen D, Ding IY, Kern FG. MCF-7 breast cancer cells overexpressing transfected c-erbb-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo. Breast Cancer Res Treat 34:97-117, ) De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G, D Agostino D, Caputo F, Cancello G, Montagna E, Malorni L, Zinno L, Lauria R, Bianco AR, De Placido S. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 11: , ) Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC, Jr. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25: , ) Smith CL, Nawaz Z, O Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 11: , ) Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25: , ) Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-her-2 therapy and personalized medicine. Oncologist 14: , ) Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF. American Society of Clinical Oncology/ College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25: , ) Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen LW, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 101: , ) Guarneri V, Giovannelli S, Ficarra G, Bettelli S, Maiorana A, Piacentini F, Barbieri E, Dieci MV, D Amico R, Jovic G, Conte P. Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management. Oncologist 13: , ) Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-her2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17: , ) Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2- overexpressing metastatic breast cancer. J Clin Oncol 20: , ) Dybdal N, Leiberman G, Anderson S, McCune B, Bajamonde A, Cohen RL, Mass RD, Sanders C, Press MF. Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res Treat 93:3-11, ) de Alava E, Ocana A, Abad M, Montero JC, Esparis-Ogando A, Rodriguez CA, Otero AP, Hernandez T, Cruz JJ, Pandiella A. Neuregulin expression modulates clinical response to trastuzumab in patients with metastatic breast cancer. J Clin Oncol 25: , ) Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol J Clin Oncol 26: ,

9 - The Korean Journal of Medicine: Vol. 77, No. 1, ) Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: , ) von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group study. J Clin Oncol 27: , ) Burstein HJ, Storniolo AM, Franco S, Forster J, Stein S, Rubin S, Salazar VM, Blackwell KL. A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2- negative advanced or metastatic breast cancer. Ann Oncol 19: , ) Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, Lombardi DP, Ben Ahmed S, Citrin DL, DeSilvio ML, Harris J, Westlund RE, Salazar V, Zaks TZ, Spector NL. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 26: , ) Crown JP, Burris HA, 3rd, Boyle F, Jones S, Koehler M, Newstat BO, Parikh R, Oliva C, Preston A, Byrne J, Chan S. Pooled analysis of diarrhea events in patients with cancer treated with lapatinib. Breast Cancer Res Treat 112: , ) Moy B, Goss PE. Lapatinib-associated toxicity and practical management recommendations. Oncologist 12: , ) Lin N, Dieras V, Paul D, Lossignol D, Christodoulou C, Laessig D, Roché H, Zembryki D, Oliva C, Winer E, Group ES. EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT). Journal of Clinical Oncology 25:1012, ) O Shaughnessy J, Blackwell KL, Burstein H, Storniolo AM, Sledge G, Baselga J, Koehler M, Laabs S, Florance A, Roychowdhury D. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol 26(May 20 suppl; abstr 1015), ) Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357: , ) Miles D, Chan A, Romieu G, Dirix L, Cortes J, Pivot X, Tomczak P, Taran T, Harbeck N, Steger G. Randomised, double-blind, placebo-controlled phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cnacer: AVADO J Clin Oncol 26:1008s, ) Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98: ,