Journal of Breast Cancer ISSN J Breast Cancer 2007; March 10 (1): 1-9 SPECIAL REPORT 2007 년 St. Gallen 유방암컨퍼런스하이라이트 김승일ㆍ박호용 1 연세대학교의과대학외과학교실

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1 Journal of Breast Cancer ISSN J Breast Cancer 27; March 1 (1): 1-9 SPECIAL REPORT 27 년 St. Gallen 유방암컨퍼런스하이라이트 김승일ㆍ박호용 1 연세대학교의과대학외과학교실, 경북대학교의과대학 1 외과학교실 Highlights of 1th St. Gallen Breast Cancer Conference: Systemic Adjuvant Treatment Seung-Il Kim, Ho-yong Park 1 Department of Surgery, Yonsei University College of Medicine, Seoul; 1 Department of Surgery, Kyungpook National University, College of Medicine, Daegu, Korea The 1th St. Gallen International Conference- Primary Therapy of Early Breast Cancer was held in March 27. The St. Gallen Conferences has focused on reaching expert consensus for patient treatment selection. Three categories were affirmed by responsiveness of endocrine treatment- endocrine responsive, endocrine responsive uncertain, endocrine non-responsive. Risk assessment will be similar than previous meeting (9th meeting) - low, intermediate, and high risk categories. The Panel recommended that patients be offered endocrine therapy or trastuzumab according to endocrine responsiveness or HER2 status. Chemotherapy offered to patients according to risk assessment. For patients with endocrine responsive and HER2 negative, selection of patient for chemotherapy is major challenge. The Panel of Expert attempted to answer many questions- endocrine therapy, chemotherapy, anti-her2 therapy, and radiation therapy. This report focused on new information related to the best use of endocrine therapy and chemotherapy. (J Breast Cancer 27;1:1-9) Key Words : St. Gallen conference 27, Endocrine therapy, Chemotherapy 중심단어 : St. Gallen 컨퍼런스 27, 호르몬치료, 항암치료 서 27년 3월 14 일부터 17일까지스위스의아름다운도시 St. Gallen에서 Primary Therapy of Early Breast Cancer- 1th International Conference 가개최되었다. 이번회의는 1 개분과에서총 42 개의주제발표가있었으며, 학회마지막날에는유방암치료와관련된여러이슈에대해각분야전문가들로구성된패널토의와투표가진행되었다. 그밖에총 9개의특별심포지엄과 185 개포스터발표가있었다. 논의된주제들은유방암의생물학, 진단, 추적검사, 수술및방사선치료, 호르몬요법, 항암요법, 표적치료등유방암치료와관련된거의전분야가논 책임저자 : 박호용 대구광역시중구삼덕동 2 가 5, 경북대학교의과대학외과 Tel: , Fax: phy123@mail.knu.ac.kr 론 의되었다. 본문헌은논의된주제중유방암의호르몬요법및항암요법에주로국한하여, 27 St. Gallen Conference 내용을정리하여보고하고자한다. 본론 1. 치료선택- 호르몬치료, 항암치료및표적치료유방암의전신치료는호르몬치료, 항암치료및최근에부각되고있는표적치료로구분할수있다. 타목시펜은가장오랜경험을갖고있는호르몬치료제로종양에서호르몬수용체가발현되는경우에만유효한이점이있어, 사실상최초의표적치료제로인정되고있다. 이에비해항암치료의경우치료대상환자선정이나약제선택과정에있어현재까지해결해야하는과제가많이남아있다. Trastuzumab은약제의개발단계에서부터임상시험과정에이르기까지종양의특정생물학적표적을대상으로하였으 1

2 2 Seug-Il Kim, et al. 며, 현대종양학에서표적치료도입의시금석이라할수있다. 25년 St. Gallen Conference에서는유방암환자의전신치료선택에있어최초로표적 ( 호르몬수용체발현여부 ) 을먼저고려하고, 이후위험도를분류하는방식을제안하였다.(1) 즉호르몬치료반응군과비반응군을먼저정의한후, 각각의군에서저위험도, 중등도위험도, 고위험도군을분류하였고, 이에따른전신보조요법선택사항을정리하였다. 이번 27년회의에서도다양한분자생물학적인자들이논의되었으나, 치료선택이나위험도분류기준에추가될만한새로운예후및예측인자는없어보인다. 또한전신보조요법선택가이드라인도 25년에비해큰변화를없을것으로보인다. 다만 25년회의부터위험도분류기준으로새롭게인정된 HER2 발현시 trastuzumab이표준치료로포함될것으로보인다 (Table 1). 특히이번회의에서 HER2 발현은호르몬수용체발현여부와함께전신치료선택에중요한판단기준으로, 2 2 marker model 이제안되었다 (Table 2). 이에따르면호르몬수용체양성인경우호르몬치료를, HER2 양성인경우 trastuzumab이표준치료로인정되며, 모두양성인경우에는두가지전신치료의대상이된다. 항암치료는위험도및호르몬수용체발현정도에따라선택된다. 이때항암치료의적절한대상을선택하는문제가중요한과제로지적되었다. 특히호르몬수용체양성이면서 HER2 음성환자중호르몬치료만으로충분한환자군을선별하는것이향후규명되어야할중요한과제로판단된다 (Table 2). St. Gallen Conference는그동안유방암환자에서전신보조요법의적절한선택기준을제안하여왔다. 25년회의이전에는모든예후및예측인자를기준으로위험도를먼저분류하고이에따른전신치료방법을선택하였다면, 25년및 27년회 Table 1. Choice of adjuvant treatments for breast cancer patients Risk category Endocrine responsive Endocrine response uncertain Endocrine nonresponsive Low risk ET ET Not applicable Nil Nil Intermediate risk ET alone, or CT ET CT CT ET (CT+ET)* (CT+ET)* Trastuzumab Trastuzumab Trastuzumab High risk CT ET CT ET CT (CT+ET)* (CT+ET)* Trastuzumab Trastuzumab *: No data exist to dictate sequential or concurrent use of chemotherapy with aromatase inhibitors or ovarian function suppression/ablation; : Trastuzumab should be added whose tumors show overexpression or amplification of HER2. ET=endocrine therapy; CT=chemotherapy. 의를거치면서치료선택시표적 ( 호르몬수용체, HER2) 을첫번째로고려하는치료개념의변화가있다고볼수있다. 이러한변화를근거로이번 27년회의에참석한많은전문가들은향후종양을분자생물학적으로규명하는연구성과가더욱축적되면서, 21년이후에는개별종양의분자생물학적특징에따른효과적인맞춤치료의시대가열릴것으로예측하였다. 2. 호르몬치료 1) 폐경후여성에서호르몬치료 폐경후여성에서호르몬치료전략은타목시펜을포함한 SERM (Selective Estrogen Receptor Modulator), Estrogen Receptor Down-regulator, 그리고아로마타제억제제 (Aromatase Inhibitor, AI) 등으로분류할수있다. 이중 AI 의치료효과에대한여러임상연구결과가최근 2-3 년사이에발표되었으며, 이번 27년회의에서그결과가인용되었다. 현재까지 AI 사용시가장이상적인제재, 치료도입시기, 치료기간, 치료대상, 다른전신치료와의병합요법등에있어의문점이있지만, 많은임상연구결과폐경후여성에서타목시펜 5년단독사용군보다우수한치료효과가입증되었다. 폐경후여성에서 AI 사용전략은처음부터타목시펜을대체하는방법 (initial protocol), 타목시펜 2-3 년사용후 AI 로전환 (switch protocol), 타목시펜 5년사용후 AI 5년추가사용 (extended protocol) 등으로분류할수있다 (Fig 1). AI에대한임상연구결과를 Table 3에요약하였다. 처음부터타목시펜대신 AI 를투여하는전략은 ATAC trial 및 BIG 1-98 trial에서타목시펜 5년단독투여군보다 AI 투여군의무병생존율 (disease free survival) 이유의하게증가함을보고하였다 (ATAC trial; hazard ratio=.83, CI= , p=.5, BIG 1-98;.82, , p=.7).(2, 3) 그러나두임상연구모두양군간생존율 (overall survival) 의유의한차이는없었다. 타목시펜 2-3년사용후 AI 로전환한환자군과타목시펜단독사용군을비교한임상실험은 ABCSG 8/ARNO 95 trial, ITA trial, IES trial 등의결과가보고되었다. 모든임상시험에서 AI 로전환한환자군에서타목시펜단독사용군보다무병생존율이유의하게증가하였다 (ABCSG Table 2. Adjuvant treatment for 2 2 marker model of breast cancer - St. Gallen Conference 27 ER positive HER2 positive Trastuzumab Trastruzumab Chemotherapy Chemotherapy Endocrine Therapy HER2 negative Endocrine Therapy Chemotherapy ±Chemotherapy* *: Selection of patient is major challenge. ER negative

3 Highlight of 27 St. Gallen Conference 3 8/ARNO 95 trial; HR.6, CI , p=.9, ITA trial; HR.35, CI , p=.1, IES trial; HR.75, CI , p=.1).(4-6) ABCSG 8/ARNO 95 trial 및 ITA trial의경우양군간생존율의유의한차이는없었으나, IES trial에서는 AI 사용군에서생존율의유의한증가를보고하였다 (HR.83, CI.69-1., p=.5). Initial protocol 및 switch protocol에의한임상연구결과에따라폐경후여성에서처음부터타목시펜을대체하거나, 타목시펜 2-3 년사용후 AI 로전환하는방법의우수성이입증되었다. 세번째전략은타목시펜 5년치료가끝난환자에서 AI 5년연장사용군과더이상호르몬치료를하지않은대조군을비교한연구로, MA 17, NSABP B-33, ABCSG 6a 등의임상연구결과가보고되었다. 이번회의에서 MA 17 결과가많이인용되었는데, 타목시펜 5년사용후추가로 letrozole를사용한환자군에서유의하게무병생존율이증가하였다 (HR.58, CI , Initial trials Switch trials Extended trials *ATAC BIG 1.98 ABCSG 8/ ARNO & ITA IEA MA 17 Letrozole Anastrozole Letrozole Letrozole Anastrozole Exemestane Letrozole Placebo Fig 1. Trial types of adjuvant aromatase inhibitors. *: Combination arm was closed; : Analysis was limited to patients on two monotherapy arms; : Combined results of ABCSG trial 8 and ARNO 95 trial; : Study was unblinded to placebo arm on 3 month from randomization. p<.1).(7) 한편 MA 17 임상연구결과가 23년최초로보고될당시에는양군간생존율의차이는없었으나, 25년보고에서는액와림프절전이환자에서 AI 사용군의유의한생존율향상이입증되었다 (HR.61, CI , p=.4). MA 17 임상연구의성공적결과를근거로타목시펜표준치료가종료된환자에서 letrozole처방이고려되어야하겠다. AI 에대한이상의임상시험결과에근거하여현재폐경후여성에서타목시펜 5년처방은더이상표준치료가아니며, AI의처방이반드시고려되어야한다. 한편 MA 17 trial은임상시험진행과정에서 letrozole 추가투여군의무병생존율이추가치료를받지않은대조군 (placebo 군 ) 에비해유의하게증가하는결과를보임에따라, 무작위임상시험시작후 3 개월에위약 (placebo) 투여군환자에게 letrozole 투약기회를제공하였다. 이결과 MA 17 trial에서타목시펜 5년투여후 2-3년간위약만복용한환자중일부가 letrozole 투약을시작하였고, 마지막까지 letrozole 투약을받지않은환자군과치료성적을비교분석 (MA 17 post-unblinding analysis) 하여, 26년 ASCO 및 27년 St. Gallen Conference에서보고되었다. 이결과타목시펜 5년투약후 2-3 년간호르몬치료를하지않은환자군에서 letrozole 추가투여시무병생존율및생존율이유의하게증가한다고보고하였다 (Fig 2). MA 17 post-unblining analysis 결과는아직까지문헌으로출판되지는않았으나, 타목시펜 5년투여후 2-3 년간호르몬치료를받은환자에서 letrozole 처방이고려되어야하겠다. AI 가타목시펜에비해유의하게우수한치료결과를보이고있지만, 현재까지가장이상적인투여시기, 약제선택, 투여기간등에대해서는알수없다. 특히 AI 처방시작시점에대해지금까지의임상연구결과로는세가지전략의직접비교가불가능하다. 이번회의에서도서로다른주장이대립하였는데, extended protocol의우수성을주장하는그룹에서는타목시펜 5년사용후 AI 5년추가사용의효과가분명히입증되었으며, 현재까지임상연구결과들을비교해볼때, 재발등의위험도감소정도를나타내 Table 3. Efficacy of adjuvant aromatase inhibitors Protocol types Trials Duration Drugs Median F/U (mos) Patients (n) HR for DFS* (95% CI) p Initial protocol ATAC Anastrozole 68 6, ( ).5 BIG Letrozole 51 4, ( ).7 Switch protocol ABCSG 8/ARNO Anastrozole 28 3,224.6 ( ).9 ITA Anastrozole ( ).1 IES Exemestane ( ).1 Extended protocol MA Letrozole 3 5, ( ) <.1 *Definition of disease free survival; ATAC: local & distant recurrence, new primary breast cancer, death from any cause; BIG 1-98: local, regional & distant recurrence, contralateral breast cancer, second non-breast cancer, death before recurrence; ABCSG/ARNO: local & distant recurrence, contralateral breast cancer; ITA: local, regional & distant recurrence; IES: local & distant recurrence, new primary breast cancer, death without recurrence; MA 17: breast, chest wall & nodal recurrence, metastases, contralateral breast cancer.

4 4 Seug-Il Kim, et al. 는 hazard ratio가 extended protocol에서가장우수하다는점을근거로주장한다 (Table 3). 이에비해폐경후여성에서호르몬치료가결정되었다면, 가능한일찍 AI 치료가시작되는것이가장좋다는주장도있다. 이들은임상시험결과의 hazard ratio 를직접비교할경우오류가발생할수있으며, 더나아가통계적계산모델을이용하여일찍 AI 를사용하는것이 switch protocol 이나, extended protocol보다향상우수한결과를보인다고주 장하였다 (Fig 3).(8) 현재까지이주제와관련한정확한결론을내릴수는없다. 이상적인 AI 의치료시작시점뿐만아니라, 이상적치료기간에대해서도현재까지정확한결론은없다. AI 치료기 N= years Risk Reduction vs No Treatment (%) MA.17 Late Extended Adjuvant Therapy: Post-Unblinding Analysis-Design and Patients Letrozole n=2593 Letrozole n=2457 Placebo n=2594 (1-6 y) -3 mo Median F/U (mo) 3 Unblinding 54 Post-unblinding anaysis Observation n=613 Letrozole n=1655 MA.17 Late Extended Adjuvant Therapy: Significant Risk Reduction Across Endpoints Risk of Breast Cancer Recurrence DFS p<.1-69% (HR.31) Risk of Distant Breast Cancer Recurrence DDFS p=.2-72% (HR.28) Risk of Death -47% (HR.53) Update of Goss et al. Breast Cancer Res Treat. 25;94 (Suppl 1):S1. Abstract 16. Update of Robert et al. J Clin Oncol. 26;24(18S):15a. Abstract 55. Risk of Contralateral Breast Cancer Recurrence -77% (HR.23) Fig 2. (A) MA 17 Post-Unblinding Cohorts, (B) Late extended adjuvant therapy- significant risk reduction across endpoint. (A, B: Presented by Dr. Goss et al. 26 ASCO, 27 St. Gallen Conference). OS CBC p=.12 A B 간과관련하여 NSABP B-42, SALSA trial (Secondary Adjuvant Long Term Study with Arimidex) 등이진행중이며, AI 제재를직접비교하는 MA 27 trial (exemestane vs. anastrozole) 및 FACE trial (anastrozole vs. letrozole) 과같은임상연구가진행중이다 (Fig 4). 또한 AI의이상적인투여대상선정, AI 와다른전신치료제재, 특히다른표적치료제등과이상적인병합투여방법등에대한연구필요성이제안되었다. 2. 폐경전여성에서의호르몬치료 폐경전여성에서타목시펜 5년투여효과는 Early Breast Cancer Trialists Collaborative Group (EBCTCG) 의최근보고에서유용성이다시입증되었다.(9) 타목시펜 5년투여의효과는나이에상관없이유효하며, 4-49세, 4 세이하모든폐경전연령군에서유의하게재발률및사망률을감소시켰다. 이번회의에서도 EBCTCG의중재분석 (meta-analysis) 결과가인용되었고, 이와같은타목시펜효과에대한장기적인경험을근거로현재까지폐경전여성에서타목시펜 5년투여는표준호르몬치료로인정되고있다. 한편 EBCTCG은약 8,명의 5세이하유방암환자에서난소기능억제 ( 수술, 약제, 방사선조사법등 ) 에따른효과에대한중재분석은약 3% 내외의재발률 (p=.1) 및사망률 (p=.4) 감소를보여주었다.(9) 폐경전여성에서난소기능억제가효과적이라는사실은 EBCTCG의이전보고에서도밝혀진바있다. 폐 Recurrence (%) year s tam 3 year s AI after 2 years tam 5 year s AI 5 year s AI after 5 years tam Follow-up time (years) Fig 3. Recurrence in the first 1 yr of follow up. (Presented by Dr. Cuzick, St. Gallen 27, Br J Cancer 26;94:46-4). Treatment duration trial Treatment duration trial Exemestane vs. Anastozole Letrozole vs. Anastozole AI 5 yr TAM AI 2-3 yr 3-2 yr Letrozole 5 yr Placebo A AI 5 yr TAM AI 2-3 yr 3-2 yr Anastrozole 5 yr Anastrozole 2 yr B Surgery for Primary breast cancer Exemestane 5 yr Anastrozole 5 yr C Surgery for Primary breast cancer Letrozole 5 yr Anastrozole 5 yr D Fig 4. Aromatase inhibitors- ongoning trials.

5 Highlight of 27 St. Gallen Conference 5 경전여성에서치료효과가밝혀진난소기능억제와항암치료의효과를서로비교하는임상연구가 199년대초부터시작되었는데 (ZEBRA, IBCSG VIII, ABCSG 5 등 ), 이들연구는폐경전, 호르몬수용체양성환자에서두치료의효과가비슷하거나 (ZEB- RA, IBCSG VIII), 오히려난소기능억제를포함한호르몬치료가우수한 (ABCSG 5) 결과를보고하였다.(1-12) 이번회의에서도 Dr. Cuzick 등이 26년 SABCS에서발표한중재분석결과, 즉폐경전여성에서난소기능억제가항암치료와유사한효과를보인다는결과가인용되었다 (Data not shown). 물론앞에서언급한임상연구는항암치료군에서사용된항암제가대부분 CMF 이며, 특히타목시펜이적절히투여되지않아, 현재의항암치료군에서시행되는표준치료 항암제 + 타목시펜 군과비교가불가능하다는단점이있다. 그러나폐경전여성중특정그룹환자에서는난소기능억제가항암치료효과와동일하며, 이러한환자군에서는난소기능억제를포함한호르몬치료가항암치료를대체할수있을것으로보인다. 그러나현재까지이러한환자군을정확히정의하지못하고있으며, 이번회의에서도이주제와관련한추가적인연구의필요성이강조되었다. 폐경전여성에서난소기능억제의효과가알려지면서, 항암치료와난소기능억제의병합요법에대한연구가진행되었다. 먼저 EBCTCG의최근중재분석결과는항암치료에난소기능억제치료를병합하여도추가적인이익이없다고보고하였다.(9) 그러나중재분석대상환자의호르몬수용체상태가일정치않고, 또한항암제로인한폐경여부가조사되지않아, 환자군이불균일하여치료효과를희석시켰을가능성을배제할수없다. 그밖에항암치료에난소기능억제추가시효과를규명하고자하는전향적임상연구는 IBCSG VIII, ECOG/SWOG INT 11, ZIPP trial 등이 있으며최근에그결과가보고되었다. IBCSG VIII의경우항암치료단독군과 항암치료 + 고세레린 (goserelin) 군사이에치료성적에차이가없다고보고하였으나, ER 양성인 4 세이하에서는고세레린추가치료환자군에서무병생존율이유의하게증가하였다고보고하였고,(11) ECOG/SWOG INT 11에서는항암제단독투여군, 항암제 + 고세레린 군, 항암제 + 고세레린 + 타목시펜 군등을비교하여, 이중 항암제 + 고세레린 + 타목시펜 군의성적이가장우수하고, 4 세이하에서는항암제단독군보다, 항암치료후고세레린을추가하는경우무병생존율이유의하게증가함을보고하였다.(13) ZIPP trial의경우표준치료 (± 항암치료, ± 방사선치료 ) 후고세레린추가치료가무병생존율및생존율을증가시킨다고보고하였으나, 항암치료가선행된경우에는고세레린투여에따른추가적인이득이없었다.(14) 이상의결과들을종합하여볼때항암치료에난소기능억제치료를추가하는것이폐경전일부환자에서추가적인이익이있을가능성을시사하지만, 현재까지표준치료로인정하기에는임상연구결과가충분치않다고판단된다. 이주제와관련하여 26년 SABCS에서 Dr. Cuzick 등이황체호르몬분비자극호르몬작용제 (LHRH agonist) 를사용한 13 개임상시험을중재분석하여보고하였고, 이결과가이번 St. Gallen Conference에서다시인용되었다. 아직문헌으로출판되지않았으나발표된결과의일부를인용하면, 항암치료이후 LHRH agonist를투여한 3,37명을분석한결과, 재발률 (HR.88, CI , p=.4) 및사망률 (HR.85, CI , p=.4) 모두에서추가적인이점이있다고보고하였다 (Fig 5). 이상의결과를종합하여볼때, 폐경전여성에서타목시펜 5년사용은표준호르몬치료이며, 폐경전특정그룹의여성에서난 5 Recurrence 5 Death after Recurrence 4 3 Chemotherapy±tamoxifen LHRH addition HR=.88, 95% CI=( ), p= Chemotherapy±tamoxifen LHRH addition HR=.85, 95% CI=( ), p=.4 % % vs. 24.% 5.4% reduction % % vs. 11.3% 1.8% reduction Years since randomisation Years since randomisation Fig 5. The impact of LHRH addition to chemotherapy on breast cancer recurrence and mortality: an overview of the randomized trials. (Presented by Cuzick et al. SABCS 26 & Presented by Davidson. St. Gallen Conference 27).

6 6 Seug-Il Kim, et al. 소기능억제를포함한호르몬치료는항암치료와동일한효과가있고, 항암치료후난소기능을추가로억제하는것은현재까지연구결과가충분치않지만이번회의에서보고된중재분석결과그가능성이보인다고할수있다. 한편폐경전여성에서 AI 단독사용은인정되지않으나, 폐경후여성에서얻은경험을바탕으로난소기능억제와병합사용시효과에대한연구가진행되고있다. 위에서언급한문제들에관심을갖고기획된몇몇임상연구가현재진행되고있으며, 대표적인연구가 SOFT (Suppression of Ovarian Function Trial), TEXT ( and Exemestane Trial), PERCHE (Premenopausal Endocrine Response Chemotherapy Trial) 등이다 (Fig 6). 이들임상연구의초기결과가보고되는약 2-3 년후에는폐경전여성의호르몬치료에대한몇몇의문점이해결될것으로기대한다. 3. 항암및표적치료 1) 항암치료선택여부- MammaPrint, Oncotype DX TM 및 Adjuvant online 이번회의에서처음논의된사항은아니지만, 주제발표에서여러번인용되어기술하고자한다. 먼저 MammaPrint 는 DNA microarray 기술을도입하여환자를저위험군과고위험군으로분류할수있다.(15) 약 4% 의환자들이저위험군에속하게되는데, 이들은 96% 의생존율을보여서항암제사용이불필요하다고보고하였다. Oncotype DX TM 는 RT-PCR을통해 16개의암관련유전자 (cancer related gene) 와 5개의참조유전자 (reference gene) 의발현을검사한후에수식으로계산하여환자군을분류하였다.(16, 17) 유방암병기 1기및 2기의환자들중림프절전이가음성이고, 호르몬수용체양성으로서타목시펜을사용하게될환자들을대상으로하였다. RS (Recurrence Score) 가 18 이하면저위험군, 18-3이면중등도위험군, 31 이상이면고위험군으로분류하여 1 년재발위험이각각 6.8%, 14.3%, 3.5% 였다. 이들중저위험군에해당하는환자는항암치료를제외하여도되며고위험군의환자는항암치료를하는것이좋다. 마지막예후예측프로그램은인터넷상에서쉽게이용할수있는 Adjuvant Online이다. 인터넷을통하여환자의나이, 호르몬수용체유무, 조직학적분화도, 유방암의크기및림프절전이유무를입력하면환자의재발위험도를보여준다. 이재발위험률은 1 년위험도이기에이를바탕으로호르몬요법, 항암요법및병용요법을했을때의재발위험도감소효과를각각보여준다. 의사는이를바탕으로환자와이러한치료들로부터얻을수있는장점과단점을상담할수있다 ( 그러나항암요법을선택할수있는이러한새로운방법을유방암치료하는임상에서직접사용할것인가에대한물음에 6% 의의사들은아직사용하지는않을것이고, 9% 정도가여전히림프절전이나 St. Gallen 위험인자그룹을이용하겠다고답하였다. 2) Anthracycline과 Taxanes을이용한 3세대항암요법 CMF와 anthracycline을이용한 1세대항암제, taxanes을이용한 2세대항암제, 그리고 anthracycline과 taxanes 계열의항암제를이용하여 combination 또는 sequential therapy, dose dense therapy 등을포함하는 3세대항암요법이연구되고있다. St. Gallen Conference에서는이러한 3세대항암요법에대한분석을보여주었다 (Fig 7).(18, 19) 먼저 Breast Cancer International Research Group (BCI- RG) 1 trial에서는 docetaxel, doxorubicin, and cyclophosphamide (TAC) 을이용한항암요법을기존의 fluorouracil, doxorubicin, and cyclophosphamide (FAC) 과비교하였다. 모두 1,491명의림프절양성유방암환자였으며 55 개월의비교연구에서무병생존율에있어서 TAC 의 hazard ratio가 FAC에비하여.72 (p=.1), 전체생존율에있어서.7 (p=.8) 으로 TAC 항암요법이우수한것으로나타났다.(2) SOFT (IBCSG 24-2, BIG 2-2) Any chemotherapy (remain premenopausal after OFS+ 5 yr chemotherapy) or OFS+Exemestane 5 yr No chmotherapy TEXT (IBCSG 25-2, BIG 3-2) GnRH analong from start of adjuvant therapy (with or without chemotherapy) GnRH+ 5 yr± Chemotherapy GnRH+Exemestane 5 yr ±Chemotherapy CMF AC*4 AD*4 FEC AC*4 P*4 (CALGB 9344) (NSABP B28) AC*4 D*4 (NSABP B27) DC*4 (US Oncology 9735) FE1C (FASG 5) AC*4 P*4 (q2w) (CALGB 9741) FE1C*3 D*3 (PACS 1) PERCHE (IBCSG 26-2, BIG 4-2) Ovarian function suppression from start of adjuvant therapy OFS+/Exemestane 5 yr OFS+Chemotherapy+/ Exemestane 5 yr FAC DAC (TAC) (BCIRG 1) Fig 6. Ongoing trials testing endocrine therapy for premenopausal women. Fig 7. Adjuvant taxane therapy for women with early-stage, invasive breast cancer.

7 Highlight of 27 St. Gallen Conference 7 PACS 1 연구는 1,999명의 65세이하의림프절양성인환자를대상으로하여기존 3주기의 FEC 1 항암요법후 docetaxel 1 mg/m 2 을 3주간격으로 3주기추가한 sequential therapy 가기존의 FEC 1 을 6주기사용한환자군보다무병생존율과전체생존율에서더좋은결과를보여주었다.(21, 22) 기존의 3주간격의항암요법에서 2주간격으로, G-CSF와함께치료하는 dose dense therapy가소개되었다. CALGB trial 9741는림프절양성인 1,973명의유방암환자를대상으로기존의 3주간격의 4주기의 AC therapy (adriamycin 6 mg/m 2 + cyclophosphamide 6 mg/m 2 ) 와 4주기의 paclitaxel (Taxol ) 을 2주간격으로 G-CSF와함께 AC T dose-dense therapy를비교한연구에서 2주간격의 dose dense therapy 가통계적으로유의하게무병생존율 (hazard ratio=.74, p=.1) 과전체생존율 (hazard ratio=.69, p=.13) 에서좋은결과를보여주었다. G-CSF를함께사용하였을때심각한중성구감소증 (neutropenia) 은보이지않았다.(23-26) U.S. Oncology (USON) 9735 trial 연구에서는 4주기의 3주간격의 DC therapy (docetaxel 75 mg/m 2 +cyclophophamide 6 mg/m 2 ) 가기존의 4주기의 3주간격의 AC therapy 보다무병생존율 (HR=.67, p=.15) 이좋았으나전체생존율은차이가없었다 (HR=.76, p=.131).(27-29) 이러한 3세대의 anthracycline과 taxanes을이용한다양한항암요법이임상연구에서좋은결과를보여주었음에도 27 St. Gallen Conference에서참가자들의투표결과는 8% 이상이아직은표준치료로사용하지않겠다고하였고, 여전히 6주기의 CAF (CEF) 와 FAC (FEC) 같은기존의항암요법을 62% 가선호한다고하였다. 3) 항암요법과 trastuzumab 의병용치료 HER2 과발현전이유방암에서항암요법및 trastuzumab 의 병용치료가생존율을향상시킴으로써 HER2 과발현조기유방암에서수술후보조적인항암요법및 trastuzumab 병용치료를연구하는대규모임상연구가진행되었다 (Fig 8).(3) NSABP B31과 North Central Cancer Treatment Group (NCCTG) N9831 연구는수술후보조임상연구에서 doxorubicin-based chemotherapy와 paclitaxel (AC T) 을순차적으로투여한환자군과 AC T에 trastuzumab을 paclitaxel과병용치료하는군을비교한연구에서 2년추적관찰에서 trastuzumab을 paclitaxel과함께치료한환자군이 56% 재발감소효과를보여주었다. Herceptin Adjuvant (HERA) trial에서는기존의수술후항암치료를마친환자를대상으로대조군, 1년간또는 2년간의 trastuzumab치료를한결과 46-47% 의재발감소효과를보여주었다. BCIRG 6 연구는 AC T (docetaxel) 환자군, AC T+ trastuzumab 그리고 docetaxel, carboplatin (Paraplatin, Bristol-Myers Squibb), trastuzumab (TCH) 항암요법을비교하였는데 4년간의 DFS 이각각 73%, 84% 그리고 8% 였다. AC T+trastuzumab군이가장좋은재발감소를보였으며, 심장독성은각군에서비슷한양상을보였다. 27 St. Gallen Conference의마지막하이라이트는 HER2 HERA NSABP-B-31/N9831 AC TH BCIRG 6 AC DH BCIRG 6 DCH Fin HER VH/DH CEF Fig 8. Adjuvant trastuzumab trials. Table 4. Top ten breast cancer research questions by expert voting- St. Gallen Conference 27 Median follow-up Two years Two years Three years Three years Three years 1 2 Favors trastuzumab HR Favors no trastuzumab Question Point 1. Identification of molecular signatures to select patients who could be spared chemotherapy Identify molecular features which indicate the optimal chemotherapy regimen (combination or sequential, anthracyclin or not, 45 taxane or not) 3. Determine the factors in DCIS and or ADH leading to progression into invasive carcinoma Determine the role of stem cell in breast cancer development, progression and treatment sensitivity Identify response resistance mechanism and thereby therapeutic targets for triple negative breast cancer Develop a system (computer etc) that will integrate all the information so far gathered about breast cancer to build robust models 35 for understanding the aetiopathogenesis, treatment and prognosis of breast cancer 7. Identifying which low risk patients require NO adjuvant therapy Determine if other growth factor pathway are important targets for therapy such as EGFR, IGFR, Notch, Hedgehog, Wnt and 287 other angiogenic pathways 9. Investigate which gene mutations in a cancer lead to metastases Identify drugable targets that can be developed/exploited for therapeutic gain to overcome primary/secondary endocrine resistance 226

8 8 Seug-Il Kim, et al. 과발현환자에서 trastuzumab을사용할것인가의질문에 63.9% 가찬성을하였고, 항암제와도함께사용하는것에 64.1% 가찬성하였다. 기존의예후인자를확인하는방법들의사용여부와 3세대항암요법의사용여부에서 65% 정도가반대하는것과는대조적이었다. 현재는 lapatinib (EGFR and HER2 inhibitor) 을이용한 ALTTO, 수술전항암요법에추가하여 trastuzumab, lapatinib 그리고병용요법의효과를알아보기위한 Neo-ALTTO 등의새로운표적치료제에관한연구가진행중이다. VEGF 억제제인 Avastin 등의표적치료제를기존의항암요법과병용하는연구도진행중이며이러한연구가끝나면곧임상에사용되리라본다. 결론 27 St. Gallen Conference 내용중전신보조요법-호르몬치료, 항암치료및표적치료에대한내용을정리하였다. 전신보조요법의선택에대한 St. Gallen Conference의권장사항은여러치료가이드라인중하나로, 임상에서개별환자의특성을충분히고려하여결정되어야할것이다. 끝으로이번회의에서향후유방암연구를위해서가장중요하다고생각되는연구주제에대한제안이있어소개하고자한다. St. Gallen Conference와 San Antonio Breast Cancer Symposium에제출된 4개의연구주제중에서 7 여가지를정리한후에유방암연구를위한전문가들 (43명) 에게보내어약 2,4번의투표를거치고난뒤에상위 1 개의질문을정리하였다. 가장중요한주제는유방암 1 기및 2기에서항암제를사용하지않아도되는환자군을선택해내는것이었고, 기존의 anthracycline 및 taxanes을이용하여효과적인항암제의조합을구하는것이두번째였다 (Table 4). 유방암치료에있어이러한여러과제를해결하기위한지속적인임상및중재적연구가필요할것으로생각된다. 참고문헌 1. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ, et al. Meeting highlight: International expert consensus on the primary therapy oh early breast cancer 25. Ann Oncol 25;16: ATAC Trialists Group. Results of the ATAC (Arimidex,, Alone or in Combination) trial after completion of 5 years adjuvant treatment for breast cancer. Lancet 25;365: 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 endocrineresponsive early breast cancer: update of study BIG J Clin Oncol 27;25: Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 25;366: Boccardo F, Rubagotti A, Puntoni M, Guglielmini P, Amoroso D, Fini A, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Anastrozole Trial. J Clin Oncol 25;23: Coombes RC, Kilburn LS, Snowdon CF, Paridaens, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 27;369: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 25;97: Cuzick J, Sasieni P, Howell A. Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen? Br J Cancer 26;94: 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 25;365: Kaufmann M, Jonat W, Blamey R, Cuzick J, Namer M, Fogelman I, et al. Survival analyses from the ZEBRA study. goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer. Eur J Cancer 23;39: International Breast Cancer Study Group (IBCSG). Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 23;95: Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 22;2:

9 Highlight of 27 St. Gallen Conference Davidson NE, O Neill AM, Vukov AM, Osborne CK, Martino S, White DR, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node- positive, steroid hormone receptor-positive breast cancer: Results From INT 11 (E5188). J Clin Oncol 25; 23: Baum M, Hackshaw A, Houghton J, Rutqvist, Fornander T, Nordenskjold B, et al. Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. Eur J Cancer 26; 42: Buyse M, Loi S, van t Veer L, Viale G, Delorenzi M, Glas AM, et al. Validation and clinical utility of a 7-gene prognostic signature for women with node-negative breast cancer. J Natl Cancen Inst 26; 98: Paik S, Tang G, Shak S. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 26;24: Kaklamani V. A genetic signature can predict prognosis and response to therapy in breast cancer: Oncotype DX. Expert Rev Mol Diagn 26;6: Trudeau M, Charbonneau F, Gelmon K, Laing K, Latreille J, Mackey J, et al. Selection of adjuvant chemotherapy for treatment of nodepositive breast cancer. Lancet Oncol 25;6: Verma S, Trudeau M, Dranitsaris G, Clemons M, Joy AA, MacKey JR. What is the best chemotherapy treatment option for anthracycline and taxane pretreated metastatic breast cancer? J Clin Oncol 25;23: Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, et al. Adjuvant docetaxel for node-positive breast cancer. New Engl J Med 25;352: Campone M, Fumoleau P, Bourbouloux E, Kerbrat P, Roche H. Taxanes in adjuvant breast cancer setting: which standard in Europe? Crit Rev Oncol Hematol 25;55: 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 1 Trial. J Clin Oncol 26;24: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial J Clin Oncol 23;21: Hudis C. The best use of adjuvant chemotherapy: new drugs and new use of old drugs. Breast 25;14: Hudis CA, Winer EP. Cancer and leukemia group B breast committee: decades of progress and plans for the future. Clin Cancer Res 26; 12: Moore HC, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE, et al. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study J Clin Oncol 27;25: Holmes FA, Jones SE, O Shaughnessy J, Vukelja S, George T, Savin M, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol 22;13: Jones SE, Clark G, Koleszar S, Ethington G, Mennel R, Paulson S, et al. Adjuvant chemotherapy with doxorubicin and cyclophosphamide in women with rapidly proliferating node-negative breast cancer. Clin Breast Cancer 22;3: Jones SE, Savin MA, Holmes FA, O Shaughnessy JA, Blum JL, Vukelja S, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 26;24: Gluck S. Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin. Oncologist 25;1:78-91.