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1 액와림프절전이가없는유방암에서 c-erbb-2 단백과 p53 변이단백 발현의의의 연세대학교대학원 의학과 고승상

2 액와림프절전이가없는유방암에서 c-erbb-2 단백과 p53 변이단백 발현의의의 지도박병우교수 이논문을석사학위논문으로제출함 2004 년 6 월일 연세대학교대학원 의학과 고승상

3 고승상의석사학위논문을인준함 심사위원박병우인 심사위원양우익인 심사위원서창옥인 연세대학교대학원 2004 년 6 월일

4 감사의글 미흡한이논문을완성하기까지많은지도편달을해주신박병우선생님께진심으로감사드리며, 자문과심사진행과정에서많은도움을주신양우익선생님과서창옥선생님께감사드립니다. 그리고조직배열슬라이드제작과판독을위해많은시간을할애하여도와주신전이경선생님, 박지영선생님께각별한감사를드립니다. 바쁜병원일과중에서도저에게항상관심을기울여주신이지현선생님께도감사드립니다. 항상묵묵히저를믿고지켜봐주신존경하는아버님과장인어른께감사드리며, 많은걱정을하셨음에도불구하고언제나용기를주셨던사랑하는어머님과장모님께감사드립니다. 특히자신을희생하며늘옆에서깊은이해와신뢰, 그리고애정으로여러가지어려움을함께해준사랑하는아내에게감사드립니다. 아울러주위에서끊임없는관심을보여주신모든분들에게감사드립니다. 저자씀

5 차 례 그림및표차례 1 국문요약 2 I. 서론 4 II. 재료및방법 7 1. 대상 7 2. 방법 7 3. 조직배열슬라이드 8 4. 면역조직화학염색 9 5. 통계 10 III. 결과 대상환자들의임상적특성 발현율과상관관계 생존율분석 다변량분석 17 IV. 고찰 21 V. 결론 25 참고문헌 26 영문요약 39

6 그림차례 표차례 - 1 -

7 국문요약 액와림프절음성유방암에서 c-erbb-2 단백과 p53 변이단백발현의의의 배경 : 일반적으로액와림프절전이가많을수록예후는나쁘지만, 액와림프절전이가있는군에서좋은예후를가지는경우가있으며, 반대로액와림프절전이음성유방암환자에서 25-30% 정도는암으로인한재발로사망하기도한다. c-erbb-2 단백및 p53 변이단백의발현은일반적으로환자의예후와연관이있으며유방암환자의예후를예측하는데도움이될것으로생각되어많은연구들이이루어졌다. 대상및방법 : 1990년 1월부터 1998년 6월까지삼성제일병원외과에서수술을시행한유방암환자중수술당시액와림프절전이가없으며, 원격전이가없는환자 326례를대상으로하였다. 이미보관되어있는포르말린고정파라핀포매조직을이용하여 4 mm직경의조직배열 (tissue microarray) 슬라이드를제작하여 ER, PR, c-erbb2, p53 에대한면역조직화학염색을시행하였다. 결과 : 면역반응은 ER이 326례중 159례로 48.8%, PR은 156례로 47.9%, c-erbb-2가 132례로 40.5%, 그리고 p53이 126례로 38.7% 의양성율을나타내었다. ER, PR, c-erbb-2, p53에따른질병특이생존율의차이는없었다. Bloom and Richardson의변형된등급체계로 1등급의 10년질병특이생존율은 100.0%, 2등급은 92.6%, 그리고 3등급은 83.7% 로조직등급이높아질수록유의하게 - 2 -

8 낮았다.(P=0.038). 핵등급 (reverse Black method) 의경우도 1등급의 10년질병특이생존율은 100.0%, 2등급은 92.5%, 그리고 3등급이 83.7% 로조직등급과같은결과를보였다 (P=0.041). ER, PR, c-erbb-2, p53에따른질병특이생존율의차이는없었다. 결론 : 조직등급과핵등급은액와림프절음성인침윤성유관암에서가장중요한예후인자였다. c-erbb-2 단백발현과 p53 변이단백발현양성은나쁜예후인자로판단되는임상 병리인자들과상관관계가있으나, 예후인자로서의유의한의미는없었다. 핵심되는말 : c-erbb-2 단백, p53 변이단백, 예후인자, 조직배열 슬라이드, 질병특이생존율 - 3 -

9 액와림프절음성유방암에서 c-erbb-2 단백과 p53 변이단백발현의의의 < 지도교수박병우 > 연세대학교대학원의학과 고승상 Ⅰ. 서론 유방암은서구여성에게가장빈발하는악성종양이며, 최근에는우리나라여성에서도가장많이발생하는악성종양이다. 유방암의치료계획을수립하고시행하는데있어서예후의예측은매우중요하다. 이러한목적으로예후인자를결정하기위한연구가지속적으로시행되었다. 유방암의전통적인예후인자로는액와림프절의전이유무및개수, 종괴의크기, 림프관및혈관의침윤, 조직유형 (histologic type), 조직과핵등급 (histologic and nuclear grade), 호르몬수용체 (estrogen and progesterone receptor) 발현여부등이알려져있다. 1 최근에는분자생물학의발전에따라호르몬수용체 (ER/PR), 2,3 c-erbb-2 단백, 4,5 p53 변이단백, 6 그리고 EGPR (epidermal growth factor receptor), ras, Ki-67, cathepsin-d, BRCA, - 4 -

10 c-myc 등이유방암에있어서예후인자로서의가치를알아보기위해활발하게연구되고있으며, 여러암유발유전자 (oncogene) 가유방암의발암과진행에중요한역할을하는것으로밝혀졌다. 1 그러나유방암에서는이러한예후인자의다양성때문에이를이용한기준이아직까지는명확하게확립되어있지않다. 최근들어선별검사의증가로인해종양의크기가작고액와림프절전이가없는조기유방암환자의분포가증가하고있으므로, 이러한조기유방암환자에게있어정확한예후인자를활용하여고위험환자군을분류하고적응이되는환자에게만보조요법을시행하여불필요한보조요법에따른단점을감소시킬수있을것이다. McGuire 등 7 은대부분화학요법을시행하지않아도될유방암환자에서화학요법이시행되었다는점을들어예후예측인자의적극적인활용을통한선택적시행을주장하기도하였다. 또한최근에알려진예후예측인자들과이미알려진다른임상 병리인자들사이에상관관계가있을것으로예측되어많은연구가시행되었으나상호연관성이있다는보고와연관성이없다는보고가있어명확한결론은없는상태이다. c-erbb-2 단백과 p53 변이단백의발현은일반적으로환자의예후와연관이있으며유방암환자의예후를예측하는데도움이될것으로생각되어많은연구가이루어졌다. 그러나우리나라에서지금까지시행된대다수의연구는 c-erbb-2 단백발현, p53 변이단백발현과이미알려진다른임상 병리예후인자들과의상관관계만을비교분석한경우가많고, p53 변이단백과 c-erbb-2 단백의발현이전체생존율이나무병생존율에독립적인예후인자로작용하는지에대한장기추적관찰연구는많이이루어지지않았다. 더욱이이러한연구들은대부분유방암이라는대상을광범위하게포함시켜연구하였고이에따라많은오차가포함되었을것이다. 본연구는액와림프절전이음성인조기유방암에서 p53 변이 - 5 -

11 단백과 c-erbb-2 단백발현여부가기존에알려진유방암의임상 병리예후인자와어떠한관계를보이는지비교분석하고더나아가생존이나국소재발, 전신전이에미치는영향도분석하여독립적인예후인자로서의 c-erbb-2 단백발현과 p53 변이단백발현의임상적의의를알아보고자하였다

12 Ⅱ. 재료및방법 1. 대상 1990년 1월부터 1998년 6월까지삼성제일병원외과에서수술을시행한유방암환자 1169례중수술당시액와림프절전이가없으며, 원격전이가없는환자를대상으로하였다. 이중조직형이특별한형은제외하고순수한침윤성관암 (invasive ductal carcinoma) 만을포함시켰다. 면역조직화학염색을하기위한파라핀포매조직이불충분한경우와추적관찰자료등의기타임상자료가불충분한경우를제외한 326례를대상으로하였다. 전체환자는변형근치유방절제술이나부분절제술을시행하였고전례에서액와림프절곽청술을시행하였다. 절제된액와림프절의개수는평균 19개였다. 중간 (median) 추적기간은 70개월 (1-156개월) 이었다. 2. 방법 대상환자의입원과외래기록을검토하여유방암환자에대한기초자료와추적관찰자료를확보하였다. 환자의폐경여부, 종양의크기, 조직등급, 핵등급등의임상 병리인자들과수술후화학요법, 호르몬치료, 방사선치료등의부가적치료여부를파악하였다. TNM 분류는 2002년의 American Joint Committee on Cancer(AJCC) 제 6판의결정기준에따라분류하였다. 조직등급은 Bloom and Richardson 8 의변형된등급체계 9 에따라 G1(favorable, well-differentiated, 고분화 ) 과 G2(intermediate, moderately differentiated, 중등도분화 ) 그리고 G3(unfavorable, poorly - 7 -

13 differentiated, 저분화 ) 으로분류하고, 핵등급은 reverse Black 방법에따라 1등급 ( 고분화 ), 2등급 ( 중등도분화 ), 3등급 ( 저분화 ) 로분류하였다. 질병특이생존율 (disease-specific survival) 은사망한환자중에서사망의원인이유방암으로인한것이확인된경우만으로정의하여분석하였다. 추적관찰기간은외래진료기록을토대로마지막으로생사여부가파악되었던날로계산하였으며최근 1년간본원진찰기록이없었던경우는주민등록번호파악후통계청, 구청, 경찰서등과의협조를통해사망여부를확인하였다. 3. 조직배열슬라이드 (Tissue Microarrays) 조직배열은기존에연구되어발표된방법 10,11 을사용하였다. 이미보관되어있는대상환자들의포르말린고정파라핀포매조직을확보한후헤마톡실린-에오신 (H&E) 염색슬라이드를통해침윤성암세포부위를확인하고표시하여공여블록 (donor block) 을준비하였다. 조직배열기 (Tissue arrayer, SuperBioChips Laboratories, South Korea) 를이용하여수여블록 (Recipient block) 에각각 4 mm직경의구멍 (Hole) 을 24개씩만든후, 그위치에공여블록의병변부위에서각각 4 mm직경의암조직을채취하여수여블록의구멍에심었다. 만들어진수여블록은파라핀으로포매한후 4µ μm두께로박절하여 Silane 코팅슬라이드 (Muto Pure Chemicals, Japan, Cat No. 5116) 에부착하였다. 4. 면역조직화학염색 (Immunohistochemical stain) ER, PR, c-erbb2, p53 에대한면역조직화학염색을시행하 - 8 -

14 였다. 위의방법으로제작된조직배열슬라이드를 xylene으로 2회탈파라핀화하고 100%, 95%, 80% 에탄올로처리한후증류수로함수시켰다. 함수시킨조직배열슬라이드를 autoclave를이용하여구연산버퍼 ph 6.0에 20분간처리한후 3% 과산화수소수로내인성과산화수소의작용을억제시켰다. 트리스완충용액으로수세한다음일차항체 ( 표 1) 로 ER, PR, c-erbb-2, p53을이용하여실온에서 1시간동안반응한후트리스완충용액으로수세하였다. 이차항체인 N-Histofine (simple stain MAX PO universal immuno-peroxidase polymer) 에 30분간반응시키고다시트리스완충용액으로수세하였다. 3-amino-ethyl carbazol(aec) 로발색한다음헤마톡실린으로대조염색하고수용성봉입제로봉입하여현미경으로관찰하였다. 면역조직화학염색의판독은각슬라이드당일차항체에염색된암세포를전체암세포에대한비율로양성여부를판별하였다 ( 그림 1). 면역조직화학염색결과는 2명의병리의사 ( 전이경, 박지영 ; 성균관대학교의과대학삼성제일병원 ) 에의하여판독되었다. ER, PR는핵에명확하게염색된세포가전체종양의 10% 이상일때양성으로판독하였다. 12 c-erbb2는세포막에고르게염색된경우를양성으로판독하였다. 13,14 p53단백은 5% 이상의종양세포의핵에염색이된경우를양성으로판정하여양성군과음성군으로분류하였다. 15,16-9 -

15 5. 통계 종양의임상 병리특성인자들간의상관성비교는교차분석 (Cross tabulation: χ 2 test / 2 2 table; Pearson) 을이용하였고, 각인자들에따른생존율단변량분석에는 Kaplan-Meier 생존분석 (log-rank method) 을이용하였다. 사망또는재발에대한위험도의다변량분석은 Cox 회귀모형 (regression model) 을사용하였다. 유의성검증은 95% 유의수준으로 P값이 0.05 미만인경우를유의한것으로하였다. 자료의통계처리는 SPSS for windows(version 11.01; SPSS Inc., Chicago, IL) 를사용하였다

16 a e i b f j c g k d h l

17 Ⅲ. 결과 1. 대상환자들의임상적특성 전체대상의임상 병리예후관련인자의분포를표 2에정리하였다. 대상환자들의평균연령은 48세이었고, 폐경전여성이 183 례 (56.1%) 로다소많았다. 수술방법으로유방보전술식을시행한경우는 53례 (16.3%), 변형근치유방절제술을시행한경우는 273례 (83.7%) 였으며, 종양의평균크기는 2.3cm이었다. 조직등급과핵등급은 1, 2 등급에비해 3등급이각각 57.6% 와 58.1% 로다소많았다. 수술후보조치료로항암약물요법을받은경우는 227례 (69.6%) 였고항호르몬치료 ( 타목시펜 ) 를받은경우는 195례 (59.8%), 방사선치료를받은경우는 49례 (15.0%) 였고대부분유방보존술식을시행한환자들이였으며, 변형근치유방절제술후방사선치료를받은환자는 3례였다. 생존율분석의오차를파악하기위해수술후보조치료방법을전신적항암약물요법의시행여부에따라크게두군로분류하여다른임상 병리예후인자와비교하였고생존율을비교하였다 ( 표 2). 첫번째군은수술후항암약물요법을시행하고방사선치료나항호르몬치료가추가된경우로하였고, 두번째군은수술후보조치료를받지않았거나방사선치료나항호르몬치료만을받은경우로분류하였다. 폐경전여성과종괴의크기가클수록항암약물요법을시행한경우가많았으며 (P<0.001), 조직등급과핵등급이높을수록항암약물치료를시행한경우가많았다. 치료방법에따른두군간의질병특이생존율은차이가없었다 ( 그림 2, P=0.300). 환자중재발하지않고건강한경우가 295례 (90.5%), 재발하였으나생존하고있던경우가 2례 (0.6%), 유방암으로인해사망한경우가 24례 (7.4%) 였고, 기타원인으로사망한경우가 4례 (1.2%) 가

18 있었다

19 Cumulative survival (%) P= Time after operation (months)

20 2. 발현율과상관관계 면역조직화학염색결과를표 3에요약하였다. 양성반응은 ER 이 326례중 159례로 48.8%, PR은 156례로 47.9%, c-erbb-2가 132례로 40.5%, 그리고 p53이 126례로 38.7% 의양성율을나타내었다. 나이, 폐경여부와는상관관계가없었으나폐경전여성의경우 PR 양성의빈도가높은양상이었다 (52.5%, P=0.060). 종괴의크기가 2cm 이하인경우 ER 양성의비율이 54.3% 로높았다 (P=0.032). 조직등급과핵등급이 ER, PR, 그리고 p53과의미있는상관관계를보였는데 ( 표 3), 조직등급과핵등급이높을수록 ER(72.4%), PR(68.7%) 은음성이많았고 (P<0.001), p53은양성이많았다 (P=0.003). 그러나 c-erbb-2와는상관관계를보이지않았다. ER, PR, c-erbb-2, 그리고 p53 상호간의비교에서는 ER과 PR이서로비례관계를보였고 (P<0.001) p53은 ER, PR과역비례관계 (P=0.002(ER), 0.010(PR)), 그리고 c-erbb-2와는비례관계 (P=0.011) 를나타냈다

21 - 16 -

22 3. 생존율분석 임상 병리인자들에따른질병특이생존율은표 4에나타내었다. 환자의나이, 폐경유무는생존율에영향을미치지않았다. 종괴의크기가클수록질병특이생존율이낮은경향을보였으나통계학적의미는미약하였다 (P=0.084). 조직 1등급의 10년질병특이생존율은 100.0%, 2등급은 92.6%, 그리고 3등급은 83.7% 로조직등급이높아질수록유의하게낮았다.( 그림 3, P=0.038). 핵등급의경우도 1등급의 10년질병특이생존율은 100.0%, 2등급은 92.5%, 그리고 3등급이 83.7% 로조직등급과같은결과를보였다 ( 그림 4, P=0.041). ER, PR, c-erbb-2, p53에따른생존율의차이는없었다. 4. 다변량분석 단변량생존율분석에서유의한차이를보였던조직등급과핵등급을가지고질병사망에대한다변량분석을실시하였다. 조직등급과핵등급은똑같은분포를보여두변수간에예후인자로서의미의차이는없었다

23 - 18 -

24 Cumulative survival (%) P= Time after operation (months)

25 Cumulative survival (%) P= Time after operation (months)

26 Ⅳ. 고찰 유방암은생물적성질뿐만아니라치료의방법역시다양하고, 질병의진행도매우장기적이다. 유방암환자는경우에따라수술후 20년이지나서도전신적재발로인해사망할수있기때문에매우장기적인추적관찰이필요하다. 17 그러므로유방암에대한예후인자로서앞서기술한다양한생물적인자들의의의를알아내는것은매우어려운일이다. 유방암에서수술후보조요법결정에가장중요한역할을하는것은액와림프절전이유무와호르몬수용체발현여부이다. 일반적으로액와림프절전이가많을수록예후는나쁘지만, 액와림프절전이가있는군에서좋은예후를가지는경우도있으며, 반대로액와림프절전이음성유방암환자에서 25-30% 정도는암으로인한재발로사망하기도한다. 18,19 액와림프절음성유방암환자군에서는원발종괴의크기, 20 조직등급, 21,22 조직유형 20,22 등이중요한예후인자로알려져있다. 본연구는액와림프절음성인침윤성유관암환자 326명을대상으로하였으며, 추적관찰기간은최고 13년이었고 10년전체생존율은 88.2% 였다. 조직등급 1, 등급 2, 그리고등급 3의 10년질병특이생존율은각각 100.0%, 92.6%, 그리고 83.7% 로등급이높아질수록생존율이낮아지는것을확인하였다 (P=0.038). 핵등급의경우도등급 1, 등급 2 그리고등급 3의 10년질병특이생존율이각각 100.0%, 92.5%, 그리고 83.7% 로같은양상의결과를보여 (P=0.041) 조직등급과핵등급이전체생존율에있어큰영향을끼친다는기존의연구결과를재확인할수있었다. 21,23,24 종괴의크기, 병기, 그리고조직등급을포함하여 Nottingham group에서제창한 'Nottingham Prognostic Index' 25 역시대규모의후향적, 전향적연구들을통해예후인자로서의의미가확인되었

27 다. 21,26 본연구에서는유의하지않았지만종괴의크기가클수록조직 등급과핵등급이높아지는경향을관찰할수있었다. 염색체 17번 (17q21) 에위치한 c-erbb-2(;her-2, neu) 는 185kDa의 transmembrane protein으로 c-erbb-2 단백의과발현이유방암의발생과관련이있다는동물실험결과의보고 27 이후에 c-erbb-2단백에대한많은연구가수행되었다. c-erbb-2 단백이어떻게정상세포혹은암세포의성장에관여하는지는아직명확하게규명되지않았으나 epidermal growth factor receptor(egfr) 와 intrinsic tyrosine kinase activity와관련이있으며, EGFR과구조적유사성을보이기때문에 EGFR이 epidermal growth factor와결합하여세포의증식과분화에작용하는것과유사한기능을하는것으로알려져있다. 액와림프절음성인유방암에서 c-erbb-2 단백의과발현율은 11-44% 정도로보고되고있고, 관상피내암 (DCIS; ductal carcinoma in situ) 에서는침윤성유관암보다발현율이높다고보고되고있다. 32,33 본연구에서는변수를줄이기위해조직배열슬라이드제작시침윤성암조직부분에서만 core를채취하였고, 발현율은 40.5% 로다소높은편이었으나보고된범위에있었다. 많은보고에서 c-erbb-2 단백발현은나쁜예후와관련이있는 ER/PR 음성, 조직고등급등과상관관계가있다고하였으나, 반대로어떤상관관계도찾을수없었다는보고도있다. 31 본연구의결과에서는 c-erbb-2 단백발현과기타다른임상 병리인자들과의상관관계는관찰할수없었다. c-erbb-2 단백의과발현은정상세포의성장조절능력을억제하여암을발생시키며유방암환자의액와림프절전이, 재발률및생존율과관계가있는나쁜예후인자로보고되고있다 그러나또다른많은연구보고에서는 c-erbb-2 단백발현이유방암의재

28 발이나생존율과상관관계가없다고하였고, 4,5,31,46-49 Rosen 등 31 도이러한관계를볼수없다고보고하였다. 본연구에서는 c-erbb-2 와환자의연령, 폐경유무, 종괴의크기, 조직등급, 핵등급, 그리고 ER, PR 등의임상 병리인자들과의상관관계를관찰할수없었다. 그러나 c-erbb-2 단백발현과다른임상 병리인자들과의상관관계는높은핵등급, 50 ER 양성, 32,51 그리고관상피내암부분이없는침윤성유방암 32 에서만찾을수있다는보고가있다. 한편젊은여성의유방암에서 c-erbb-2 단백의발현은중요한예후인자로여겨지며, 40 에스트로젠수용체양성인환자의혈청에서 c-erbb-2 단백이발현된경우호르몬치료제인 Tamoxifen에대해저항성이있고생존율도나쁘다는보고도있다. 52 염색체 17번 (17p13.1) 에위치한암억제유전자 (tumor suppressor gene) 인 p53은세포증식을조절하는 nuclear phosphoprotein과관련이있다 정상 p53 유전자는암유전자에의한형질전환을억제하고형질전환된세포의성장을억제하는기능을가지나이유전자의부분적소실이나돌연변이에의해서생성된 mutant p53은이와같은정상기능이억제되어악성종양을유발한다 또한이 mutant p53은 wild-type p53보다긴반감기를가지므로세포내에축적된다. 54,61 환자중 p53 변이단백이발현된군은불량한예후를보이는것으로보고되는데 42-44,61 그기전은명확하지않으나 p53 유전자의변이에의해종양의발생이나증식에대한억제기능이상실되어종양의증식과전이를통한임상적진행양상이더공격적이기때문이라고보고된다 p53 변이단백의발현은이미알려진임상 병리예후인자들과연관이있을것으로생각되어지고있으며, 종양의크기, DNA ploidity, 세포의 proliferation, 호르몬수용체, 그리고핵분화도가유의한관계를보인다는보고가있다. 30,65-68 그러나 p53 단백발현이

29 종양의 크기, 림프절 전이, 병기 그리고 호르몬 수용체 31,42,56,76,78,79 와유의성이없다는보고도있다. 한편다른연구에서는 액와림프절 전이에 대해서 유의한 상관관계가 있다고 하였 다 ,68,77 본연구에서는전체 326례중 126례 (38.7%) 에서 p53 변이 단백이양성을보였다. 일반적으로유방암에서 p53 변이단백발현율 은보고에따라다양하지만 10-60% 정도이다. 30,61,64,80,81 면역조직화 학염색시앞서기술한 c-erbb-2 단백이나 p53 변이단백의발현율 이연구들간에차이를보이는이유는각단백의면역조직화학염색 에각기다른 1차항체가이용되었기때문이거나, 82,83 조직을포르말 린에고정하는시간에따라차이가난다고설명되고있다. 84 면역조직 화학적 검색에 이용되는 일차항체로는 monoclonal antibody, polyclonal antibody등의종류가있는데, Elledge 등 85 의보고에서 monoclonal antibody로써검색한경우는단백발현이예후를잘반 영하였지만, polyclonal antibody로써검색한경우는예후를잘반영 하지못하였다. 림프절전이가없는유방암의경우에도이러한단백발현이예후가불량함을반영하는독립적인예후인자라는연구들 30,86-92 과그렇지않다는연구들이있다 본연구에서 p53 변이단백발현은생존율에미치는영향은없었고, 환자의나이, 폐경유무, 그리고종양의크기와는상관관계가없었으나, 높은조직등급 (P=0.011), 높은핵등급 (P=0.011), 호르몬수용체음성 (P=0.002(ER), 0.010(PR)), 그리고 c-erbb-2 단백발현양성 (P=0.011) 과유의한상관관계를보였다. 이것은이전의보고들과같은결과였다. 6,27,42,45,65,73,77,86,93, 잠재적예후인자인 p53변이와 c-erbb-2 단백의발현은서로연관성이있다는보고가있으나, 42 아직까지이러한상관관계는명

30 확히규명되지못하고있다. 76,102 특히 Rosen 등 100 은 p53 변이단백과 c-erbb-2 단백이모두양성인경우특히매우나쁜예후를보인다고하였으나, 반대로관계가없다는보고도있다. 79, 본연구에서비록통계적유의성은없었으나 c-erbb-2 단백과 p53 변이단백의발현은유방암의예후에영향을준다고알려져있는인자들과상관관계를보였으며, 이는예후인자로서의잠재적의미를가진다고판단된다. 수술후보조요법에적용할수있는기준을마련하기위해서는 c-erbb-2 및 p53 변이단백발현에대한장기생존율을포함한보다많은연구가이루어져야하겠다. Ⅴ. 결론 조직등급과핵등급은액와림프절음성인침윤성유관암에서가장중요한예후인자이다. c-erbb-2 단백발현과 p53 변이단백발현양성은나쁜예후인자로판단되는임상 병리인자들과상관관계가있으나, 예후인자로서의유의한의미는없었다

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43 Abstract The significance of c-erbb-2 and p53 expression in patients with axillary lymph node negative breast cancer Ko, Seung Sang Department of Medicine The Graduate School, Yonsei University (Directed by Professor Park, Byeong Woo) BACKGROUNDS: Approximately 25-30% of breast cancer patients with negative axillary lymph nodes die of their disease. Biologic markers such c-erbb-2 and p53 protein have been reported to be related to tumor progression, but their prognostic value remains controversial. METHODS: A total of 326 axillary lymph node negative breast cancer patients from the Samsung Cheil Hospital treated between January 1990 and June 1998 were analyzed with respect to tumor size, histologic grade, and immunohistochemical staining for estrogen receptor(er), progesterone receptor(pr), p53 and c-erbb-2. To evaluate the ER, PR, c-erbb-2 and p53 status. We constructed a tissue microarray from 326 breast tumors, with a single 4mm core per specimen

44 RESULTS: c-erbb-2 immunoreactivity was present in 132 of 326 tumors (40.5%), and p53 immunostaining was present in 126 of tumors (38.7%). One hundred and fifty nine tumors (48.8%) were positive for ER, and 156 tumors (47.9%) were positive for PR. No significant differences in disease-specific survival were found according to ER, PR, c-erbb-2, and p53 expression status. After 10 years of follow-up, the disease-specific survival rate for patients with tumors of histologic grade 1, grade 2, and grade 3 (according to Elston and Ellis' modification of the Bloom and Richardson method) were 100.0%, 92.6%, and 83.7%, respectively(p=0.038), and were 100.0%, 92.5% and 83.7%, respectively(p=0.041), for patients with tumors of nuclear grade 1, grade 2, and grade 3 (reverse Black method). The multivariate analysis selected these two variables as the best predictors of disease-specific survival. CONCLUSIONS: Histologic grade and nuclear grade were found to be major prognostic factors for patients with axillary lymph node negative breast cancer after 10 years of follow-up. c-erbb-2 and p53 expression does not appear to have significant independent prognostic value. Key Words : c-erbb-2, p53, prognostic factor, tissue microarray, disease-specific survival