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1 Journal of Breast Cancer ISSN J Breast Cancer 2008; March 11 (1): ORIGINAL ARTICLE 전이성유방암환자에서혈청 HER-2/neu 와 CA15-3 의상관성 박래경ㆍ우희두ㆍ손두민ㆍ김성용ㆍ임철완ㆍ최태윤 1 ㆍ김재준ㆍ이민혁 순천향대학교의과대학외과학교실 1 진단검사의학과학교실 The Correlation of Serum HER-2/neu and CA15-3 in Patients with Metastatic Breast Cancer Nae-Kyeong Park, Hee-Doo Woo, Doo-Min Sohn, Sung-Yong Kim, Cheol-Wan Lim, Tae-Youn Choi 1, Jae-Jun Kim, Min-Hyuk Lee Departments of Surgery and 1 Laboratory Medicine, Soonchunhyang University, College of Medicine, Seoul, Korea Purpose: The extracellular domain (ECD) of the HER-2/ neu oncoprotein, whose molecular weight is the range from the 95 kd to 105 kd, is shed into the blood from the cell surface via, proteolysis by a metalloprotease. A monoclonal antibody immunoassay has been developed for measuring the circulating concentrations of serum HER-2/neu ECD (following serum HER-2/neu). Serum HER-2/neu has been reported to be correlated with an increased tumor volume in those patients suffering with breast cancer. We measured the serum CA15-3 level, which is a surrogate marker of the tumor burden, we analyzed the correlation of the serum CA15-3 with the serum HER-2/neu and we analyzed the association of both markers with the clinical outcomes. Methods: The sera for the analysis of both HER-2/neu and CA15-3 were obtained from 99 healthy Korean women, 66 primary breast cancer patients and 43 metastatic breast caner patients. The serum HER-2/neu level was measured quantitatively with using an ADVIA Centaur automated immunoassay analyzer (Bayer Health Care LLC, Diagnostics Division, Tarrytown, New York, USA) and the CA 15-3 level was measured via radioimmunoassay. Results: The serum HER-2/neu level was increased 23 metastatic cancer patients (53%). On the analysis of the correlation of serum HER-2/neu and CA15-3, the correlation coefficient (r) was Thus a positive serum HER-2/neu test in breast cancer patients was highly associated with the CA15-3 level for assessing whether metastasis was present or not. For the relationship between primary breast cancer and metastatic breast cancer, the former was classified as the control group and the latter as the patient group. The results of the Receiver Operation Characteristic (ROC) curve for serum HER-2/neu and CA15-3 showed no statistically significant differences (p=0.176) but the diagnostic efficacy of the serum HER-2/neu test was measured more exactly than that of CA15-3 and CA15-3 a tool for measuring a tumor marker for the diagnosis of whether metastasis was present or not. Conclusion: Serum HER-2/neu is a significant independent predictive prognostic factor for metastatic breast cancer patients. In view of the results we have achieved so far the serum HER-2/neu level in metastatic breast cancer patients may play an important roll as an independent tumor marker. Key Words : Serum HER-2/neu, Extracellular domain (ECD), CA15-3, Primary breast cancer, Metastatic breast cancer 중심단어 : 혈청 HER-2/neu, 세포외영역, CA15-3, 원발성유방암, 전이성유방암 책임저자 : 이민혁 서울시용산구한남동 , 순천향대학교의과대학외과 Tel: , Fax: mhlee@hosp.sch.ac.kr 접수일 : 2007년6월 15일게재승인일 : 2007년11월26일 * 본논문의요지는 2005년대한외과학회추계통합학술대회에서구연되었으며한국유방건강재단학술연구비지원에의해이루어진것임. 서론 2002년한국중앙암등록사업연례보고서를보면, 1998년도의여성암발생빈도중유방암은 14.1% 로위암에이어두번째로흔한암이었으나, 2002년에는 16.8% 로위암을제치고 1위로나타나 18

2 Correlation of Serum HER-2/neu and CA15-3 in Breast Cancer 19 한국에서도유방암은점점증가추세에있는질환이다.(1) 이와같이유방암은유병률과사망률에있어서점점증가하는추세에있으므로치료에대한연구가최근활발히진행되고있다. 또한치료법의개발과함께재발암과전이성유방암에대한추적관찰을위한물질에대한연구도활발히이루어지고있는실정이다. 유방암에서이용하는혈청종양표식자 (serum tumor markers) 로는 CA15-3, BR27.29 (CA27.29), carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), HER-2/neu ECD (HER-2/neu) 등이있고, 이중가장널리이용하는것은 CA15-3과 CEA이다.(2) 특히 CA15-3은유방암환자에서종양의부피를대표하는표식자이며, 유방암의원격전이를조기에알수있는표식자이고, 또한전이성유방암환자의치료의감시에유용하게사용되는표식자로 96% 의높은특이도및 70% 의중간정도민감도를나타내는것으로알려져있다.(3-6) 유방암환자를감시하는데유용한혈청종양표식자로 CA15-3이널리이용되지만, American Society of Clinical Oncology (ASCO) 지침서에서는유방암재발을초기에알아내는데 CA15-3 검사의이용을권장하지않는다.(7) 그이유는초기유방암에서 CA15-3 값이상승하는경우가적고, 재발된암덩어리가적을경우감지할수있는민감도가낮으며, 또한암을감지하는종양표식자로서의낮은효율성으로인해재발된환자에서는증가가없는경우가있고, 재발이없는환자에서도비특이적으로증가된경우가있기때문이다. HER-2/neu (c-erbb-2) 종양유전자 (proto-oncogene) 는인체의 17번염색체장완 (q21) 에위치하는 c-erbb-2 원발암종양유전자로써 4.5 kd mrna에의해서만들어지는 185 kd 크기의표피막단백 (surface membrane protein) 으로, 구조적으로는표피성장인자수용체와유사하며, 인체표피성장인자수용체-2 (Human Epidermal growth factor Receptor-2, HER-2) 로써 tyrosine kinase 작용을가지고있으며, 세포의성장을유도한다.(8, 9) HER-2/neu 종양단백질구조중분자량이 95에서 105 kd 사이인세포외영역은 metalloprotease에의한단백질분해절단에의해세포표면으로부터떨어져순환항원이되어혈액내로들어와서순환하게된다. 이혈청 HER-2/neu에대한단클론항체 (monoclonal antibody) 가개발되어면역분석방법으로혈청에서도 HER-2/neu를정량적으로측정할수있게되었다. 유방암환자에서 HER-2/neu 종양단백질의과다발현은환자의예후에대한예측뿐만아니라항암화학치료와호르몬치료의반응예측및최근전이성유방암치료제로개발된 HER-2/neu 수용체를표적으로하는단세포군항체인 trastuzumab (Herceptin, Genetech/Roche, San Francisco, Califonia, USA) 의 치료환자선택기준을결정하는데이용하고있다. 혈청 HER- 2/neu는유방암환자에서종양의부하 (tumor burden) 와상관관계가있는것으로알려져있으며, CA15-3도전이성유방암환자를추적관찰하고재발을발견하는데있어서유용한표식자로알려져있지만, 현재국내에는추적관찰을위한항암표식자로써의유용성에대한연구가없는실정이다. 이에본연구는전이성유방암환자에서혈청 HER-2/neu와 CA15-3의검사결과치를비교하여상관성을분석하고, 또한추적관찰을위한항암표식자로써의유용성을알아보고자하였다. 방법 1. 대상연구대상자는총 208명으로, 이중건강한한국여성 99명을대조군 (control group) 으로선정하였고, 환자군 109명중 66 명은전이가없는원발성유방암환자 (primary breast cancer), 43명은전이성유방암환자 (metastatic breast cancer) 로선정하였다. 2. 방법 1) 혈액채취및혈청분리혈액채취방법으로원발성유방암환자는수술전에, 전이성유방암환자는추적검사에서전이가발견된경우치료전에혈액을채취하였다. 혈액채취전대상자모두에게고지에입각한자발적동의를받았다. 혈청 HER-2/neu와 CA15-3 측정을위해대상자로부터혈액을채취한후원심분리를시행하여혈청을분리하였고, 이를영하 70 냉동고에검사전까지보관해놓았다. 2) 검사방법혈청 HER-2/neu는 ADVIA Centaur automated immunoassay analyzer (Bayer Health Care LLC, Diagnostics Division, Tarrytown, New York, USA) 와 ADVIA Centaur HER- 2/neu assay (Bayer Health Care LLC, Subsidiary of Bayer Corporation, Tarrytown, New York, USA) 시약을이용하여정량적으로측정하였다. 검사원리는혈청 HER-2/neu에위치한항원결정인자들 (epitopes) 에대한두개의단세포군항체 (monoclonal antibody) 를이용한샌드위치면역측정법 (sandwich immunoassay) 인직접화학발광면역측정법 (chemiluminescence immunoassay, CLIA) 으로측정하는것이다. CA15-3 검사는방사면역법 (Radioimmunoassay) 을이용하여측정하였다.

3 20 Nae-Kyeong Park, et al. 3) 판정기준혈청 HER-2/neu 검사의판정참고치 (cutoff value) 는한국여성을대상으로본교실에서연구한문헌에근거하여 12 ng/ml로정하였고,(10) CA15-3 검사의판정참고치는검사시약지침서에의거하여 30 U/mL로정하였다. 4) 통계처리통계학적인분석은 Stata/SE 9.2 for Windows (Stata Corp. USA) 프로그램을이용하여유의성, 상관성, 효율성등을분석하였다. 결과 2. 각군에서의혈청 HER-2/neu의비교분석건강한여성군, 원발성유방암환자군, 그리고전이성유방암환자군에서혈청 HER-2/neu 값의중위수 (median) 는건강한여성군에서는 9.1 ng/ml, 원발성유방암환자군에서는 7.9 ng/ml, 전이성유방암환자군에서는 12.1 ng/ml로측정되었다 (Fig 1). 통계학적으로세군간에유의한차이를보였으며 (p<0.001), 특히전이성유방암환자군에서다른군보다높은수치를보여주었다 (Table 1). 각군을서로비교분석을하였을때, 건강한여성군과원발성유방암군간에유의한차이는없었으나 (p=0.998), 건강한여성군과전이성유방암환자군 (p=0.001), 그리고원발성유방암환자군과전이성유방암환자군 (p=0.002) 에서유의한차이를보였다 (Table 2). 1. 혈청 HER-2/neu 와 CA15-3 의과발현율 전이성유방암환자에서혈청 HER-2/neu의과발현은대상환자 43명중 23명으로 53% 에서나타났고, CA15-3의과발현은 43명중 14명으로 32.5% 에서나타났다. 원발성유방암환자에서혈청 HER-2/neu의과발현은대상환자 66명중 9명으로 13.6% 에서나타났다. Table 1. Distribution of the serum HER-2/neu in the healthy women and breast cancer patients Group Number Median 25% 75% HER-2/neu (ng/ml) Median Healthy women 9.1 ng/ml Primary cancer 7.9 ng/ml Metastasis 12.1 ng/ml Healty women Primary cencer Metastasis p- value* Control <0.001 Primary cancer Metastasis control=healthy Korean women. *Kruskal-Wallis test with Scheffe crrection. Fig 1. Distribution of the serum HER-2/neu in the healthy women and breast cancer patients. The median levels of the serum HER-2/neu were 9.1 ng/ml in the health women, 7.9 ng/ml in the primary breast cancer patients and 12.1 ng/ml in the metastatic breast cancer patients. 3. 혈청 HER-2/neu 검사와혈청 CA15-3 검사사이의상관성분석 전이성유방암환자군에서혈청 HER-2/neu와 CA15-3의상관성을보았을때상관계수 R=0.8072로서로강한상관관계가있는것으로나타났다 (Fig 2). 4. 혈청 HER-2/neu 검사와 CA15-3 검사사이의효율성평가 전이성유방암환자에서혈청 HER-2/neu 와 CA15-3 검사의 Table 2. Multiple comparison of the serum HER-2/neu in the healthy women, primary and metastatic breast cancer patients Comparison Difference of ranks Q* p Metastasis vs primary tumor Metastasis vs control Control vs primary tumor control=healthy Korean women. *, the minimum false negative rate;, Kruskal-Wallis test with Scheffe crrection (Stata/SE 9.2 for Windows, Stata Corp. USA). CA 15-3 (U/mL) 1, ,000 Fig 2. Scatter plot showing correlation of serum HER-2/neu and CA15-3 in metastatic breast cancer patients. Serum correlation of the two markers were strongly correlated (r=0.8072).

4 Correlation of Serum HER-2/neu and CA15-3 in Breast Cancer 21 Sensitivity specificity Fig 3. ROC curve of serum HER-2/neu and CA 15-3 in breast cancer patients. There were not statistically significant diffrences (p=0.176). But the diagnostic efficacy of serum HER-2/neu test was measured more exactly than that of CA15-3. 효율성평가를위해 ROC 곡선 (Receiver Operation Characteristic Curve) 을이용한결과혈청 HER-2/neu의 AUC (area under curve) 는 , CA15-3의 AUC는 로두군간에통계학적으로유의한차이는없었으나 (p=0.716) (Fig 3), 검사효율성은혈청 HER-2/neu가더높았다. 두가지검사를비교할때혈청 HER-2/neu 검사가 CA15-3 검사보다더적합한검사인것으로확인되었다. 고 현재유전성유방암환자의거의 80% 는 BRCA1이나 BRCA2 유전자의돌연변이가원인으로알려져있고,(11, 12) 일반적인유방암의위험인자로는조기초경 (12 세이하 ), 만기폐경 (55 세이상 ), 노령첫출산 (30 세이상 ) 이나출산경력이없는여성, 양성유방질환의과거력, 유방암에대한가족력등이알려져있다.(13) 또한유방암의예후에대한임상적인기준으로는종양의크기, 전이된액와부림프절의개수, 조직학적분화도, 여성호르몬수용체 (estrogen receptor, ER) 와황체호르몬수용체 (progesterone receptor, PgR) 의상태, HER-2/neu 종양항원의존재등이알려져있으며, 최근유방암이증가하는추세에따라다양한분자생물학적기술을이용한유방암의예후인자에대한연구가활발히진행되고있다.(14) 일반적으로종양표식자는표현이나혹은표현정도가암과관련되어지는물질로물리적, 화학적발암물질이암성변이를일으키고이러한변이는물질의변형된표현을초래한다. 따라서종양표지자는단백질, 효소, 탄수화물, DNA, RNA ganglioside, immunoglobulin, glycoprotein 등과같은물질이될수있다. 이와같 찰 CA 15-3 AUC: HER-2/neu AUC: p=0.176 이종양표식자의광범위한다양성에도불구하고몇개는많은혹은모든종양에의해공유된다. 이러한것이암의다인자성원인의선천적결과인지혹은종양표식자를감지하여이용할수있는수단의부족에서오는것인지는아직분명하지않다. 최근에분자생물학의발전으로종양표식자를감지할수있는많은방법이개발되었고이에따라종양표식자의수도훨씬늘어났다. 동시에종양표식자를발생시키는과정또한한층분명하게되었다. 일반적으로유방암환자의진단과추적검사에가장흔히이용하는혈청종양표식자는 CA15-3으로종양의부피를대표하는표식자 (surrogate marker of tumor burden) 로알려져있고, 전이성유방암환자치료의감시 (monitor) 에사용되며, 종양의재발을미리예견할수있는데주로사용된다. CA15-3에대한여러연구결과를요약하면다음과같다. 1) 정상인에서 CA15-3 검사치는 0 에서 30 U/mL로다양하고 30 U/mL 이상일때는증가된것이다. 2) 유방암이외의악성종양이나신부전, 간부전등의질환에서도증가될수있다. 3) CA15-3 값은암덩어리의크기에의존적이다. 4) CA15-3은일차적암및국소적으로재발된암을감지하는데는충분치못하여이와같은암의감별검사, 진단혹은추적검사에일상적으로사용할수없다. 5) 원격전이와증가된 CA15-3 값이밀접한관계가있다. 6) 일부연구에서는원격전이가되기전환자의 50% 에서 CA15-3 값이상승하는것으로나타났다. 7) 원격전이장소에따라서 CA15-3 값이변화하지않는다. 8) 다른종양표지자와동시에사용하는것이민감도를향상시킨다. 9) 환자예후와의연관성은불분명하다.(5, 15, 16) HER-2/neu 종양유전자는 transmembrane receptor tyrosine kinase 작용을하며실험용쥐에서발생시킨신경교아세포종 (neuroblastoma) 에서처음발견된 neu 종양유전자와같은유전자임이확인되었다.(17) 쥐에서 HER-2/neu는막통과영역 (transmembrane domain) 의 single point mutation으로인해종양유전자로활성화되지만인체에서 HER-2/neu는종양유전자의증폭이나종양단백질의과발현형태로활성화된다. 인체고형암에서 HER-2/neu 종양유전자의증폭은 20-30% 의빈도로나타나고 HER-2/neu 종양단백질의과발현은유방암환자들의불량한예후와연관되어있다.(18) 유방암세포주 (breast cancer cell line) 에서 HER-2/neu의종양단백질의과발현은세포성장을촉진시키고흉선없는쥐의이종이식모델 (xenograft model) 에서암을유발시킨다.(19) 인체고형암에서 HER-2/neu의과발현과불량한예후와의연관은세포주실험에서보이는 HER-2/neu의세포성장촉진기능으로설명되고있다. HER-2/neu는다른인체표피성장인자수용체들보다발암과정에서더강력한암유발기능을하며침윤성유방암 (invasive ductal carcinoma) 보다관상피내암 (ductal carcinoma in situ) 에서 HER-2/neu의발현이빈번

5 22 Nae-Kyeong Park, et al. 히관찰된다.(20) 그러나, 인체의폐, 방광, 췌장, 유방, 전립선과같은많은기관의상피세포에서도정상적으로발현된다.(21) 상피내암 (carcinoma in situ) 종에서 HER-2/neu 유전자의증폭이나단백의과발현은세포막내부에서 HER-2/neu의밀도를강력하게증가시킨다.(22) HER-2/neu 종양유전자의증폭은 Slamon 등 (18) 이유방암환자의불량한예후와관련이있다고처음발표후예후와의연관성은여러연구에따라서차이가있으나, HER- 2/neu 종양유전자에대한연구결과는검색방법에따라차이를보이는것이특징적이다. HER-2/neu 종양단백질 (oncoprotein) 의구조는세포내 tyrosine kinase 영역, 막통과영역 (transmembrane domain), 세포외영역 (extracellular domain, ECD) 등 3가지영역으로이루어져있다.(23, 24) HER-2/neu 종양단백질은세포막수용체로서의역할을가짐으로써발암의과정에관여하는것으로알려져있고, HER-2/neu 종양단백질의생물학적특성은세포의성장을조절하며, 또한종양의증식능력을향상시키는것으로알려져있다.(25) 유방암환자에서 HER-2/neu 종양단백질의과다발현은환자의예후에대한예측뿐만아니라항암치료와호르몬치료의반응예측및최근전이성유방암치료제로개발된 HER-2/neu 수용체를표적으로하는단세포군항체인 trastuzumab (Herceptin, Genetech/Roche, San Francisco, Califonia, USA) 의치료환자선택기준을결정하는데이용하고있다. 혈청 HER-2/neu 역시유방암환자에서종양의부하 (tumor burden) 와상관관계가있는것으로알려져있다.(26) 유방암에서예측인자로써의 HER-2/neu 검색은 20세기말부터유방암치료에이용되고있는 trastuzumab의개발로인한호르몬수용체검색과함께필수적인요소가되었다. HER-2/neu의 ECD에대한특이항체인 trastuzumab은 HER-2/neu 과발현을보이는유방암환자에서만치료효과를기대할수있기에 trastuzumab의개발은 HER-2/neu 검색의표준화를유발시키는효과도유도했다. 이러한 HER-2/neu 종양유전자및종양단백의검사방법에는유전자증폭을측정하는방법, mrna의전사를측정하는방법, HER-2/neu 수용체단백을측정하는방법, HER- 2/neu ECD를측정하는방법이있다.(27) 유전자증폭을측정하는방법은 southern blot이나연쇄효소중합반응 (polymerase chain reaction, PCR), 제자리부합법 (in situ hybridization) 이사용되며특히면역형광제자리부합법 (Fluorescence in situ hybridization, FISH) 은일반적으로미세침흡입세포검사 (fine needle aspiration cytology, FNAC) 조직이나 formalin에고정된조직표본에서도잘나타나고재생이가능하며가장신뢰할수있는방법으로알려져있다. mrna의전사를측정하는방법은동결종양조직을이용한 northern blot이 나역전사-연쇄효소중합반응 (reverse transcription-polymerase chain reaction, RT-PCR) 등으로측정이가능하나종양조직내의 mrna의불안정성으로방해받을수있다.(28) HER-2/ neu 수용체단백질발현을정량또는정성측정하는방법은면역조직화학염색법 (immunohistochemistry, IHC) 이나 western blot에의해측정이가능하며, 보존조직에서항 HER-2 항체 (anti- HER-2 antibody) 에의한면역조직화학염색법은현재가장보편적으로사용된다. 혈액내에순환하는 HER-2/neu ECD을측정하는방법은효소면역측정 (enzyme immunoassay) 에의해측정이가능하다.(29) 조직으로검사하는 IHC와 FISH 및혈청에서검출하는방법인 enzyme-linked immunosorbent assays (ELISA) 가현재가장많이사용되며, 이중미국식품의약청 (Food and drug administration, FDA) 에서승인을받은 ELISA법인 manual microtiter plate assay (Oncogene Science/Bayer Corporation, Cambridge, USA) 와 automated version on the Bayer Immuno1 platform (Bayer Diagnostics, Tarrytown, New York, USA), ADVIA Centaur automated immunoassay analyzer (Bayer Health Care LLC, Diagnostics Division, Tarrytown, New York, USA) 등이있으며이들중본연구에서는가장최근에개발된혈청에서검사하는방법인 ADVIA Centaur automated immunoassay analyzer를이용하였으며, 이는조직에서검사하는 IHC나 FISH을했을경우나타나는파라핀포맷조직과신선조직의차이, 조직의고정방법, 항체의선택및희석정도, 판독기준의차이에서나오는주관적인관점을극복하여결과의객관성을유지하려하였다. 또한조직을이용하는두검사법은종양이제거된뒤에는검사할수없다는제한점을가지고있다. 반면에혈청 HER- 2/neu를측정하는검사법은정량적으로측정할수있고종양제거후에도검사가가능하며임상에서의적용이용이하다는장점을가지고있다. HER-2/neu 유전자증폭과단백질의과발현은원발성유방암의약 25-30% 에서발견된다.(30) 유방암의분자생물학적병인은대개알려져있지는않지만 HER-2/neu 유전자증폭이나단백의과발현, 암억제유전자 p53 의변화된표현이유방암에서발견되면불량한예후와관련되어있다고알려져있다.(31) 유방암환자의재발과연관된 HER-2/neu의발현은불량한예후와연관되어있지만대부분의연구들이림프절전이양성환자군을대상으로한것이며, 소수의연구만이림프절전이음성인조기유방암환자를대상으로한것이다.(32) 우리나라의경우는 HER-2/neu 단백질의발현과기존의유방암예후인자와의연관성에대한연구가극히소수의환자들만을대상으로시행되었거나다른종양표식자들과연관하여재발분석을시도한것이유일하다.(33, 34) 특히추

6 Correlation of Serum HER-2/neu and CA15-3 in Breast Cancer 23 적관찰을위한항암표식자로써의유용성에대한연구도또한없는실정이다. 건강한한국여성에서혈청 HER-2/neu의참고치는 12 ng/ml 로일반적으로알려진미국여성의참고치인 15 ng/ml 보다낮은것으로알려져있다.(10) 전이성유방암환자에서혈청 HER- 2/neu의발현은 Gasparini 등 (35) 이 27%, Osaki 등 (36) 이 42%, 박등 (37) 이 64.1% 를보고하였고, 본연구에서는대상환자 43명중 23명으로 53% 로나타났다. 이같은차이는각논문들의측정방법들이 IHC의방법으로 HER-2/neu를측정함으로써앞서언급한주관적인차이로다른결과가나타났을것으로생각되고, 우리의연구는혈청에서검사하는방법인 ADVIA Centaur automated immunoassay analyzer를이용하여보다객관성을유지하려하였다.(38) 혈청 HER-2/neu 측정치는임상의에게예후적인정보를제공하여전이성유방암환자의추적관찰에사용될수있으며, 혈청검사는조직에서 HER-2/neu 상태를결정시켜주는보조적인정보를제공함으로써특히표적치료를위한환자선정을적합하게할것이다.(39) Ali 등 (40) 은 CA15-3값과혈청 HER-2/neu 값을측정하여임상적인결과와의연관성을분석하였고, 분석결과 CA15-3는다변량분석에서반응률에대한예측인자가되지못하나, 혈청 HER- 2/neu 값은단변량과다변량분석모두에서예측인자로써의의가있음을보고하였다. 또한 CA15-3은단독검사보다는혈청 HER- 2/neu 검사를함께실시하는것이불량한예후를예측할수있다고하였다. 본연구에서도전이성유방암환자에서혈청 HER-2/ neu와 CA15-3의예측인자로써의적합도검정을시행한결과, 혈청 HER-2/neu가 CA15-3보다더적합한것으로확인되었다. 따라서본연구에서는혈청 HER-2/neu가전이성유방암환자에있어서새롭게적용가능한항암표식자로써유용하다고생각한다. 결론건강한한국여성 99명, 원발성유방암환자 66명및전이성유방암환자 43명을대상으로혈액을채취하여혈청 HER-2/neu와 CA15-3을측정하여분석한결과, 혈청 HER-2/neu 검사는유방암진단검사로는부족하나, 전이성유방암환자에서 CA15-3 검사를대치해서사용할수있는유용한종양표식자로생각된다. 참고문헌 1. Korean Breast Cancer Society. Nationwide Korean breast cancer data J Breast Cancer 2004;7: Michael JD. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem 2006;52: Bates SE. Clinical applications of serum tumour markers. Ann Intern Med 1991;115: Beastall GH, Cook B, Rustin GJ, Jennings J. A review of the role of established tumour markers. Ann Clin Biochem 1991;28: Gang Y, Adachi I, Okhura H, Yamomoto H, Mizuguchi Y, Abe K. CA15-3 is present as a novel tumour marker in the sera of patients with breast cancer and other malignancies. Gan To Kagaku Ryoho 1985;12: (English abstract). 6. Tomlinson IP, Whyman A, Barrett JA, Kremer JK. Tumour marker CA15-3: possible use in the routine management of breast cancer. Eur J Cancer 1995;31A: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 1996;14: Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319: Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230: Kim JW, Kim SY, Lee HS, Woo HD, Son DM, Lim CW, et al. Establishment for reference range of serum HER-2/neu in Korean healthy women. J Breast Cancer 2006;9: Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266: Collins N, McManus R, Wooster R, Mangion J, Seal S, Lakhani SR, et al. Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q Oncogene 1995;10: Yoo KY, Tajima K, Kuroishi T, Hirose K, Yoshida M, Miura S, et al. Independent protective effect of lactation against breast cancer: a case-control study in Japan. Am J Epidemiol 1992;135: Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer(1). N Engl J Med 1992;327: Gunczler P, Ogris E, Maca S, Danmayr E. Tumour markers in breast cancer: on the diagnostic value of serum determinations in clinical freedom from tumour and manifest disease. Onkologie 1989;12: (English abstract). 16. Suzuki S. Early diagnosis for bone metastases of breast cancer based

7 24 Nae-Kyeong Park, et al. on bone metabolism. Fukushima J Med Sci 1990;36: Shih C, Padhy LC, Murray M, Weinberg RA. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 1981;290: Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235: Rait AS, Pirollo KF, Xiang L, Ulick D, Chang EH. Tumor-targeting, systemically delivered antisense HER-2 chemosensitizes human breast cancer xenografts irrespective of HER-2 levels. Mol Med 2002;8: Storm FK, Gilchrist KW, Warner TF, Mahvi DM. Distribution of Hsp-27 and HER-2/neu in in situ and invasive ductal breast carcinomas. Ann Surg Oncol 1995;2: Padhy LC, Shih C, Cowing D, Finkelstein R, Weinberg RA. Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell 1982;28: Brandt-Rauf PW, Monaco R, Pincus MR. Conformation of the transmembrane domain of the epidermal growth factor receptor. J Protein Chem 1994;13: Gullick WJ, Bottomley AC, Lofts FJ, Doak DG, Mulvey D, Newman R, et al. Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein. EMBO J 1992;11: Guerin M, Gabillot M, Mathieu MC, Travagli JP, Spielmann M, Andrieu N, et al. Structure and expression of c-erbb-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: prognostic significance. Int J Cancer 1989;43: Sahin AA. Biologic and clinical significance of HER-2/neu (cerbb- 2) in breast cancer. Adv Anat Pathol 2000;7: Krainer M, Brodowicz T, Zeillinger R, Wiltschke C, Scholten C, Seifert M, et al. Tissue expression and serum levels of HER-2/neu in patients with breast cancer. Oncology 1997;54: Bofin AM, Ytterhus B, Martin C, O Leary JJ, Hagmar BM. Detection and quantitation of HER-2 gene amplification and protein expression in breast carcinoma. Am J Clin Pathol 2004;122: Tse C, Brault D, Gligorov J, Antoine M, Neumann R, Lotz JP, et al. Evaluation of the quantitative analytical methods real-time PCR for HER-2 gene quantification and ELISA of serum HER-2 protein and comparison with fluorescence in situ hybridization and immunohistochemistry for determining HER-2 status in breast cancer patients. Clin Chem 2005;51: Kim SY, Kim TY, Kim JJ, Kim CH, Song OP, Lee MH, et al. Clinical correlation of HER-2/neu overexpression in patients with breast cancer. J Korean Breast Cancer Society 2004;7: Toikanen S, Helin H, Isola J, Joensuu H. Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up. J Clin Oncol 1992;10: Barnes DM, Dublin EA, Fisher CJ, Levison DA, Millis RR. Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol 1993;24: Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S, et al. neu/erbb-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol 1998;16: Noh DY, Choe KJ, Kim JP, Park IA, Park SH, Yoo KY. DNA ploidy, S-phase activity and c-erbb-2 oncogene protein expression in breast cancer and its relationship to prognosis. J Korean Cancer Association 1992;24: Han SH, Yun IJ, Noh DY, Choe KJ, Song SY, Chi JG. Abnormal expression of four novel molecular markers represents a highly aggressive phenotype in breast cancer. Immunohistochemical assay of p53, nm23, erbb-2, and cathepsin D protein. J Surg Oncol 1997;65: Gsaparini G, Bevilacqua P, Pozza F, Meli S, Boracchi P, Marubini E, et al. Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer. Br J Cancer 1992;66: Osaki A, Toi M, Yamada H, Kawami H, Kuroi K, Toge T. Prognostic significance of co-expression of c-erbb-2 oncoprotein and epidermal growth factor receptor in breast cancer patients. Am J Surg 1992;164: Park W, Paik NS, Kim YK, Moon NM, Lee JI, Choi DW, et al. The expression of c-erbb-2 oncoprotein and epidermal growth factor receptor (EGFR) in breast cancer patients in Korea. J Korean Cancer Association 1994;26: Luftner D, Cheli C, Mickelson K, Sampson E, Possinger K. ADVIA Centaur HER-2/neu shows value in monitoring patients with metastatic breast cancer. Int J Biol Markers 2004;19: Luftner D, Luke C, Possinger K. Serum HER-2/neu in the management of breast cancer patients. Clin Biochem 2003;36: Ali SM, Leitzel K, Chinchilli VM, Engle L, Demers L, Harvey HA, et al. Relationship of serum HER-2/neu and serum CA15-3 in patients with metastatic breast cancer. Clin Chem 2002;48:

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Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean