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ORIGINAL ARTICLE Journal of Breast Cancer J Breast Cancer 2011 February; 14(S): S1-9 DOI: 10.4048/jbc.2011.14.S.S1 유방암환자에서의은제자리부합법의유효성 : 체계적문헌고찰 장선영ㆍ이선희ㆍ김수진ㆍ이유경 1 ㆍ임영혁 2 ㆍ한원식 3 ㆍ박희숙 4 한국보건의료연구원신의료기술평가사업본부, 1 순천향대학교의과대학진단검사의학과, 2 성균관대학교의과대학내과학교실혈액종양내과, 3 서울대학교의과대학외과학교실, 4 순천향대학교의과대학내과학교실혈액종양내과 The Effectiveness of Silver In Situ Hybridization in Patients with Breast Cancer: A Systematic Review Sunyoung Jang, Seon-Heui Lee, Soojin Kim, You-Kyoung Lee 1, Young-Hyuck Im 2, Wonshik Han 3, Hee-Sook Park 4 Health Technology Assessment Department, National Evidence-Based Healthcare Collaborating Agency, Seoul; 1 Department of Laboratory Medicine, Soonchunhyang University College of Medicine, Seoul; 2 Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul; 3 Department of Surgery, Seoul National University College of Medicine, Seoul; 4 Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea Purpose: The purpose of this study was to evaluate silver in situ hybridization (SISH) as an effective test to identify HER2 gene amplification in patients with breast cancer. Methods: A systematic literature review was used to evaluate the effectiveness of SISH. The literature review covered from October 27, 2009 to December 1, 2009, and eight domestic databases including KoreaMed and foreign databases including Ovid-MEDLINE, EMBASE, and Cochrane Library were used. Keywords, such as silver in situ hybridization and SISH, were used to search 63 documents. Ten studies regarding the evaluation of diagnostics were included in the final evaluation. The Scottish Intercollegiate Guidelines Network (SIGN) tool was used by two evaluators to independently evaluate the quality of the ten studies. Results: A total of ten studies (nine diagnostic evaluation studies and one correlation study) were identified to evaluate SISH. The effectiveness of this test was evaluated based on diagnostic accuracy, concordance rate, and correlation with fluorescence in situ hybridization (FISH) results. The sensitivity of SISH was 0.81-1.00, and the specificity was 0.82-1.00. The positive predictive value was 0.95-1.00, negative predictive value was 0.81-1.00, and the test accuracy was 0.90-1.00. The concordance rate of SISH was 87.0-100% and two studies reported a correlation with FISH results. The body of evidence as a whole suggests a Grade D for SISH. Conclusion: SISH is a safe and useful test in patients with breast cancer and at least grade D evidence based on existing positive studies. Key Words: Breast neoplasms, Fluorescence in situ hybridization, Meta-analysis 중심단어 : 유방암, 형광제자리부합법, 체계적문헌고찰 서 론 책임저자 : 박희숙 140-743 서울시용산구한남동 657-58, 순천향대학교의과대학내과학교실혈액종양내과 Tel: 02-709-9185, Fax: 02-709-9200 E-mail: parkhs@schmc.ac.kr 접수일 : 2010년12월3일게재승인일 : 2011년2월 11일본논문은 2009년보건복지부의연구기금에서연구비를지원받음. Human epidermal growth factor receptor 2 (HER2)/neu 원종양유전자 (proto-oncogene) 의증폭또는 HER2 단백질과발현은침습성유방암종의예후적, 예측적요인들중하나이다. 나쁜예후, 더침습적인질병경과, 높은재발가능성, 전체생존기간의단축등과연관되어있으며, 항암화학요법에대한저항성과상관관계가있다.(1) S1

S2 Sunyoung Jang, et al. HER2 유전자의증폭또는과발현은유방암환자에게있어나쁜예후와관련이있고, 타목시펜 (tamoxifen) 을이용한호르몬치료에저항성을나타내지만 anthracycline 계열의항암제나 paclitaxel의치료에비교적좋은반응을나타낸다. 또한 HER2 표적치료제인 trastuzumab (Herceptin ; Genentech, South San Francisco, USA) 이나 lapatinib (Tykerb ; GlaxoSmith- Kline, Philadelphia, USA) 이개발됨으로써 HER2 상태는유방암환자치료방침결정에필수적인요소가되었다.(2) 2007년 American Society of Clinical Oncology (ASCO) tumor marker guideline에서는새로진단받은원발유방암환자와재발유방암환자및전이유방암환자등에서 HER2 검사시행을권장하였고, 2007년발표된 ASCO/College of American Pathologist (CAP) guidelines에서는 HER2 상태를평가하기위한방법으로면역조직화학검사 (immunohistochemistry, IHC) 와형광제자리부합법 (Fluorescence in situ hybridization, FISH) 을포함하는두가지검사체계를제안하고있다. IHC 염색은 HER2 단백의과발현을관찰하는방법으로서, 사용되는항체의종류가매우다양하며민감도와특이도, 판정기준에따라다른결과를보여표준화에대한지속적인노력이필요한검사법이다. FISH법은 HER2 유전자의증폭여부를직접검사하기때문에항암제에대한효과와예후에대한보다정확한예측이가능하며, IHC 염색보다민감도와특이도및정확도가우수하고안정성이높으며소량의조직만으로도검사가가능하다는장점을가지고있다.(3) 최근유전자증폭을직접평가하는검사법으로은제자리부합법 (silver-enhanced in situ hybridization, SISH) 이소개되었는데, 이방법은탐색자 (probe) 가해당 DNA 부위에부착하면침착을유도하여조직내에서오랫동안유지되는검은색점으로반응결과를나타내어광학현미경으로판독이가능한검사방법이다.(2) 은제자리부합법은유방암환자의진단및적절한치료제선택을위하여 HER2 유전자의증폭여부를검사하는기술로, 기존 Table 1. Ovid-MEDLINE search strategy PICO No. Search term Searched no. Patients 1 Breast Neoplasms/ 170,188 Index test 2 In Situ Hybridization/ 42,451 3 Silver/ 9,461 4 silver in situ hybridization.mp. 5 5 sish.mp. 18 6 And/2-3 27 Index test total 7 or/4-6 43 Total 9 1 and 7 10 PICO=Patients, Index test, Comparators, Outcomes. 의형광제자리부합법과비교시검사시간이짧고자동화가가능하며, 검사후결과물보관이가능하다는장점이있다. 따라서현존하는 HER2 유전자의증폭여부를확인하는표준검사인형광제자리부합법과은제자리부합법을비교한보고된문헌들을데이터베이스검색을통하여선택한후 HER2 양성진단의정확성을확인하여은제자리부합법검사의유효성을판단하고자한다. 방 은제자리부합법의유효성은유방암환자를대상으로은제자리부합법과형광제자리부합법과의비교를통해검사의진단정확성, 비교검사와의일치율및상관성을평가하였다. 은제자리부합법은 KoreaMed를포함한 8개국내데이터베이스와 Ovid-MEDLINE, EMBASE 및 Cochrane Library의국외데이터베이스를이용하여 2009년 12 월 1일최종검색을완료하였다. 국내문헌은 silver in situ hybridizaion, SISH, 은제자리부합법 과같은관련검색어를위주로한검색전략을통해 8개의인터넷검색데이터베이스를이용하여검색하였다. 국외문헌은 MEDLINE과 EMBASE를이용하여 Tables 1, 2와같은검색전략을도출하였다. 총 63 개의문헌을검색하였고, 동물실험및전임상시험, 원저가아닌연구, 초록만발표된경우및한국어와영어로기술되지않은문헌은배제하였다. 중복검색을포함하여총 36 개문헌이제외되었고진단법평가연구 9편, 기타연구 ( 상관성연구 ) 1편, 총 10 개의연구가최종평가에포함되었다 (Figure 1). 문헌선택기준 선택기준 (Inclusion criteria) 법 은제자리부합법이수행된연구 적절한의료결과 (outcome) 가하나이상보고된연구 한국어나영어로출판된연구 배제기준 (Exclusion criteria) 동물실험 (non-human) 원저 (original article) 가아닌연구나초록만발표된경우혹은회색문헌등 (non-systematic reviews, editorial, Table 2. EMBASE search strategy PICO No. Search term Searched no. Patients 1 breast tumor /exp 232,309 Index test 2 silver in situ hybridization 8 Total 3 1 and 2 7 PICO=Patients, Index test, Comparators, Outcomes.

The Effectiveness of SISH in Breast Cancer Patients: A Systematic Review S3 letter, comment, opinion pieces, review, congress or conference material, guideline, note, news article, abstract, etc.) 문헌의질평가선택된문헌의질평가도구는영국 Scottish Intercollegiate Guidelines (SIGN) 의 Methodology Checklist (2004년 3월 ) 를채택하였다. SIGN의질평가도구는원래체계적문헌고찰, 무작위임상시험, 코호트연구, 환자-대조군연구, 진단법평가및경제성평가연구로구분되어있으나, 의료기술평가에서대부분의문헌이비무작위임상시험 (quasi-experimental studies) 과비교관찰연구 (observational study) 가많아 SIGN과협의하에 일부도구를수정하였고, 연구유형별질평가도구는 Table 3과같다.(5) 문헌검색부터선택기준적용및자료추출까지각단계는 2명의평가자가각과정을독립적으로수행하였으며이에따라근거의수준과권고의등급을선정하였다 (Table 4). 자료추출평가에포함된문헌이한유형으로만한정되지않아자료의추출은여러차례반복되었다. 자료추출은 2명의평가자가각각중복하여분석하였으며, 연구를진행하면서나타난문제점을토의하는과정이여러차례반복되었다. 동과정에서문헌에기술된내용과결과에영향을주는연구대상의특성및필수적으로기술되어야하는유효성에대한자료를구분하였다. 1차자료추출은 2명 63 Documents searched according to the literature search strategy Total searched documents (n=63) Domestic (n=36), Foreign (n=27) Foreign: Ovid-MEDLINE 10, EMBASE 17 Induded: Hand searching domestic (n=3), foreign (n=0) 46 Overlapping documents excluded Domestic (n=32), Foreign (n=14) 41 Documents published as original articles Domestic (n=32), Foreign (n=9) 10 Documents with silver in situ hybridization being the major test Domestic (n=3), Foreign (n=7) 10 Documents selected for evaluation of silver in situ hybridization Excluded: Overlapping documents (n=20) domestic (n=7), foreign (n=13) Excluded: Studies that are not original articles (n=5) Excluded: Studies in which no silver in situ hybridization was performed (n=31) Total excluded papers (n=36: Domestic 29, Foreign 7) Total included papers (n=10: Domestic 3, Foreign 7) Figure 1. Documents selected for evaluation of silver in situ hybridization according to the literature search strategy. Table 3. Levels of evidence (From Scottish Intercollegiate Guidelines Network. SIGN 50: a guideline developer s handbook) (4) 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2++ High quality systematic reviews of case control or cohort or studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2+ Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2- Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series 4 Expert opinion RCT=randomized controlled trial.

S4 Sunyoung Jang, et al. Table 4. Grades of recommendations (From Scottish Intercollegiate Guidelines Network. SIGN 50: a guideline developer s handbook) (4) A At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+ C A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++ D Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+ RCT=randomized controlled trial. Table 5. Documents selected for evaluation of silver in situ hybridization No. Publication yr Author Research location Research type Subjects Comparators Level of evidence 1 2010 Sung et al.(2) Korea Diagnostic 144 invasive IHC, FISH 2+ breast cancer tissue 2 2009 Bartlett et al.(6) England Diagnostic 45 breast cancer tissue FISH 2-3 2009 Francis et al.(7) Australia Diagnostic 593 cancer patients IHC 2-4 2009 Kang et al.(8) Korea Diagnostic 165 invasive breast cancer FISH 2-5 2009 Kim et al.(9) Korea Diagnostic 58 breast cancer patients FISH 2-6 2009 Shousha et al.(10) England Diagnostic 56 breast cancer tissue IHC, FISH 2-7 2008 Capizzi et al.(11) Italy Diagnostic 83 women breast cancer IHC 2- patients 8 2008 Carbone et al.(12) Italy Diagnostic 89 breast cancer tissue IHC, FISH 2-9 2007 Dietel et al.(13) Germany Diagnostic 99 breast cancer tissue IHC, FISH 2+ 10 2007 Sińczak-Kuta et al.(1) Poland Correlation study 63 breast cancer tissue IHC, FISH 3 IHC=immunohistochemistry; FISH=fluorescence in situ hybridization. 의평가자가각각중복하여분석하였으며, 이후실무회의를통해나타난문제점을토의하고재차자료추출과정을수행하였다. 통계분석본연구에사용된문헌들의진단정확성을확인하기위하여부정을제외한후고정효과모형 (fixed effect model) 에기초하여메타분석을실시하였고, 전반적인은제자리부합법의유용성을 receiver operating characteristics (ROC) curve와 area under the curve (AUC) 를통해평가하였다. 추가적으로출판편향정도를확인하기위하여 funnel plot을확인하였다. 본연구의메타분석을위해서, STATA 통계프로그램 11.1 MP version (Stata Corp., College Station, USA) 와 MetaDiSc 1.4 version (Hospital Universtario Ramon y Cajal, Madrid, Spain) 을사용하였다. 결과은제자리부합법은총10 편 ( 진단법평가연구 10 편 ) 의문헌적근거로평가하였으며, 본평가에포함된문헌의주요자료추출목록은 Table 5와같다. 은제자리부합법의유효성은진단의정확성, 비교검사와의일치율, 비교검사와의상관성에대하여평가하였다. 은제자리부합법은 HER2 유전자과발현여부를확인하고그결과에따라예후예측및치료방향을선택하는데도움을주는검사로현재 HER2 유전자를확인하는검사중표지자만상이하고원리는동일한표준검사인형광제자리부합법을비교자로하여진단정확성및일치율과상관성에초점을두어문헌의결과를해석하기로결정하였다. 은제자리부합법의진단정확성평가는 7편의문헌 (2,8-13) 을근거로평가하였다. 은제자리부합법의경우보통양성, 부정, 음성으로나누어결과를보고하여, 진단의정확성을명확하게평가

The Effectiveness of SISH in Breast Cancer Patients: A Systematic Review S5 Table 6. Summary of diagnostic accuracy Author Critical value No. of cases Sensitivity Positive predictive value Negative predictive value Positive likelihood ratio Negative likelihood ratio Accuracy Diagnostic odds ration Sung et al.(2) Positive >2.2 144 0.92 0.99 0.96 0.98 103.39 0.08 0.98 1,332.00 Kang et al.(8) Positive >2.2 165 0.95 1.00 1.00 0.98-0.05 0.99 - Kim et al.(9) Positive >2.2 58 1.00 1.00 1.00 1.00-0.00 1.00 - Shousha et al.(10) Positive >2.2 56 0.85 0.98 0.95 0.95 33.85 0.16 0.94 214.50 Capizzi et al.(11) Positive >2.2 83 0.81 1.00 1.00 0.81-0.19 0.90 - Carbone et al.(12) Positive >3.0 89 0.95 1.00 1.00 0.98-0.05 0.99 - Negative <1.5 Dietel et al.(13) Positive >2.2 99 0.98 0.82 0.98 0.82 5.37 0.03 0.96 186.75 하기어려웠으나부정을제외한양성및음성을대상으로재구성하여진단정확성을산출하였다 (Table 6). Sung 등 (2) 의한국에서유방암으로진단받은 144 명의유방암환자의조직을대상으로한연구에서는 1.8 미만일경우음성, 1.8 이상 2.2 이하인경우부정 (equivocal), 2.2를초과하면양성으로판정하였다. 부정인경우를제외하고형광제자리부합법과비교한결과민감도는 0.92 (95% confidence interval [CI], 0.82-0.95), 특이도는 0.99 (95% CI, 0.97-1.00), 양성예측도는 0.96 (95% CI, 0.85-0.99), 음성예측도는 0.98 (95% CI, 0.96-0.99), 양성우도비는 103.39 (95% CI, 25.14-542.13), 음성우도비는 0.08 (95% CI, 0.05-0.19), 검사의정확도는 0.98 (95% CI, 0.94-0.99), 진단교차비는 1,332.00 (95% CI, 135.81-1,175.15) 로보고하였다. Kang 등 (8) 의한국의 165 개유방암조직을대상으로한연구에서는 1.8 미만일경우음성, 1.8 이상 2.2 이하인경우부정, 2.2 를초과하면양성으로판정하였다. 부정인경우를제외하고형광제자리부합법과비교한결과민감도는 0.95 (95% CI, 0.89-0.95), 특이도는 1.00 (95% CI, 0.98-1.00), 양성예측도는 1.00 (0.94-1.00), 음성예측도는 0.98 (95% CI, 0.97-0.98), 음성우도비는 0.05 (95% CI, 0.05-0.11), 검사의정확도는 0.98 (95% CI, 0.96-0.99) 로보고하였다. Kim 등 (9) 의한국에서유방암으로진단받은 58 명의유방암환자의조직을대상으로한연구에서는 1.8 미만일경우음성, 1.8 이상 2.2 이하인경우부정, 2.2를초과하면양성으로판정하였다. 형광제자리부합법과비교한결과민감도는 1.00 (95% CI, 0.90-1.00), 특이도는 1.00 (95% CI, 0.96-1.00), 양성예측도는 1.00 (0.90-1.00), 음성예측도는 1.00 (95% CI, 0.96-1.00), 음성우도비는 0.00 (95% CI, 0.00-0.11), 검사의정확도는 1.00 (95% CI, 0.94-1.00) 로보고하였다. Shousha 등 (10) 의영국에서총 65 개의유방암조직과동일한환자의 56 개의중심부생검조직을대상으로한연구에서는 1.8 미만일경우음성, 2.2 를초과하면양성으로판정하였다. 형광제자리부합법과비교한결과민감도는 0.85 (95% CI, 0.66-0.92), 특이도는 0.98 (95% CI, 0.92-1.00), 양성예측도는 0.92 (0.72-0.98), 음성예측도는 0.96 (95% CI, 0.89-0.97), 양성우도비는 33.85 (95% CI, 7.77-182.88), 음성우도비는 0.16 (95% CI, 0.09-0.37), 검사의정확도는 0.94 (95% CI, 0.85-0.97), 진단교차비는 214.50 (95% CI, 20.98-1973.78) 로보고하였다. Capizzi 등 (11) 의이탈리아에서유방암으로치료받은 83 명여성의조직을대상으로한연구에서는 1.8 미만일경우음성, 1.8 이상 2.2 이하인경우부정, 2.2 를초과하면양성으로판정하였다. 부정인경우를제외하고형광제자리부합법과비교한결과민감도는 0.81 (95% CI, 0.70-0.81), 특이도는 1.00 (95% CI, 0.70-1.00), 양성예측도는 1.00 (95% CI, 0.87-1.00), 음성예측도는 0.81 (95% CI, 0.70-0.81), 음성우도비는 0.19 (95% CI, 0.19-0.35), 검사의정확도는 0.90 (95% CI, 0.77-0.90) 로보고하였다. Carbone 등 (12) 의이탈리아에서유방암으로치료받은 89 명여성의조직을대상으로한연구에서는 1.5 미만일경우음성, 1.5 이상 3.0 이하인경우부정, 3.0 를초과하면양성으로판정하였다. 부정인경우를제외하고형광제자리부합법과비교한결과민감도는 0.95 (95% CI, 0.85-0.95), 특이도는 1.00 (95% CI, 0.96-1.00), 양성예측도는 1.00 (0.90-1.00), 음성예측도는 0.98 (95% CI, 0.95-0.98), 음성우도비는 0.05 (95% CI, 0.05-0.15), 검사의정확도는 0.99 (95% CI, 0.93-0.99) 로보고하였다. Dietel 등 (13) 의독일에서

S6 Sunyoung Jang, et al. Study ID OR (95% CI) % Weight Sung et al. (2010)(2) 1332.00 (116.02, 15292.29) 8.46 Kang et al. (2009)(8) 3765.00 (176.85, 80153.35) 4.40 Kim et al. (2009)(9) 2905.00 (55.40, 152317.59) 2.43 Shousha et al. (2009)(10) 214.50 (17.75, 2592.24) 22.04 Capizzi et al. (2008)(11) 136.11 (6.80, 2722.76) 32.85 Carbone et al. (2008)(12) 1571.67 (61.55, 40133.51) 5.48 Dietel et al. (2007)(13) Overall (I-squared=0.0%, p=0.477) 0.1 1 10 186.75 (23.40, 1490.59) 24.34 572.52 (193.92, 1690.28) 100.00 Figure 2. Diagnostic meaning of silver in situ hybridization (fixed-effect model). OR=odds ratio; CI=confidence interval. Sensitivity SROC curve 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 0.2 0.4 0.6 0.8 1.0 1-specificity Figure 3. Receiver operating characteristics (ROC) curve of silver in situ hybridization (area under the curve [AUC]=0.9872). 유방암으로치료받은 99 명여성의조직을대상으로한연구에서는 1.8 미만일경우음성, 1.8 이상 2.2 이하인경우부정, 2.2를초과하면양성으로판정하였다. 부정인경우를제외하고형광제자리부합법과비교한결과민감도는 0.98 (95% CI, 0.95-0.99), 특이도는 0.82 (95% CI, 0.59-0.93), 양성예측도는 0.98 (95% CI, 0.95-0.99), 음성예측도는 0.82 (95% CI, 0.59-0.93), 양성우도비는 5.37 (95% CI, 0.31-13.75), 음성우도비는 0.03 (95% CI, 0.01-0.09), 검사의정확도는 0.96 (95% CI, 0.91-0.98), 진단교차비는 186.75 (95% CI, 25.69-1369.13) 로보고하였다. 이에부정을제외한진단정확성을산출할수있는문헌들을고정효과모형에기초하여메타분석을실시하였다. 은제자리부합법의진단적의미를분석한연구들간의이질성을검정한결과 (Figure 2), 통합교차비는 572.52 (95% CI, 193.92-1690.28) 로통계적으로유의하였으며 (χ 2 =500.29, df=1, p<0.001), 병합된연구 0 0.2 0.4 0.6 0.8 1.0 Sensitivity 0 0.2 0.4 0.6 0.8 1.0 0 0.2 0.4 0.6 0.8 1.0 Sung et al. (2010)(2) Kang et al. (2009)(8) Kim et al. (2009)(9) Shousha et al. (2009)(10) Capizzi et al. (2008)(11) Carbone et al. (2008)(12) Dietel et al. (2007)(13) Figure 4. Forest plot of sensitivities and specificities. CI=confidence interval. Sensitivity (95% CI) 0.92 (0.75-0.99) 0.95 (0.83-0.99) 1.00 (0.80-1.00) 0.85 (0.55-0.98) 0.81 (0.58-0.95) 0.95 (0.76-1.00) 0.98 (0.92-1.00) Pooled Sensitivity=0.94 (0.90 to 0.97) Chi-square=10.52; df=6 (p=0.1043) Inconsistency (I-square)=43.0% Sung et al. (2010)(2) Kang et al. (2009)(8) Kim et al. (2009)(9) Shousha et al. (2009)(10) Capizzi et al. (2008)(11) Carbone et al. (2008)(12) Dietel et al. (2007)(13) Sung et al. (2010)(2) Kang et al. (2009)(8) Kim et al. (2009)(9) Shousha et al. (2008)(10) Capizzi et al. (2008)(11) Carbone et al. (2008)(12) (95% CI) 0.99 (0.95-1.00) 1.00 (0.97-1.00) 1.00 (0.91-1.00) 0.98 (0.87-1.00) 1.00 (0.80-1.00) 1.00 (0.94-1.00) 0.82 (0.48-0.98) Pooled =0.99 (0.97 to 1.00) Chi-square=13.65; df=6 (p=0.0338) Inconsistency (I-square)=56.0% (95% CI) 0.99 (0.95-1.00) 1.00 (0.97-1.00) 1.00 (0.91-1.00) 0.98 (0.87-1.00) 1.00 (0.80-1.00) 1.00 (0.94-1.00) Pooled =0.99 (0.98 to 1.00) Chi-square=4.32; df=5 (p=0.5041) Inconsistency (I-square)=0.0% 간의동질성을보였다 (χ 2 =5.53, df=6, p=0.477). 또한이문헌들을대상으로 ROC curve를확인한결과는 Figure 3과같으며, AUC가 0.99로나타났다. 유방암에서의은제자리부합법의진단적의미를분석한연구들

The Effectiveness of SISH in Breast Cancer Patients: A Systematic Review S7 간의이질성을검정한결과통합민감도는 0.94 (95% CI, 0.90-0.97) 이었으며, 병합된연구간이질성이없음을보였고 (χ 2 = 10.52, df=6, p=0.104), 통합특이도는 0.99 (95% CI, 0.97- S.E. of InOR 0 0.5 1 1.5 2 Funnel plot with pseudo 95% confidence limits 2 4 6 8 10 InOR Figure 5. Funnel plot of selected studies. S.E.=standard error; InOR=natural log of odds ratio. 1.00) 이었으며, 병합된연구간이질성을보였다 (χ 2 =13.65, df= 6, p=0.034). 통합특이도에서이질성을보인 Dietel 등 (12) 의연구를제외한연구들간의병합을살펴본결과이질성을보이지않 았다 (χ 2 =4.32, df=5, p=0.504) (Figure 4). 문헌의이질성검 정을위해 funnel plot을확인한결과출판편향은없는것으로나타났다 (p=0.349) (Figure 5). 형광제자리부합법과의일치율은총 8편 (2,5,7-12) 의문헌에의해평가되었다 (Table 7). Sung 등 (2) 은형광제자리부합법에서양성혹은음성으로판독된경우와은제자리부합법과의일치율은 98.5% (135/137건) 로, 면역조직화학검사에서양성혹은음성으로판독된경우와은제자리부합법과의일치율은 98.5% (133/135건) 로보고하였고, 두병리의사간판독결과는 96.4% (134/139건; κ=0.89; p<0.001) 로보고하였다. Bartlett 등 (6) 의연구에서는형광제자리부합법과의전반적인일치율을 96.0% (88.9-100%) 로보고하였고, 검사자간변이 8.0%, 검사실간변이를 12.66% 로보고하였다. Kang Table 7. Summary table of diagnostic concordance rate Author No. of cases criteria Comperators Concordance rate Sung et al.(2) 144 negative<1.8 / equivocal 1.8-2.2 / positive>2.2 FISH 98.5% (135/137) IHC 98.5% (133/135) Bartlett et al.(6) 45 - FISH 96.0% (88.9-100.0%) Kang et al.(8) 165 negative <1.8 / equivocal 1.8-2.2 / positive>2.2 FISH 98.2% (κ=0.81) Kim et al.(9) 58 negative <1.8 / equivocal 1.8-2.2 / positive>2.2 FISH 100% Shousha et al.(10) 56 negative <1.8 / positive>2.2 FISH 94.0% Capizzi et al.(11) 83 negative <1.8 / equivocalv1.8-2.2 / positive>2.2 FISH 87% (total 42, p<0.002) Carbone et al.(12) 89 negative <1.5 / equivocal 1.5-3.0 / positive>3.0 FISH 91% Dietel et al.(13) 99 negative <1.8 / equivocal 1.8-2.2 / positive>2.2 FISH 96.0% (95/99; κ=0.89; 95% CI, 0.52-0.99) IHC=immunohistochemistry; FISH=fluorescence in situ hybridization; CI=confidence interval. Table 8. Correlation with comparators Author No. of cases Comperators Methods Values p-value Kim et al.(9) 58 FISH HER2 copy enumeration Correlation coefficient (Pearson) R=0.83 <0.001 Linear regression R 2 =0.69 FISH CEP17copy enumeration Correlation coefficient (Pearson) R=0.23 <0.078 Linear regression R 2 =0.04 FISH HER2/CEP17 ratio Correlation coefficient (Pearson) R=0.75 <0.001 Linear regression R 2 =0.56 Sińczak-Kuta et al.(1) 63 IHC Pearson χ 2 test 13.27 <0.01 Gamma correlation coefficient 0.69 - Spearman rank correlation coefficient 0.45 Kappa coefficient 0.58 FISH Pearson χ 2 test 39.91 <0.01 Gamma correlation coefficient 0.96 - Spearman rank correlation coefficient 0.72 Kappa coefficient 0.38 IHC=immunohistochemistry; FISH=fluorescence in situ hybridization.

S8 Sunyoung Jang, et al. 등 (8) 은형광제자리부합법과비교한결과, 총 165 조직중 162 조직이일치하여 98.2% (κ=0.94) 의일치율을보고하였다. 또한면역조직화학검사와의일치율은총 157 조직중 147 조직이일치하여 92.5% (κ=0.81) 로보고하였다. Kim 등 (9) 은형광제자리부합법과 100% 의일치율을보였다. Shousha 등 (10) 은형광제자리부합법과의전반적인일치율은 94.0% 로보고하였다. Capizzi 등 (11) 의전반적인형광제자리부합법과은제자리부합법과의일치율은 87% ( 총 42건, p<0.002) 로보고하였다. Carbone 등 (12) 의전반적인형광제자리부합법과은제자리부합법과의일치율은 91% 로보고하였다. Dietel 등 (13) 의전반적인형광제자리부합법과은제자리부합법과의일치율은 96.0% (95/99건; κ=0.89; 95% CI, 0.52-0.99) 로보고하였다. 비교검사와의상관성은 2편 (1,8) 의문헌을근거로평가되었으며형광제자리부합법과의 HER2/CEP17의비율의상관관계를확인한결과두편모두통계적으로유의한상관관계를나타내는것으로보고하였다 (Table 8). 이러한결과를토대로유방암환자에서의은제자리부합법은기존임상에서사용되는형광제자리부합법결과와의일치율및상관성이높아유효성의근거가있는검사로평가하였다. 근거의등급은제자리부합법은진단법평가연구 (1,2,6-13) 총10편을근거로평가하였고, 질 (level of evidence) 평가결과증례연구를제외한문헌중 2+ 가2편, 2- 가 7편이었다. 따라서현존하는문헌을근거로은제자리부합법은권고등급 D 의유효성이있는기술로판단하였다. 고찰현재까지유방암의발병과직접적이고도확실한인과관계를갖는인자가정확히밝혀져있지는않지만몇몇위험인자들이발병에관여하는것으로알려져있다. 이러한위험인자로는여성, 고령, 유방암가족력, 임신및월경력, 장기간의호르몬요법, 유전자이상등이거론되고있다. 최근 HER2 유전자의증폭여부가임상적으로크게주목을받기시작한것은 tratuzumab, lapatinib와같은 HER2에대한표적치료제의치료가밝혀지면서부터이다. 현재가장정확한 HER2 상태판단기준은 FISH로여겨지나비용과시간이많이들고, 검사여력을갖춘기관이부족하다는점등제약이있어널리보급되지는못한상태이다.(9) 그대안으로국내에서는일부병원에서표지자로형광물질대신은을사용하는은제자리부합법을도입하게되었는데, 이는기존의형광제자리부합법으로시행하던검사를 자동으로시행할수있고, 그결과물을보관할수있어추후결과확인이가능하다는장점을가지고있다. 현재국내문헌을포함하여여러문헌에서형광제자리부합법과은제자리부합법의일치율및진단정확성을확인하였는데, 검사실마다차이가있으나높은진단정확성을보고하고있다. 하지만이에대한명확한근거가제시되고있지않아체계적문헌고찰방법을통해유방암환자에서의은제자리부합법의유효성을평가하였다. 형광제자리부합법과비교한 7편에서은제자리부합법의진단정확성은민감도 0.81-1.00, 특이도 0.82-1.00, 양성예측도 0.95-1.00, 음성예측도 0.81-1.00, 검사정확도 0.90-1.00으로보고되었다. 형광제자리부합법과의일치율은총 8편의문헌에의해평가되었는데, 87.0-100.0% 로보고되었다. 비교검사와의상관성은 2편의문헌을근거로평가되었으며형광제자리부합법과의 HER2/CEP17의비율의상관관계를확인한결과두편모두통계적으로유의한상관관계를나타내는것으로보고하였다. 따라서은제자리부합법은기존임상에서사용되는형광제자리부합법결과와의일치율및상관성이높고, 기존검사에비해간편하고신속한방법으로, 유방암환자의 HER2 유전자과발현여부를확인하고그결과에따라예후예측및치료방향을선택하는데있어유효성의근거가있는검사로평가하였다 ( 권고등급, D). 본연구의제한점은연구들간의이질성의검증없이은제자리부합법을평가하였다는점이다. 즉, 결과에영향을줄수있는연구에사용된검체의특성, 채취자및검사자의변이등이보정되지않았고, 진단정확성의경우문헌에서제시한부정의단계를제외하고음성과양성만으로산출하였다. 따라서은제자리부합법을실제임상에적용할시에는이러한점을고려하여검사를시행하여야할것이다. 그럼에도불구하고, 본연구는현존하는문헌을근거로은제자리부합법은기존임상에서사용되는형광제자리부합법결과와의일치율및상관성이높고, 기존검사에비해간편하고신속한방법으로, 유방암환자의 HER2 유전자증폭여부를확인하고그결과에따라예후예측및치료방향을선택하는데있어유효성의근거가있는검사로평가하였다. 참고문헌 1. Sińczak-Kuta A, Tomaszewska R, Rudnicka-Sosin L, Okoń K, Stachura J. Evaluation of HER2/neu gene amplification in patients with invasive breast carcinoma. Comparison of in situ hybridization methods. Pol J Pathol 2007;58:41-50. 2. Sung WJ, Park SJ, Gu MJ, Bae YK. Automated silver-enhanced in situ hybridization for evaluation of HER2 gene status in breast carci-

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