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1 Journal of Breast Cancer ISSN J Breast Cancer 2008; June 11 (2): 71-6 ORIGINAL ARTICLE 유방암에서뇌전이예측인자와생존율 이정아ㆍ배정원ㆍ우상욱ㆍ이재복ㆍ구범환 고려대학교의과대학외과학교실 Predictive Factors and Survival Rate for Brain Metastasis from Breast Cancer Jung Ah Lee, Jeoung Won Bae, Sang Uk Woo, Jae Bok Lee, Byum Whan Koo Department of Surgery, Korea University College of Medicine, Seoul, Korea Purpose: The incidence of symptomatic brain metastases from breast cancerhas ranged from 10% to 16%. Brain metastases are traditionally viewed as a late complication of systemic disease, for which few effective treatment options exist. The aim of this study was to evaluate the factors that can predict brain metastases and to analyze the survival rate as compared with other systemic metastases. Methods: Between February 1983 and October 2005, 119 patient who developed systemic metastasis during the follow up period after optimal surgical treatment at Korea University Hospital were included in this study. Twenty-nine of these 119 patients had complaints of symptoms and they were consequently diagnosed as having brain metastases. Results: Estrogen receptor (-), progesterone receptor (-) and Her2 (-), and Triple negative were a significantly higher in the patients with brain metastases (p=4). The other clinicopathologic factors showed no difference between the patients with brain metastases and the patients without brain metastases. Lung metastases existed previously more often than the other systemic metastases (p=4). The overall survival of the patients with brain metastases was not significantly different from the patients with other systemic metastases. However, the disease specific survival of patients with brain metastases, as compared with other systemic metastases was poorer than that for patients with bone and lung metastases, respectively (p=1 and 3). A poor prognosis was shown for the cases with brain metastases within 1 yr after operation. Conclusion: Clinician should give attention to the possibility of brain metastases for the breast cancer patients with triple negative findings or the patients who have developed lung metastases as this represents a symptom of central nervous system. Key Words : Breast cancer, Brain metastases, Predictive factor, Survival 중심단어 : 유방암, 뇌전이, 예측인자, 생존율 서 유방암의항암요법과표적치료의발전으로유방암환자의생존율은증가하고있으나, 중추신경계의전이발생시에는혈액뇌장벽으로항암치료제의효과적인결과를기대할수없다. 증상이발현되는유방암의뇌전이는전이성유방암환자중 10-16% 의발 책임저자 : 배정원 서울시성북구안암동 5가 126-1, 고려대학교의과대학외과 Tel: , Fax: kujwbae@korea.ac.kr 접수일 : 2007년 8월 6일게재승인일 : 2008년 3월 27일 * 본논문은 2007년한국유방암학회춘계학술대회발표논제입니다. 론 병률을보이나, 대규모부검연구에서는모든전이성암환자중 30% 의환자에서뇌전이를발견할수있었으며,(1) 중추신경계에전이된암중폐암과유방암이가장높은빈도를보인다.(2, 3) 그러나, 유방암의전이빈도에서뼈, 폐및간의전이에비해뇌전이는빈도가낮아유방암수술후의통상적인추적검사를시행하지는않으나증상발생후질환의진행이매우빠르며치료에반응이좋지않아사망하는특징을가지고있다. 유방암의뇌전이시에는두통, 인지반응, 정신상태와행동학적인이상, 오심, 구토, 간질및감각, 운동, 언어및시각의결손등의증상이발현될수있다. 그러나, 유방암의뇌전이는증상의발현후방사선학적인검사로진단시이미 78% 에서다발성의전이를보이며 14% 에서만 71

2 72 Jung Ah Lee, et al. 단독전이로발견되었으며, 8% 에서는연수막전이로나타났다.(4) 또한유방암에서뇌전이발견시에는대다수에서이미뼈, 간및폐등의전신전이가진행된상태였다.(5) 따라서뇌전이는유방암에서의독특한분자생물학적인특징이기보다는질환의진행에따른악성종양의질환경과로이해되고있다. 유방암의뇌전이발생시 1년생존율은약 20% 이며, 일반적으로중추신경계의광범위한전이시 2년이상의생존은 2% 이하로보고된다.(6, 7) 유방암에서의뇌전이의위험인자로는젊은연령일때위험도가올라가는것으로보고되며,(1, 4) 에스트로겐수용체음성인경우에는 9%, 양성인경우는 5% 에서만이뇌전이가발견되었다. (8) Her-2의과발현은낮은무병생존율과전체생존율을보이며,(9) 또한높은뇌전이발생률을보인다.(10-12) 본연구는유방암으로수술후추적관찰중전신전이가발생한환자중뇌전이환자와비뇌전이환자의임상병리학적특징을비교하여뇌전이에관여하는인자와생존율을비교하였다. 방법 1. 대상 1983년 2월부터 2005년 10 월까지고려대학교병원에서유방암으로수술받은 1,151예중에서전신전이가발생한경우는 119 예였다. 수술전원격전이가발견된환자는대상에서제외하였다. 중추신경계의이상증상발현으로방사선학적인검사를시행하여뇌전이로진단된경우는 29 예였으며, 뇌전이군과비뇌전이군으로구분하여두군간의임상병리적특징과생존율을비교하였다. 중앙추적기간은뇌전이군 48.6 ( ) 개월이고, 비뇌전이군은 43.1 ( ) 개월이었다. 2. 통계방법뇌전이군과비뇌전이군간의임상병리적특징의비교는 chisquare 방법을이용하여분석하였다. 두군간의생존율비교는 Kaplan-Meier 방법을사용하였으며, 생존율에관여하는요인의분석은 Cox-regression 방법을이용하였다. SPSS for Window 체계를사용하여 p<5인경우를통계적으로유의한것으로판단하였다. 결과 1. 뇌전이환자와비뇌전이환자의임상병리적위험인자의분석두군간에연령의차이는없었으며, 모두여성이었다. 종양병기에있어두군간에통계적차이는없었으나 (p=0.53), 림프병기에있어두군간에유의한차이를보였다 (p=4). TNM병기 는 Ⅰ기, Ⅱ기및 Ⅲ기가뇌전이군에서는 1 (3.4%) 예, 17 (58.6 %) 예및 11 (37.8%) 예로, Ⅱ기에서가장높은빈도를보였다 (p= 5). 그러나, 증례의수가적어유의성판단에있어서는증례의확대가필요하다고생각된다. 수용체발현의상태를알수없는경우를제외하였을때에스트로겐수용체와프로제스테론수용체의발현에서, 두군간의유의한차이는없었으며 (p=, p= 6), Her-2의발현에있어서도두군간의유의한차이는없었다 (p=3). 그러나, 에스트로겐수용체또는프로게스테론수용제가양성이며, Her-2가양성인경우는 25 예로뇌전이군과뇌 Table 1. Clinicopathologic features of breast cancer patients with brain metastases versus without brain metastases Features With brain meta Without brain meta p- value Age median 43 (29-73) 47.5 (26-77) NS > Tumor stage I II III IV Node stage I II III Stage I IIA IIB IIIA IIIB IIIC Estrogen receptor Negative Positive Unknown Progesterone receptor Negative Positive Unknown Her-2 Negative Positive Unknown 4 33 ER or PR (+), Her-2 (+) ER or PR (+), Her-2 (-) ER & PR (-), Her-2 (+) ER & PR (-), Her-2 (-) MRM=modified radical mastectomy; BCT=breast conserving treatment; ER=estrogen receptor; PR=progesterone receptor.

3 Brain Metastasis with Breast Cancer 73 전이가동반되지않은군에서 9 (36.0%) 예와 16 (64.0%) 예이고, 에스트로겐수용체또는프로게스테론수용제가양성이며, Her- 2가음성인경우는 23예로두군이각각 4 (17.4%) 예와 19 (82.6 %) 예였다. 두호르몬수용체가모두음성이며 Her-2가양성인경우는, 두군에서 3 (17.6%) 예와 14 (182.4%) 예였고, 세수용체가모두음성인경우는 9예로각각 9 (56.3) 예와 7 (43.8%) 예로유의한차이를보였다 (Table 1) (p=4). Table 2. Adjuvant therapy and metastatic location in breast cancer patients with brain metastases versus without brain metastases Features With brain meta Without brain meta p- value Adjuvant therapy Hormone therapy Yes No Adjuvant chemotherapy Anthrcycline (A) Taxane (T) A+T Metastatic location Bone Yes No Lung & pleura Yes No Liver & abdomen Yes No 수술후보조항암요법과전이장기뇌전이군과비뇌전이군간의수술후보조요법인방사선치료, 항암치료요법및항호르몬치료에서유의한차이는없었다. 뇌전이환자군에서뼈전이와간전이가동반되는경우보다폐전이가동반되었을때뇌전이가유의하게많았다 (p=4) (Table 2). 3. 전체생존율과질환관련생존율뇌전이후의중앙생존기간은 4.0 ( ) 개월이고, 비뇌전이군의중앙생존기간은 1 ( ) 개월이었다. 뇌전이군과비뇌전이군간의전체생존율의차이는없었다. 그러나, 질환관련생존율에서는최초의전이가뼈전이와뇌전이를비교하였을때유의한차이를보였으며 (p=1), 페전이와도유의한생존율의차이가있었다 (p=3). 뇌전이와간전이의생존율의차이는없었다 (p=1) (Fig 1). 4. 뇌전이환자의생존율에영향을미치는요소뇌전이환자에서 1차적으로뇌압상승에대하여스테로이드치료를시행하였으며, 전뇌방사선치료는 20 (68.9%) 예에서시행하였다. 수술적치료는 3예에서시행하였으며, Trastuzumab은 4예에서사용하였다. 뇌전이환자에서생존율에영향을미치는요소는연령, 원발유방암의병기, 수술방법및수술후보조요법등에서유의한차이가없었으며, 뇌전이후전뇌방사선요법도생존율에영향을주지는못했다. 하지만, 뇌전이의발병시기가수술후 1년이내인 10 예의평균생존율은 3.1 개월이고 1년이후에뇌전이가발견된 19 예의평균생존율은 6.7 개월로유의하게낮은생존율을보였다 (p=2) (Fig 2). Overall survival Disease specific survival p=0.14 Without brain metastases With brain metastases p=1 Without mbain metastases With brain metastases A B Fig 1. Overall survival and disease specific survival of breast cancer patients with brain metastases versus without brain metastases.

4 74 Jung Ah Lee, et al. Lung vs brain metastases Bone vs brain metastases p=1 Bone metastases Brain metastases p=3 Lung metastases Brain metastases Liver vs brain metastases A B p=1 Liver metastases Brain metastases C Fig 2. According to metastatic location, disease specific of breast cancer patients with systemic metastases. 고찰유방암의뇌전이는질환의진행에의한과정이며, 증상의발현에의해진단되어도특정한치료에의한생존율의향상이어려운특징을가지고있다. 뇌전이의병소가한개로국한된경우에는상대적으로장기무병생존율을보고하고있다.(13, 14) 본연구에서단독병소인경우는 3 (10.3%) 예에불과하였으며, 진단당시에대다수에서다발성병변으로발견되었다. Her-2/neu 과발현환자를대상으로뇌전이에대한선별검사를시행한연구에서 15% 의유방암환자에서뇌전이를발견할수있었으며, 이러한잠재성뇌전이의생존율은비뇌전이환자군에비해짧았으나, 증상이발현된뇌전이환자군의생존율과는유사한결과를보였다.(12) 이러한결과를통해모든유방암환자에대한뇌전이의선별검사를시행하는것은논란이있다고생각된다. Her-2/neu의과발현은진행이빠르고, 원격전이가증가하고, 예후가불량한유방암과관 련이보고되어있다.(10, 15, 16) Bendell 등 (10) 은 trastuzumab으로치료한 122명중 34% 에서중추신경계의전이를보고하였다. Clayton 등 (17) 은 trastuzumab 치료중 25% 의환자에서뇌전이를발견하였으며, 뇌전이가발생한환자의 78% 에서다른장기의전이는 trastuzumab 치료로다른장기의전이는진행이억제된것을보고하였다. 본연구에서는 tastuzumab 치료를 4예에서시행하였으나, 환자의수가적어 Her-2/neu의과발현과뇌전이의상관관계를찾을수없었다. 하지만삼중수용체음성인환자에서통계적인유의한차이를보였으며 (p=4), 이것은삼중수용체음성인환자에서뼈전이보다는내부장기의전이가많았으며, 뇌전이의비율이높았다는보고와일치하는결과였다.(18, 19) 따라서, 삼중수용체음성인환자에서중추신경계증상을호소한다면세심한주의가필요하다고생각된다. 유방암에서최초전이장소로뼈전이가가장높은빈도를보이나,(20, 21) 본연구에서는최초전이장소가폐전이일때뇌전이와동반된경

5 Brain Metastasis with Breast Cancer 75 Interval of brain metastases Hormone treatment p=2 Within 1 yr Over 1 yr p=6 Hormone treatment (+) Hormone treatment (-) Palliative radiotherapy A B p=4 Radiotherapy (+) Radiotherapy (-) C Fig 3. Contributing factors of survival in breast cancer with brain metastases. 우가유의하게많았다 (p=4). 따라서폐전이가있는환자에서중추신경계의증상을호소시에는뇌전이를의심하여야하겠다. 유방암의뇌전이시 1년생존율은약 20% 이며중추신경계전이후 2년이상의생존을보이는환자는 2% 미만이다.(6, 7) 본연구에서도뇌전이후중앙생존기간은 4.0 ( ) 개월이었고, 최초전이가뼈전이환자와폐전이환자에서뇌전이가동반되었을때생존율에있어유의한차이를보였다 (p=1, p=3). 간전이환자의생존율과는유의한차이를보이지않았으며, 이러한결과는뇌전이환자의생존율에있어전신전이의치료조절이제한인자로작용한다는보고와일치한결과를보였다.(6, 7) 뇌전이에서스테로이드는종양주위의부종을감소시켜증상을경감시켜주나, 항암요법은혈액뇌장벽으로약물의효과적인이동이제한되어효과적인치료효과를기대하기힘든것으로알려져있다. 뇌전이시방사선치료는 4-5 개월의생존율향상시키고,(13, 14) 수술적치료는신속히증상을경감시키며, 생존율을증가시키고삶 의질을향상시키는것으로보고한다.(22-24) 이러한결과는제한된병변에적용되며다발성병변은그효과를기대하기힘든것으로보고하고있다. 본연구에서도방사선요법은 20 예와수술적으로치료를시행한 3예이었으나, 환자의증례가적어생존율의차이는찾을수없었다. 생존율에영향을미치는요인으로는수술후 1년이내에뇌전이가발생한경우에 3.1 개월이고 1년이후에발견된경우는 6.7 개월로유의한차이를보였다. 결론유방암환자에서뇌전이는질환의진행단계로이해되며효과적인치료를시도가지속적으로시행되고있으나, 아직은모든유방암환자에서뇌전이에대한선별검사의효용성은논란이있다. 본연구결과에의해삼중수용체음성인환자나폐전이가있는환자에서중추신경계의증상이발현된다면세심한검사의필요성을

6 76 Jung Ah Lee, et al. 제안한다. 또한, 수술후 1년이내에뇌전이가발생한환자의생존율은상대적으로낮으므로적극적인치료를고려해야한다고생각된다. 참고문헌 1. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 2004;22: Lassman AB, DeAngelis LM. Brain metastases. Neurol Clin 2003; 21: Chang EL, Lo S. Diagnosis and management of central nervous system metastases from breast cancer. Oncologist 2003;8: Evans AJ, James JJ, Cornford EJ, Chan SY, Burrell HC, Pinder SE, et al. Brain metastases from breast cancer: identification of a highrisk group. Clin Oncol 2004;16: Issa CM, Semrau R, Kath R, Hoffken K. Isolated brain metastases as the sole manifestation of a late relapse in breast cancer. J Cancer Res Clin Oncol 2002;128: Engel J, Eckel R, Aydemir U, Aydemir S, Kerr J, Schlesinger-Raab A, et al. Determinants and prognoses of locoregional and distant progression in breast cancer. Int J Radiat Oncol Biol Phys 2003;55: Shaffrey ME, Mut M, Asher AL, Burri SH, Chahlavi A, Chang SM, et al. Brain metastases. Curr Probl Surg 2004;41: Clark GM, Sledge GW Jr, Osborne CK, McGuire WL. Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol 1987;5: 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: Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003;97: Lai R, Dang CT, Malkin MG, Abrey LE. The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma. Cancer 2004;101: Miller KD, Weathers T, Haney LG, Timmerman R, Dickler M, Shen J, et al. Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 2003;14: Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37: Lagerwaard FJ, Levendag PC, Nowak PJ, Eijkenboom WM, Hanssens PE, Schmitz PI. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys 1999;43: Shmueli E, Wigler N, Inbar M. Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment. Eur J Cancer 2004;40: Kallioniemi OP, Holli K, Visakorpi T, Koivula T, Helin HH, Isola JJ. Association of c-erbb-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor longterm survival in breast cancer. Int J Cancer 1991;49: Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, Stewart AL, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004;91: Tsuda H, Takarabe T, Hasegawa F, Fukutomi T, Hirohashi S. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. Am J Surg Pathol 2000;24: Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, Benitez J, et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res 2006;12: Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004; 350: Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2: Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33: Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322: Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B, et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996;78:

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy