09)

ORIGINAL ARTICLE Journal of Breast Cancer J Breast Cancer 11 February; 14(S): S57-63 DOI: 1.48/jbc.11.14.S.S57 수술후보조적방사선치료를포함한근치적치료를받은유방암환자들의뇌전이발생률과연관된인자분석 배선현ㆍ최두호ㆍ허승재ㆍ임도훈ㆍ박원ㆍ남희림ㆍ양정현 1 ㆍ남석진 1 ㆍ이정언 1 ㆍ임영혁 2 ㆍ안진석 2 ㆍ박연희 2 성균관대학교의과대학삼성서울병원방사선종양학과, 1 외과, 2 혈액종양내과 Incidence of Brain Metastasis and Related Subtypes in Patients with Breast Cancer Receiving Adjuvant Radiation Therapy after Surgery Sun Hyun Bae, Doo Ho Choi, Seung Jae Huh, Do Hoon Lim, Won Park, Heerim Nam, Jung-Hyun Yang 1, Seok-Jin Nam 1, Jeong Eon Lee 1, Young-Hyuck Im 2, Jin-Seok Ahn 2, Yeon Hee Park 2 Departments of Radiation Oncology, 1 Surgery, 2 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Purpose: To assess the incidence of brain metastasis in patients with breast cancer receiving surgery and adjuvant radiotherapy (RT) and to evaluate subtypes associated with brain metastasis. Methods: We retrospectively reviewed the medical records of 1, patients with breast cancer who were treated with surgery and adjuvant RT for a cure between January 1 and July 5 at Samsung Medical Center. Seventy-one patients received neoadjuvant chemotherapy before surgery. The pathological stage was I in 43 patients, II in 327, and III in 243. We divided the patients into three subtypes according to immunohistochemistry: triple negative (TN, 245 patients), human epidermal growth factor 2 (HER2) enriched (HE, 166 patients) and positive estrogen receptor or progesterone receptor without HER2 overexpression (EP, 589 patients). The median follow up time was 72 months after surgery. Results: Locoregional failure-free survival rate and distant metastasis-free survival rate at 5 years were 92.8% and 86.1%, respectively. The disease free survival rate and overall survival rate at 5 years were 84.6% and 94.7%, respectively. Thirty-nine patients had brain metastasis, and the brain metastasis-free survival rate at 5 years was 97.2%. A univariate analysis showed that younger age, neoadjuvant chemotherapy, modified radical mastectomy, advanced pathological stage and the TN and HE subtypes were significant risk factors for brain metastasis. A multivariate analysis revealed that age, neoadjuvant chemotherapy, pathological stage and the TN and HE subtypes were statistically significant factors for brain metastasis. Conclusion: The cumulative incidence of brain metastasis was 3.9% after curative treatment. If patients have a clinically suspicious symptoms suggesting brain metastasis, clinicians should be aware that an early brain imaging work up and management are necessary. Because patients with the TN or HE subtypes accompanied by younger age and advanced pathological stage have increased brain metastasis (>1%), annual regular imaging follow-up may be recommended for these high risk patients. Key Words: Breast neoplasms, Immunohistochemistry, Neoplasm metastasis, Brain, Radiotherapy 중심단어 : 유방암, 면역조직화학적아형, 뇌, 전이, 방사선치료 책임저자 : 최두호 135-71 서울시강남구일원동 5, 성균관대학교의과대학삼성서울병원방사선종양학과 Tel: 2-341-2436, Fax: 2-341-2619 E-mail: doho.choi@samsung.com 접수일 : 1 년 11 월 5 일게재승인일 : 11 년 2 월 7 일 서론유방암은고형암의뇌전이원발암중두번째로흔한원인으로알려져있고임상적으로뇌전이율은 16% 까지보고되었다.(1,2) S57

S58 Sun Hyun Bae, et al. 하지만유방암환자 1,44명의중추신경계전이에대한부검연구에의하면부검결과뇌전이는 193 명 (18%) 에서발견되었고중추신경계전이환자의 31% 만이사망전에임상적으로전이가진단되었다는것을고려하면실제뇌전이율은저평가되었을것으로생각된다.(3) 또한최근새로운표적치료제와항암제의발달로유방암환자의무병기간과생존율이증가하였고전이성환자의예후는증진되었지만, 이들약제가혈액뇌관문을통과하지못하기때문에동시적으로뇌전이율이증가하여연구에따라뇌전이율을 25-36% 까지보고하였다.(4-7) 가장높은뇌전이율을보고한 Ono 등 (7) 에따르면 human epidermal growth factor 2 (HER2) 과발현인재발성혹은전이성유방암환자에서 trastuzumab를포함하는항암치료제를사용하였을때 36.3% 에서경과관찰중뇌전이가발견되었다. 년 Perou 등 (8) 은유방암이특이한유전자발현정도에따라다양한표현형을나타내고이를여러개의분자학적아형으로구분할수있다고발표하였다. 그뒤분자학적아형에따른예후의차이와항암치료의반응도의차이가보고되었다.(9-11) 최근에는유전자발현정도에따라원격전이가기관특이적으로나타난다는연구결과들이발표되었고,(12-16) Smid 등 (16) 에따르면 HER2 과발현혹은 basal subtype의경우뇌전이율이다른분자생물학적아형보다높다고보고하였다. 한편, 면역조직화학적검사를통한호르몬수용체유무에따른연구결과들도발표되어에스트로겐수용체 (estrogen receptor, ER) 음성이거나 HER2 과발현의경우뇌전이위험성이높다고보고되었다.(17-19) 그러나근치적치료를시행한원발성유방암과재발성혹은전이성유방암은생물학적행태가다르다는것을고려할때근치적치료를시행한환자에서뇌전이율과이와연관된인자는거의보고되지않았다.(16,) 이에본연구는유방암진단후수술을시행하고보조적방사선치료를받은환자들을대상으로뇌전이발생률을알아보고이와연관된면역조직화학적아형을분석하였다. 방법 1년 1월부터 5년 7월까지삼성서울병원에서유방암으로진단받고수술후보조적방사선치료를받은환자는총 1,2 명이었다. 유방보존수술을시행한환자는모두방사선치료를받았고변형근치적유방절제술을시행한환자는병리학적원발병소의병기가 3기이상혹은액와림프절전이가 4개이상인경우에만시행되었다. 이중에서진단시호르몬수용체에대해서면역조직화학적검사결과가보고되었고 HER2의경우는면역조직화학적검사에서 2+ 인경우형광제자리부합법을시행하여유전자증폭여부를확인한환자 1,명을대상으로후향적으로분 석하였다. 환자의연령분포는 21-세로중앙값은 46 세였고모든환자는전신수행도 (Eastern Cooperative Oncology Group 분류 ) 가 1 이하로연령에상관없이임상적혹은병리학적병기에따라근치적목적의모든치료를받았다. 환자는치료전절제생검이나초음파유도하에서핵생검법을통해유방암진단후수술을시행하였다. 대상환자의특성은 Table 1에정리하였다. 71 명은임상적 Table 1. Patients characteristics Characteristic No. (%) Age (yr)* 244 (24.4) > 756 (75.6) Neoadjuvant chemotherapy Yes 71 (7.1) No 929 (92.9) Operation MRM 234 (23.4) BCS 766 (76.6) Pathologic stage I 43 (43.) II 327 (32.7) III 243 (24.3) Pathology IDC 881 (88.1) Others 119 (11.9) Estrogen receptor Positive 627 (62.7) Negative 373 (37.3) Progesterone receptor Positive 5 (54.) Negative 458 (45.8) Unknown 2 (.2) HER-2 Positive 166 (16.6) Negative 834 (83.4) Hormone treatment Yes 631 (63.1) No 342 (34.2) Unknown 27 (2.7) Adjuvant chemotherapy Yes 841 (84.1) No 159 (15.9) MRM=modified radical mastectomy; BCS=breast conserving surgery; IDC=invasive ductal carcinoma. *Median age was 46 yr; Others are including invasive lobular carcinoma, infiltrating cribriform carcinoma, invasive micropapillary carcinoma, mucinous carcinoma, infiltrating apocrine carcinoma, metaplastic carcinoma, medullary carcinoma and tubular carcinoma; Eight patients refused hormone therapy; Nine patients refused adjuvant chemotherapy; two patient could not receive chemotherapy due to neutropenia and thrombocytopenia.

Incidence of Brain Metastasis and Related Subtypes in Breast Cancer S59 원발병소병기가 3기이상혹은액와림프절전이가있었던국소진행성유방암으로수술전선행항암화학요법을받았고세명을제외한환자에서 anthracycline을포함하는복합항암요법을사용하였다. 수술방법은원발병소의임상적병기에따라변형근치적유방절제술이 234 명에서시행되었고유방보존수술은 766 명에서시행되었다. 병리조직학적유형은침윤성관상피암종이 881 명으로가장많았다. 수술후병리학적병기는제7판 American Joint Committee on Cancer (AJCC) 병기결정기준에따라분류하였고 43 명이 1기, 327 명이 2기, 그리고 243 명이 3기였다.(21) 수술검체의면역조직화학검사에서 ER 양성은 627 명, 프로게스테론수용체 (progesterone receptor, PR) 양성은 5명, 그리고 HER2 과발현은 166 명이었다. 이들을면역조직화학적특성에따라삼중음성군 (245명), HER2 과발현군 (166명), 그리고 HER2 과발현이없으면서 ER 혹은 PR 양성인군 (589명) 의세가지아형으로나누었다 (Table 2). 수술후항암화학요법은환자의연령과병리학적병기를고려하여초기에는 cyclophosphamide+methotrexate+5-fluorouracil 복합항암요법을시행하였고, 1년도후반부터는주로 anthracycline 또는 docetaxel을포함하는항암화학요법이시행되었다. ER 혹은 PR 양성인환자중 619 명은타목시펜혹은아로마타제억제제로호르몬치료를받았고, HER2 과발현으로 trastuzumab 치료를받은사람은 16명이었다. 수술후보조적방사선치료는 4-6MV 광자선을이용하여동측흉벽이나남은유방부위에접사면조사 (tangential technique) 로치료하였다. 방사선조사량은하루에 1.8-2. Gy씩총 5-5.4 Gy를조사하였고유방보존수술을시행한환자는수술부위에하루에 2-3 Gy씩 9-1 Gy 를전자선으로추가조사하였다. 그리고 271 명은쇄골상부림프절영역에 5-5.4 Gy를조사받았다. 재발여부는국소재발과원격전이로나누어분석하였고국소재발의경우는동측흉벽, 남은유방조직, 동측액와림프절, 동측 Table 2. Immunohistochemical subtypes according to status of ER, PR, and HER2 overexpression Subtype No. (%) Triple negative* 245 (24.5) HER2 enriched 166 (16.6) ER/PR positive without HER2 overexpression 589 (58.9) ER=estrogen receptor; PR=progesterone receptor. *Negative estrogen receptor (ER), negative progesterone receptor (PR) and without HER2 overexpression; HER2 overexperssion regardless of status of ER and PR; ER positive or PR positive or both positive. 쇄골상부림프절과동측내유림프절에서발생한것으로정의하였고, 그외다른부위에재발한경우는전신재발로정의하였다. 뇌전이는경과관찰중시행한뇌자기공명영상에서뇌실질에병변이관찰되는경우로정의하였다. 척수연수막전이나뇌실질전이를동반하지않는경막전이는제외하였다. 생존율은 Kaplan-Meier 분석을사용하였으며, 생존곡선의비교는단변량분석으로 log-rank test를, 다변량분석으로 Cox multivariate regression model을사용하였고통계학적유의수준은 p<.5으로하였다. 통계프로그램은 The SAS System (SAS 8.; SAS Institute Inc., Cary, USA) 을이용하였다. 결 추적조사기간은수술시행후 7-111개월로중앙값이 72개월이었다. 전체환자의 5년국소제어율은 92.8%, 원격전이제어율은 86.1%, 무병생존율은 84.6%, 전체생존율은 94.7% 이었다. 뇌전이는근치적목적으로치료를받은 1,명의환자중, 39 Cumulative incidence of brain metastasis 과 3.9% 5 4 3 2 1 12 24 36 48 72 84 96 18 Figure 1. Cumulative incidence of brain metastasis. 97.2% at 5 yr 12 24 36 48 72 Figure 2. Five-years brain metastasis (BM) free survival rate.

S Sun Hyun Bae, et al. 명 (3.9%) 의환자에서관찰되었고뇌전이발생의중앙값은 46 개월 ( 범위, 9-97개월 ) 이었다 (Figure 1). 전체환자의 5년뇌전이무병생존율은 97.2% 였다 (Figure 2). 뇌전이에영향을미치는인자를알아보기위해단변량분석을시행하였을때 세이하, 선행항암화학요법을시행한경우, 변형근치적유방절제술을시행한경우, 병리학적병기가높을수록, ER 음성, PR 음성, 그리고 HER2 과발현의경우통계적으로유의하게뇌전이의위험성이증가하였다 (Table 3). 추가적으로면역조직화학적특성에따른세가지아형에따라서단변량분석을시행하였을때, 5년뇌전이무병생존율이 HER2 과발현군에서 91.9% 로가장낮았고삼중음성군이 95.2%, HER2 과발현이없으면서 ER 혹은 PR 양성인군이 99.4% 으로세군사이의뇌전이율은통계적으로유의하게차이를보였다 (p<.1) (Figure 3). Cox multivariate regression model을이용한다변량분석 Table 3. Univariate analysis of factors associated with brain metastasis free survival Characteristic 5-yr BMFS rate (%) p-value Age (yr) 94.1.3 > 98.1 Neoadjuvant chemotherapy Yes 85.8 <.1 No 98. Operation MRM 92.2 <.1 BCS 98.7 Pathologic stage I 98.7 <.1 II 98.4 III 92.8 Pathology IDC 97..4637 Others* 98.2 Estrogen receptor Positive 98.2.318 Negative 95.3 Progesterone receptor Positive 98.5.135 Negative 95.6 HER2 Positive 91.9 <.1 Negative 98.2 BMFS=brain metastasis free survival; MRM=modified radical mastectomy; BCS=breast conserving surgery; IDC=invasive ductal carcinoma. *Others are including invasive lobular carcinoma, infiltrating cribriform carcinoma, invasive micropapillary carcinoma, mucinous carcinoma, infiltrating apocrine carcinoma, metaplastic carcinoma, medullary carcinoma and tubular carcinoma. 에서연령, 선행항암화학요법, 병리학적병기그리고면역조직화학적아형이뇌전이율과연관하여통계적으로유의한인자였다 (Table 4). 단변량분석과다변량분석에서모두유의하게나온인자들을가지고뇌전이위험성에대해서하위군분석을시행하였다 (Table 5). 하위군중에서 세이하이면서병리학적병기가 3기인경우뇌전이가 13.7% 에서발생하고 5년뇌전이무병생존율이 9.9%, 수술후뇌전이발생의중앙값은 43.5개월이었다 ( 범위, 14-97개월 ). 세이하이면서병리학적병기가 3기, 선행항암화학요법을시행한환자군에서는 35.7% 에서뇌전이가발생하고뇌전이무병생존율이 68.1%, 수술후뇌전이발생의중앙값은 32개월이었다 ( 범위, 14-82개월 ). 두환자군모두에서면역조직화학적아형에따라삼중음성군이나 HER2 과발현군이 HER2 과발현이없으면서 ER 혹은 PR 양성인군보다뇌전이를많이하는차이를보였으나통계적으로유의하지는않았다 (Figure 4). 9 ER/PR(+) without HER2 overexpression p<.1 Triple negative HER2 enriched 12 24 36 48 72 Figure 3. There was a statistically significant difference in brain metastasis (BM) free survival according to hormone subtype: 91.9% in HER2 enriched group, 95.2% in triple negative group and 99.4% in ER+/- PR positive without HER2 overexpression (p<.1). ER=estrogen receptor; PR=progesterone receptor. Table 4. Cox multivariate regression analysis of risk factors affecting brain metastasis free survival Characteristic Hazard ratio (95% confidence limits) p-value Age > yr.4 (.25-.89).2 Use of neoadjuvant chemotherapy 2.7 (1.28-5.82).88 MRM 1.8 (.76-4.64).165 Pathologic stage III 1.4 (1.7-1.95).155 ER/PR positive* without.6 (.48-.79).2 HER2 overexpression MRM=modified radical mastectomy; ER=estrogen receptor; PR= progesterone receptor. *ER positive or PR positive or both positive.

Incidence of Brain Metastasis and Related Subtypes in Breast Cancer S61 Table 5. Subgroups analysis according to risk factors affecting brain metastasis free survival on both univariate and multivariate analysis No. of patients with BM (%) 5-yr BM free survival rate (%) TN HE EP p-value All patients 39/1, (3.9) 97.2 95.2* 91.9 99.4 <.1 Age 19/244 (7.8) 94.1 9.3 89.7 98..543 Age +pstage III 1/73 (13.7) 9.9 63.9 88.1.544 Age +pstage III+ 5/14 (35.7) 68.1 26.6 66.7.75 neoadjuvant chemotherapy BM=brain metastasis; TN=triple negative (negative estrogen receptor [ER], negative progesterone receptor [PR] and without HER2 overexpression); HE=HER2 enriched (HER2 overexperssion regardless of status of ER and PR); EP=ER positive or PR positive or both positive without HER2 overexpression; pstage=pathologic stage. *5-yr BM free survival rate. ER/PR(+) without HER-2 overexpression ER/PR(+) without HER2 overexpression p=.544 HER2 enriched Triple negative p=.75 HER2 enriched Triple negative 12 24 36 48 72 A 12 24 36 48 72 B Figure 4. There was a difference in brain metastasis (BM) free survival according to immunohistochemical subtypes (A) in patients with younger age ( yr) and pathologic stage III (B) in patients with younger age ( yr), pathologic stage III and neoadjuvant chemotherapy. ER=estrogen receptor; PR=progesterone receptor. 고찰본연구에서근치적치료를받은유방암환자를후향적으로분석하였을때뇌전이발생률은 3.9% 였다. 그동안뇌전이의빈도가 1-16% 정도로인식되다가최근새로운표적치료제와항암제의사용으로 25-36% 까지증가한것을고려하면본연구와많은차이가발견된다.(1-7) 그러나지금까지보고된연구들의연구대상은대부분재발성혹은전이성유방암환자였고초기유방암에서 -3% 가원격전이를한다는것을고려하면전체환자중에서뇌전이환자의비율은훨씬적을것으로생각된다.(22) Lee 등 (23) 은 199년부터 6년까지조직학적으로진단된유방암환자중에서 198명 (2.5%) 이뇌전이가발생하였다고보고하였다. Gonzalez-Angulo 등 () 은선행항암화학요법을시행한원격전이가없었던국소진행성혹은염증성유방암환자 768명중 8% 에서중추신경계전이가발생하였고이중 % 가뇌전이였다고보고하였다. 따라서원격전이가없는유방암환자에서근치적치 료를시행후뇌전이가발생할위험성은 6.5% 이내로추정되고, 한국유방암학회에서발간한유방암백서 (24) 에서국내조기유방암의비율이 6년도에 48.8% 이고그비율이점차증가하는경향을보이는것을고려하면우리나라에서근치적치료후뇌전이가발생할위험성은더낮을것으로추정되고본연구결과와일치하는것으로생각된다. 본연구에서뇌전이는 9-97개월사이에발생하였고중앙값이 46개월로이전의보고된 27-32개월보다늦게진단되었는데이는대상환자군의차이때문으로생각된다.(,23) 본연구에서는 1기가 43.2%, 2기가 32.7% 로조기유방암이 5% 이상을차지한다. Gonzalez-Angulo 등 () 은종양의크기가클수록, 액와림프절전이가양성일때그리고병리학적병기가높을수록통계적으로유의하게뇌전이위험성이증가하고, 따라서질병경과가더진행된종양일수록뇌전이까지간격이짧아진다고하였다. 발생시기에있어서는세연구간에차이가있지만시간이경과하더라도뇌전이는계속발생한다는점과 5년이상경과한후에도다른

S62 Sun Hyun Bae, et al. 부위의재발없이뇌전이가발견되거나, 원격전이와동반해서함께혹은추가적으로발생하는경우가지속적으로관찰된다는점은일치한다. 본연구는이미알려져있는임상적, 병리학적요인들외에도호르몬수용체에따라 ER 음성, PR 음성, HER2 과발현그리고면역조직화학적아형중 HER2 과발현군혹은삼중음성군모두가뇌전이에대한단변량분석과다변량분석에서통계적으로유의한인자임을보고하였다. 이는 Smid 등 (16) 이유전자발현정도에따라유방암환자를여러분자생물학적아형으로나누었을때 HER2 과발현혹은기저형 (basal subtype) 의경우뇌전이율이증가한다는보고와재발성혹은전이성유방암환자를연구한최근의연구들에서 HER2 과발현군의경우나 ER 음성혹은 PR 음성일경우뇌전이가증가한다는보고와일치한다.(8,17-19) 그러나여러연구들에서보고한것처럼 HER2 과발현군에서 trastuzumab로치료할때뇌전이율이증가하는현상은본연구에서 HER2 과발현환자중에서 2년도후반기부터 1% 만이 trastuzumab 치료를받았다는점을고려할때아직해석하기에어려움이있다. Graesslin 등 (19) 은재발성혹은전이성유방암환자의뇌전이에영향을미치는인자들을분석하였고연령, 종양의분화도, ER 상태, HER2 과발현유무, 원격전이의수, 그리고진단부터재발까지시간간격이독립적으로중요한인자임을확인하였고, 각각의인자를점수화하여계산도표를만들고환자특성에따라뇌전이위험성을예측하려고시도하였다. Slimane 등 (17) 은전이성유방암환자의특성을분석하였을때처음원격전이가발생한장기가폐이거나호르몬수용체음성인경우가그렇지않은환자에비해뇌전이의위험성이크기때문에해당환자의경우뇌전이여부를확인하기위한선별검사가필요하고, 예방적전뇌조사 (prophylactic cranial irradiation) 혹은혈액뇌관문을통과하는약제사용에대한연구가필요하다고제안하였다. 근치적치료를시행한유방암환자를대상으로한본연구에서는하위군분석에서 세이하, 병리학적병기가 3기인경우뇌전이가 13.7%, 세이하, 병리학적병기가 3기그리고선행항암화학요법을시행한경우뇌전이가 35.7% 로전체환자군에비해뇌전이위험성이높았다. 이들환자군에서면역조직화학적아형에따라분석할때삼중음성군이나 HER2 과발현일경우그위험성이더증가하는것이관찰되었으나통계적으로유의하지는않았는데이는환자수가적어서유의성판단을위해서는더많은환자수가필요하다고생각된다. 이러한고위험군에서, 수술후 14 개월이후에지속적으로뇌전이가발생하는것을고려할때수술후 1년마다뇌전이여부를확인하기위한선별검사를고려할수있을것으로생각된다. 결론적으로근치적치료를받은유방암환자에서뇌전이발생 률은 3.9% 였다. 뇌전이는시간이경과하더라도계속발생하기때문에경과관찰중에환자가임상적으로뇌전이가의심되는증상 ( 두통, 구역, 구토, 행동장애, 성격변화, 신경학적증상등 ) 을호소하는경우뇌전이의가능성을고려하여빠르고적절한검사와처치가필요할것으로생각된다. 특히 세이하, 병리학적병기가 3기인경우뇌전이발생률이 1% 를넘고, 이를면역조직화학적아형에따라분류할때삼중음성군이나 HER2 과발현에서그위험성이증가하는경향성을보였다. 본연구결과를고려하면이러한위험군의특성을지닌환자들에서는근치적치료후 1년마다뇌전이유무를확인하기위한선별검사를고려할수있을것으로생각되지만, 본연구가후향적으로분석되었고연구대상이된환자의표본수가충분하지않아결과적으로뇌전이발생수가 39 예에불과하여향후대규모환자를대상으로한추가적인연구가필요할것으로생각된다. 참고문헌 1. Zimm S, Wampler GL, Stablein D, Hazra T, Young HF. Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer 1981;48:384-94. 2. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 4;22:38-17. 3. Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer 1983;52: 2349-54. 4. Lai R, Dang CT, Malkin MG, Abrey LE. The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma. Cancer 4;11:81-6. 5. Lower EE, Drosick DR, Blau R, Brennan L, Danneman W, Hawley DK. Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival. Clin Breast Cancer 3;4:114-9. 6. 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 4;91:639-43. 7. Ono M, Ando M, Yunokawa M, Nakano E, Yonemori K, Matsumoto K, et al. Brain metastases in patients who receive trastuzumab-containing chemotehrapy for HER2-overexpressing metastatic breast cancer. Int J Clin Oncol 9;14:48-52. 8. Perou CM, Sorlie T, Eisen MB, Van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature ;6: 747-52. 9. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al.

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