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REVIEW ARTICLE 유방암의골전이에대한치료 Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine Su Yun Choi, MD, Won Hyuk Choi, MD, Chan Heun Park, MD.

1 REVIEW ARTICLE 유방암의골전이에대한치료 Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine Su Yun Choi, MD, Won Hyuk Choi, MD, Chan Heun Park, MD. 한림대학교의과대학강동성심병원외과학교실최수윤, 최원혁, 박찬흔 서론골전이는암이진행과정중최종단계로서많은합병증과함께사망률의증가가따르게된다. 여러종류의암에서골전이가많은원인에대하여 Stepem Paget(2) 은 The seed and soil 가설을주장하였다. 이것은어떤조직 (soil) 은어떤암세포 (seed) 가생존하고성장하는데알맞은환경을제공한다는가설이다. 현재이에대한분자생물학적인설명은혈중의암세포들이골수조직과같이비옥한곳에머물게되고미세전이성장을시작한다는 The seed and soil 가설을뒷받침하고있다. 다른장기에비해뼈는역동적이며복잡한구조로서암세포에적절한미세환경을제공함으로써전이의호발부위가되고있다. 암세포가뼈에서성장하려면혈액이풍부하게공급되어야하는데적색골수가많은축골, 늑골, 장골의근위부골간단, 척추가이에해당한다. 가장전이를잘하는장소는척추, 대퇴골, 골반골, 상완골순이다. 유방암의골전이는대개골용해성이며 15% 의경우골아세포성으로나타난다. 반대로전립선암의골전이는대개골아세포성으로비정상적인골형성을유발하게되는데이러한병태생리는골흡수와골형성의균형이깨지면서발생한다. 골전이의가장흔한증상은통증이며점차진행되면골절이생긴다. 골전이된유방암환자의 30% 가골파괴로인한고칼슘혈증이유발되며척수압박으로인한사지마비까지초래될수있다. 특히골용해성전이인경우에는전이된암세포에서분비되는물질이뼈의말초신경의통 골전이가진단된때로부터골합병증이일어난평균시간은전체적으로는 27개월이었고뼈에만전이된경우에는 11개월이었다. 뼈에만전이된환자의평균생존기간은 26개월이었으며다른장기에전이된경우에는 21개월로보고되었다. 6,7) 오랫동안암세포가뼈로전이되면서직접골파괴를일으켜서골융해를일으킨다고여겨져왔으나최근들어파골세포의활성도가증가됨으로써골파괴의원인이된다는증거가늘어나고있다. 그러므로이러한골파괴로인한합병증을막는새로운치료의개발에있어서파골세포가주요표적이되고있다. 3,4) 본론골전이는여러단계의과정을거치게되는데, 일단골전이가일어나게되면주위의미세환경과암세포간에상호교류 (crosstalk) 가일어나고이로인하여골전이및골파괴가악화되는상황이발생하게된다. 30) (Fig.1) 증수용체를자극하여지속적인통증을유발할수있다. 1) 책임저자 : 박찬흔 , 서울시강동구길동한림대학교의과대학강동성심병원외과학교실 Tel : , Fax : , hhh@hallym.or.kr 접수일 : 2008년 4월 21 일 ; 게재승인일 : 2008년 5월 19 일 Fig. 1. 골전이의악성순환 (from Molecular Cancer Therapeutics 2007;6) 15

2 유방암의골융해전이모델에서관여하는주요인자중의하나는암세포에존재하는 PTHrP이다. 골전이에의한골파괴의결과뼈에서 TGF-β가분비되는데이는다시 PTHrP를상승시키고결국파골세포를활성화시켜골파괴현상을악화시킨다. 파골세포생성은 RANK 리간드로부터유도되는데이것은 TNF 계 cytokine으로서골수기질세포나골아세포에서분비된다. 암세포에서생성된 PTHr는골아세포 (osteoblast) 및기질세포로부터 RANK리간드분비를자극하고이 RANKL은 RANK(receptor) 에결합하여파골세포를활성화시키게되는데파골세포의전구세포는 RANK 리간드의수용체를가지고있어서이것과결합하여파골세포형성및활성화를일으키게된다 PTH-rP외에 IL-1, IL-6, TCF-a 도파골세포를활성화시킨다. 한편 OPG(osteoprotegerin) 는 TNF계열의 cytokine으로, RANK 리간드를억제하는역할을하며이두물질의작용으로골전이양상이조절된다. 골전이의치료는증상에따르는치료가되며, 통증완회를위한방사선치료및진통제, 병적골절에대한정형외과치료, 그리고직접적으로암세포를사멸시키기위한치료 ( 항암제, 호르몬제, 표적치료 ) 가될수있으며, 최근에는골세포및골전이세포를표적으로하는치료로서골표적치료가사용되고있다.(Fig.2) Fig. 2. 골전이와연관된인자들에대한표적치료 (from The cancer journal.vol 14,2008) 골표적치료로는방사선약물제제 (Strontium-89, Samarium-153), Endothelin A receptor antagonist (Atrasentan), ZD4054, 비타민 D유사제 (calcitriol), Anti IGF-1receptor antibody(cp ), CXCR-4 표적제 (MSX-122), Bisphosphonate, Anti RANKL antibody(denosumab), Dasatinib(tyrosine kinase inhibitor that target Src), Anti IL-6 antibody(cnto328), 이외에혈관신성억제제로서 Bevacizumab, thalidomide가사용되고있으며, PDGF receptor 억제제로서 Imatinib, Sunitinib 를사용하는임상시험도진행되고있다. 29) 현재가장널리쓰이고있는 Bisphosphonate에대하여간단하게설명하고자한다. Bisphosphonate Pyrophosphate유도체인 bisphosphonate는파골세포와결합하여골파괴를감소시키며, 실험실결과파골세포의형태를변형시켜 Iysozyme 생성과분비를억제시키고, 파골세포의생성이나성숙도억제하는것으로나타났다. Bisphosphonate가유방암세포를사멸시키고암세포의침투능력을억제한다는보고도있다. 파골세포억제능력은 bisphosphonate의구조에따라다른데 amino를가진약제가가지지않은약제보다강력하다. Amino bisphosphonate는 mevalonate경로를차단함으로써억제효과를나타내는데, 이로써단백질의프레닐화를억제하여파골세포의모양과기능을변화시키고결국파골세포가사멸하게된다. 실험실검사상 Zoledronic acid가 bisphosphonate 중가장강력한프레닐화억제제로나타났다. Bisphosphonate 는 mevalonate경로억제작용외에 caspase를활성화시켜세포사멸에도작용하며, 골아세포로부터 OPG 생성을증가시켜파골세포의활성화를억제한다. 골전이시골형성과골흡수에관련된생화학적암표지자가진단과치료에도움이될수있다. 골형성표지자로는골특이 ALP(bone-specific alkaline phosphatase) 와 PINP (propetide of type 1 procollagen) 가있으며, 골흡수표지자로는소변내 NTX(collagen cross-linked N- telopeptide), CTX(collagen 1 carboxy-terminal telopeptide), PYD(pyridinolines), DYPD(deoxypyridinolines) 등이있다. 이러한생화학적표지자는 bisphosphonate요법의반응을확인하는데효과적이며이중 NTX가가장민감하다고보고하였다 (1) Clodronate 경구용과정맥주사용두가지가있다. Elomaa등은clo- dronate로인한골통증의감소, 새로운골용해병소의감소, 골절과고칼슘혈증의저하를보고하였고 Iveson 등은경구용 clodronate를 1,600mg씩매일 133명에게무작위로투여하여대조군과비교한결과새로운골전이가감소하였다고발표했다. Diel 등은골수미세전이가있는 302명의환자에서경구용 clodronate 1,500mg을 2년간투여한군과대조군을비교하여 bisphosphonate의골전이예방가능성에대해조사하였는데 16 Su Yun Choi Won Hyuk Choi Chan Heun Park

3 Korean Journal of Clinical Oncology Summer 2008 ; Vol.4, NO.1: clodronate를투여한군에서원격전이, 골전이, 내장전이가감소했고생존율이향상되었다고보고했다. 그후 288 명을 53개월추적관찰한결과 clodronate 사용군에서골전이와사망은감소했으나내장전이의예방효과는없었다고하였다. Clodronate는골통증에대한진통효과는크지만경구용보다는정맥주사가더효과적인데경구용은위장관에서잘흡수되지않는단점이있다. 13,14, 17,18) (2) Pamidronate 정맥주사용이있으며골통증과골절, 방사선요법빈도, 고칼슘혈증의빈도모두감소시킨다. Pamidronate는첫골전이가나타날때까지의시간을연장시키며합병증의빈도를줄인다고보고하였다. Pamidronate는골용해성골전이에효과가있으며, 골용해성골전이환자에서호르몬요법을받고있는환자중 pamidronate를사용한군이대조군에비해골합병증이낮고, 항암화학요법을받고있는골전이환자에서대조군에비해첫골합병증이나타날때까지의기간이연장되었으며골통증도감소하였다고하였다. Pamidronate는 90mg을 3~5주간격으로정맥으로 2시간이상주입한다. 15,16,19,20,21) (3) Zoledronic acid pamidronate에비해파골세포억제능력이매우강하며, 쥐의고칼슘혈증모델에서 pamidronate에비해조절능력이 850~ 1,000배강력하다고보고되었다. 고칼슘혈에서 pamidronate에비해빠르게저칼슘을유도하며약효가오래지속된다. 골전이환자에서 zoledronic acid 4mg을 4주마다 15분이상정맥주입하는것은 pamidronate 90mg을 4주마다정맥주입하는것과효과가비슷하며, Zoledronic acid는어떤형태의골전이에도효과가있다는장점이있다. 21,26,27) (4) Ibandronate Single amino bisphosphonate 인 ibandronate는유럽에서많이사용되고있는제제로서 Body 등은 ibandronate 6mg 을 3~4주간격으로 60주에서최대 96주를투입한결과, 대조군에비해 SMPR(skeletal morbidity period rate) 가감소했다고보고하였다. Tripathy 등은경구용 ibandronate 50mg을매일 96주간투여한결과 20% 의 SMPR의감소를보였다고했다. ibandronate는경구용이나정맥주사용모두골통증의감소와골합병증을줄이는데효과적인것으로나타났으며, 특히주목할만한것은체내에서의축적이적고조직내에서체류시간이짧아서신독성이매우적다는장점을가지고있다. 이는 bisphosphonate의사용기간을고려할때장기간사용시나타니는부작 용이적은제제로서매우중요하다고하겠다. 경구용 Ivandronate는 clodronate에비하여크기가작고한번에복용하는양이매우적어서경구용제제의단점인위장관내흡수율및위장관부작용이현격히개선되었다. 따라서경구용 Ivandronate는골전이환자의생활의질적인면에서상당한우수성을가진다고보고하고있다. 최근 zoledronic acid와의직접비교를통하여주사제및경구용 Ibandronate 모두 Zoledronic acid와비슷한효과를보인다고하였다. 22,24,25) 결론골전이는골절, 신경증상, 고칼혈증같은합병증을동반할수있으므로척추골절이나대퇴골골절같은합병증에특히유의해야한다. 골전이된경우호르몬요법이나전신항암화학요법이필요하며, 이와동시에 Bisphosphonate를병용하면어떤형태의골전이에서도골절을지연시키거나통증완화및다른합병증을줄일수있다. 특히골전이만있는경우대개서서히오랜기간을두고진행하게되므로장기간사용함에있어서사용이간편하고부작용이적은제제를선택하는것이좋을것으로사료된다. 최근보조요법으로서의사용및항암화학요법에따르는골손실에대한 Bisphosphonate 병합요법에대한연구가행하여지고있으며이외골세포및골전이세표를표적으로하는표적치료가항암제와병용요법으로임상시험중에있으므로머지않아골전이의예방및치료에대한새로운치료방침이나올것으로기대된다. REFERENCES 1. Martin TJ & Moseley JM(2000) mechanism in the skeletal complications of breast cancer. Endocrine Related Cancer,7, Paget S. The distribution of secondary growths in cancer of breast. Lancet, 1, Mundy GR. Metastasis to bone: causes consequences and therapeutic opportunities. Nat Rev Cancer 2002; 2: Coleman RE, Smith P, Rubens RD. Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 1998;77: Nielsen OS, Munro Al, Tannock If. Bone metastases. Pathophysiology and management policy. J Clin Oncol 1991;9: Singletary SE, Walsh C, Vauthey JN, et at. A role for curative surgery in the treatment of selected patient with metastatic breast cancer. Oncologist 2003;8: Keene JS, Sellinger DS, McBeath AA, et at. Metastatic breast cancer in the femur: a search for the lesion at risk for fracture. Clin Orthop 1986;203: Wilner D. Cancer metastasis to bone. In: Viler D, eds. Radiology 17

4 of bone tumors and allied disorders. Philadelphia:W.B. Saunders 1982: Domchek SM, Younger J, Finkelstein DM, et at. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 2000;89: Senaratne SG, Pirianov G, Mansi JL, et at. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000;82: Jagdev SP, Coleman RE, Shipman CM, et al. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 2001;84: Boissier S, Ferreras M, Peyruch Ì O, et al. Bisphosphonates inhibit prostate and breast carcinoma cell invasion, an early event in the formation of bone metastasis. Cancer Res 2000;60(11): Bisaz S, Jung A, Fleisch H.uptake by bone of pyrophosphonate, diphosphonate and their technitium derivatives. Clin Sci Mol Med 1978;54: Elomaa 1, Blomqvist C, Porkka L, et at. Treatment of skeletal disease in breast cancer: a controlled clodronate trial. Bone1987;8: Iveson TJ, Powle TJ, Tidy A, et at. Coldronate decrease the incidence of bone metastases in patients with advance or metastatic breast cancer but no clinical evidence of bone metastases. Br J Cancer 1995;71 (Suppl 24):15(abst 5,7). 16. Diel IJ, Solomayer EF, Costa SD, et at. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;6: Diel IJ, Solomayer E, Gollan C, et at. Bisphosphonates in the reduction of metastases in breast cancer: results of the extended follow up of the first study population. Proc Am Soc Clin Oncol 2000;19:82a (abst). 18. Major PP, Lipton A, Berenson J, et at. Oral bisphosphonates: areview of clinical use in patients with bone metastases.cancer 2000;88: Hortobagyi GN, Theriault RL, Porter L, et at. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and Iytic bone metastases: Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996;335: Theriault RL, Lipton A, Hortobagyi GN, et at. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and Iytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. JClin Oncol 1999; 17: Major p, Lortholary A, Hon J, et at. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001 ;19: Body JJ, Diel IJ, Lichnitzer MR et al Intravenous Ivandronate reduces skeletal complications in patients with breast cancer and bone metastasis. Ann Oncol 2003;14: Lichinitser M, Coleman R, Tjulandin S, et al. Non-inferiority of oral ibandronate to intravenous zoledronic acid for reducing markers of bone turnover in metastatic breast cancer patients. Presented at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA,8?-11 December Poster Body JJ, Lichinitser M, Tjulandin SA, et al. Safety of oral ibandronate and intravenous zoledronic acid in breast cancer patients with metastatic bone disease. Presented at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 8?-11 December Poster Coleman R, Gralow J, Bell R et al. Zoledronic acid is being invescigated for the prevention of bone metastasis in patients with early stage breast cancer.(2004) Bone 34(Suppl 1):S Gant M, Hausmaninger IL Samonigg Het al. Changes in bone mineraldensity caused by anaseazole or tamox-ifen in combination with goserelin(+/- zoledronate) as adjuvant treatment for hormone receptor positive Pre-menopausal breast cancer; results of a randomized multicenter trial Breast Cancer Res Treat 76(Suppl 1): Shi Ming Tu, Sue Hwa Lin. Current trials using bone target agents in prostate cancer The Cancer Journal 2008 vol 14 No 1: Lauren A. Kingsley et al. Molecular biology of bone metastasis Mol Cancer Ther 2007;6(10) Su Yun Choi Won Hyuk Choi Chan Heun Park

5 Korean Journal of Clinical Oncology Summer 2008 ; Vol.4, NO.1: Treatment Systemic Overview of Bone metastasis of 5-FU in Breast Cancer Based Chemotherapy in stomach Cancer Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine Su Yun Choi, MD. Won Hyuk Choi, MD. Chan Heun Park, MD. Abstract Bone is the most common site of metastasis from breast cancer, which cause various complication such as pain, fracture, and hypercalcemia. Patients with bone metastasis are at the risk of skeletal related events that can results in decreased quality of life. This complications depends on the osteolysis by the cancer cells, and cancer cells release some substances that activate osteoclast to cause bone destruction. The osteoclast also release various growth factors that can act back on the cancer cells to activate growth. This vicious cycle facilitates the growth of metastasis in bone. There are many treatment methids for patient with bone metastasis from breast cancer. These include bisphosphonate, antitumor endocrine and cytotoxic systemic therapies, radiotherapy, radionucleotides, and analgesics. Bisphosphonate are recommended still gold standard therapy and treatment guideline tend to recommend starting bisphosphonate at the time of diagnosis of bone metastasis. Currently a variety of new agents are developed that have evolved from a better understanding of the interaction between tumor cells and the cells on bone marrow microenvironment. These new bone targeted therapies show promising results and can improve treatment of bone metastasis from breast cancer. Key Words : breast cancer, brain metastasis Correspondence : Chan Heun Park, MD Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine. TEL : , FAX : , hhh@hallym.or.kr Received : April 21, 2008; Accepted : May 19,

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R