Premenapozal meme kanserli hastalarda tamoksifene bağlı hepatosteatoz

Öz

While aromatase inhibitors are replacing tamoxifen in postmenopausal breast cancer patients, tamoxifen continues to be the first-line hormonal therapy in premenopausal patients. Tamoxifen-induced hepatosteatosis may lead to nonalcoholic steatohepatitis (NASH), and NASH may develop into cirrhosis. If the development of hepatosteatosis is predicted, these patients may be treated with fibrates and statins. This study examines the development of hepatosteatosis in our premenopausal breast cancer patients that were taking tamoxifen for adjuvant therapy and were positive for the hormone receptors. Patients histopathologically diagnosed with breast cancer and with immunohistochemically demonstrated estrogen and/or progestron receptor expression were recruited for the study. All patients were assessed with ultrasonography by the same radiologist before tamoxifen therapy, at the sixth month of the follow-up and at the end of the first year. The study results were evaluated in thirty patients. Initial ultrasonography revealed grade 2 hepatosteatosis in four patients (13.3%), no change occurring at the repeat ultrasonography performed at the sixth month of the follow-up. Seven patients (23. 3%) were diagnosed as having grade 1 hepatosteatosis. A total of 12 patients (40%) were found to have hepatosteatosis at the end of the first year. Findings at the outset and those at the end of the first year were significantly different (p=0.021) as determined with the Wilcoxon test and Bonferroni correction performed to ascertain the difference in hepatosteatosis between the outset and the follow-up periods. No difference was obtained between the findings for the sixth month and those obtained at the end of the first year. In conclusion, the rate of hepatosteatosis as assessed with ultrasonography shows an increase with tamoxifen use in premenopausal patients. There was no difference between ultrasonography findings at the end of the first year and those at the sixth month of the follow-up. We think that the sitxh-month ultrasonography bears importance from the viewpoint of hepatosteatosis in these patients.

Anahtar Kelimeler

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Tamoxifen-induced hepatic steatosis in premenopausal breast cancer patients

Öz

Meme kanserli postmenopozal hastalarda aromataz inhibitörleri tamoksifenin yerini alırken premenopazal hastalarda tamoksifen ilk basamak hormonal tedavi olmaya devam etmektedir. Tamoksifen kullanımına bağlı hepatosteatoz sonrası nonalkolik steatohepatit (NASH) gelişebilmekte ve NASH siroza ilerleyebilmektedir. Hepatosteatoz gelişimi önceden tespit edilirse fibratlar veya statinler ile bu hastalar tedavi edilebilirler. Biz bu çalışmamızda adjuvan tedavisinde tamoksifen kullandığımız hormon reseptörü pozitif premenopozal meme kanseri hastalarımızda hepasteatoz gelişimini araştırdık. Histopatolojik olarak meme kanseri olduğu tespit edilmiş ve östrojen ve/veya progesteron reseptör ekspresyonu immünohistokimyasal olarak gösterilmiş premenopozal hastalar çalışmaya alındı. Bütün hastalara tamoksifen kullanmadan önce, takibinin altıncı ayında ve birinci yılı sonunda aynı radyolog tarafından karaciğer ultrasonografisi yapıldı. Çalışma sonuçları 30 hastada değerlendirildi. Hastalardan dördünde (%13.3) başlangıç ultrasonografisinde grade 2 hepatosteatoz, takibinin altıncı ayında yapılan ultrasonografide bu hastaların hepatosteatozunda değişiklik tespit edilmez iken 7 hastada (%23.3) grade 1 hepatosteatoz, birinci yıl sonunda toplam 12 hastada (%40) hepatosteatoz saptandı. Ultrasonografi takip zamanları arasında hepatosteatoz farkını araştırmak için yapılan Wilcoxon testi ve Bonferroni düzeltmesi ile başlangıç ile altıncı ay bulguları anlamlı farklı idi (p=0.021). Başlangıç bulguları ile birinci yıl bulguları anlamlı farklı bulundu (p=0.003). Altıncı ay bulguları ile birinci yıl bulguları arasında fark tespit edilemedi. Sonuç olarak tamoksifen kullanımı ile ultrasonografik olarak tespit edilen hepatosteatoz oranı premenapozal hastalarda artmaktadır. Birinci yıl sonundaki ultrasonografi bulguları ile altıncı ay ultrasonografi bulguları arasında fark bulunmamaktadır. Bu hastalarda hepatosteatoz açısından altıncı ay ultrasonografisinin önemli olduğunu düşünmekteyiz.

Anahtar Kelimeler

• Meme kanseri, hepatosteatoz, tamoksifen

Kaynakça

1. 1. International Breast Cancer Study Group, Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, et al. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 2006;24(9):1332-41.
2. 2. Swedish Breast Cancer Cooperative Group, Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 1996;88(21):1543- 9.
3. 3. Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R, Col NF. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003;18(11):937-47.
4. 4. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116(6):1413-9.
5. 5. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346(16):1221-31.
6. 6. Farrell GC. Drugs and steatohepatitis. Semin Liver Dis 2002;22:185-94.
7. 7. Chu C-H, Lin S-C, Shih S-C, Kao C-R, Chou S-Y. Fatty metamorphosis of the liver in patients with breast cancer: possible associated factors. World J Gastroenterol 2003;9(7):1618-20.
8. 8. Coşkun U, Törüner FB, Günel N. Tamoxifen therapy and hepatic steatosis. Neoplasma 2002;49(1):61-4.

9. 9. Murata Y, Ogawa Y, Saibara T, Nishioka A, Fujuwara Y, Fukumoto M, et al. Unrecognized hepatic steatosis and nonalcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. Oncol Rep 2000;7(6):1299-304.
10. 10. Kotiloglu G, Aki ZS, Ozyilkan O, Kutlay L. Tamoxifen-induced cirrhotic process Breast J 2001;7(6):442-3.
11. 11. Nemoto Y, Saibara T, Ogawa Y, Zhang T, Xu N, Ono M, et al. Tamoxifen-induced nonalcoholic steatohepatitis in breast cancer patients treated with adjuvant tamoxifen. Intern Med 2002;41(5):345-50.
12. 12. Cai Q, Bensen M, Greene R, Kirchner J. Tamoxifen-induced transient multifocal hepatic fatty infiltration. Am J Gastroenterol 2000;95(1):277-9.
13. 13. Hozumi Y, Kawano M, Miyata M. Severe hypertriglyceridemia caused by tamoxifen-treatment after breast cancer surgery Endocr J 1997;44(5):745-9.
14. 14. Jonkers GH. Tamoxifen and hypertriglyceridemia. Neth J Med 1999;55(2):84-5.
15. 15. Love RR, Newcomb PA, Wiebe DA, Surawicz TS, Jordan VC, Carbone PP, et al. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with nodenegative breast cancer. J Natl Cancer Inst 1990;82(16):1327-32.
16. 16. Larosche I, Lettéron P, Fromenty B, Vadrot N, Abbey-Toby A, Feldmann G, et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther 2007;321(2):526-35.
17. 17. Gudbrandsen OA, Rost TH, Berge RK. Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. J Lipid Res 2006;47(10):2223-32.
18. 18. Lee MH, Kim JW, Kim JH, Kang KS, Kong G, Lee MO. Gene expression profiling of murine hepatic steatosis induced by tamoxifen. Toxicol Lett 2010;199(3):416-24.
19. 19. Ohnishi T, Ogawa Y, Saibara T, Nishioka A, Kariya S, Fukumoto M, et al. CYP17 polymorphism as a risk factor of tamoxifen-induced hepatic steatosis in breast cancer patients. Oncol Rep 2005;13(3):485-9.
20. 20. Elefsiniotis IS, Pantazis KD, Ilias A, Pallis L, Mariolis A, Glynou I, et al. Tamoxifen-induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance. Eur J Gastroenterol Hepatol 2004;16(6):593-8.
21. 21. Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005;330(7497):932.
22. 22. Liu CL, Huang JK, Cheng SP, Chang YC, Lee JJ, Liu TP. Fatty liver and transaminase changes with adjuvant tamoxifen therapy. Anticancer Drugs 2006;17(6):709-13.
23. 23. Bilici A, Ozguroglu M, Mihmanli I, Turna H, Adaletli I. A casecontrol study of non-alcoholic fatty liver disease in breast cancer. Med Oncol 2007;24(4):367-71.
24. 24. Saphner T, Triest-Robertson S, Li H, Holzman P. The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer 2009;115(14):3189-95. 25. Siegelman ES, Rosen MA. Imaging of hepatic steatosis. Semin Liver Dis 2001;21(1):71-80.
25. 26. Joseph AEA, Saverymuttu SH, Al-Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol 1991;43:26-31.
26. 27. Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol 2003;180(1):129-34.
27. 28. Ashraf M, Biswas J, Majumdar S, Nayak S, Alam N, Mukherjee KK, Gupta S. Tamoxifen use in Indian women adverse effects revisited. Asian Pac J Cancer Prev 2009;10(4):609-12.