1. Erken Evre Meme Kanseri Tedavisinde Yan Etkiler: OSTEOPOROZ Dr. Sercan Aksoy Ankara Numune Eğitim ve Araştırma Hastanesi Tıbbi Onkoloji Kliniği 26 MART 2011, MEME KANSERİ VE HORMONLAR KURSUANKARA

3. Kemik Mineral Dansitometrisi Ölçümlerine Göre Osteopeni ve Osteoporoz için Tanı Sınıflaması Data from The World Health Organization Assessment of osteoporosis at the primary health care level. Summary report of a WHO Scientific Group. 2007; WHO, Geneva Kemik Kitlesi (T skoru) Normal ≥ -1 Düşük Kemik Kitlesi (osteopeni) 1 ile -2.5 arası Osteoporoz ≤ -2.5 Yerleşmiş Osteoporoz ≤ -2.5 + osteoporotik kırık

4. Tedavi ilişkili Kemik Kaybı Nedenleri Kemik kaybı GnRH agonist leri Bilateral oo ferektomi Bilateral or şiektomi Kemoterapiye bağlı o v er yetmezliği Artmış kemik turnover ı Pfeilschifter J, et al. J Clin Oncol. 2000;18:1570-1593. Theriault RL. Oncology (Williston Park). 2004;18(5 suppl 3):11-15. Dempster DW. Osteoporos Int. 2003;14 suppl 5:S54-S56. Azalmış kemik kalitesi Aromata z inhibit örleri Glu kokortikoidler H i pogonadi zm

5. Kanser Tedavileri ile Kemik Kaybı 1. Kanis JA. The European Foundation for Osteoporosis and Bone Disease. Osteoporos Int. 1997;7:390-406. 2. Eastell R, et al. J Bone Miner Res. 1990;5:1237-1241. 3. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311. 1. Yılda Kemik Kaybı (%) Doğal Gelişen Kemik Kaybı Kanser Tedavisi İlişkili Kemik Kaybı 0 2 4 6 8 10 Normal Erkek [1] Postmenop ozak Kadın [1] Menopozal kadın [1] Al T tedavisinde Postmenop ozal Kadın [2] ADT [3] Al Te davisi + GnRH agonist Premenop ozal Kadın [4] Kemoterapiye sekonder Prematur Menop oz [5] 0.5 1.0 2.0 2.6 4.6 7.0 7.7

7. Aromataz İnhibitörleri Klasifikasyonu Kuşak Tip I (Steroidal) Tip II (Non-Steroidal) Birinci YOK Aminoglutethimide İkinci Formestane Fadrozole Rogletimide Üçüncü Exemestane ( Aromasin ) Anastrozole Letrozole Vorozole

9. Letrozole Suppresses Plasma Estradiol and Estrone Sulphate More Completely Than Anastrozole in Postmenopausal Women With Breast Cancer J Clin Oncol 2008

10. Letrozole reduces plasma E2 and E1S levels to a significantly greater extent than anastrozole in postmenopausal women taking AIs as part of their adjuvant therapy for hormone receptor–positive breast cancer.

11. Serum E stradiol ve Kırık Riski Serum estradiol concentrations at base line and age-adjusted risk of subsequent hip or vertebral fracture in postmenopausal women over the age of 64 years. Compared to the reference group of the women with undetectable serum estradiol concentrations (below 5 pg/mL), those with higher baseline serum estradiol concentrations had a significantly lower relative risk of fracture of 0.3 to 0.5. To convert serum estradiol values to pmol/L, multiply by 3.67 Cummings, et al . N Engl J Med 1998; 339:733.

12. Steroidal ve Non - steroidal AI Tmx göre Kırık riskini artırıyor Tamoxifen Letrozole Anastrozole Pla s ebo Kırıklar (%) 11.0 7.7 5.7 4.0 5.3 4.6 7.0 5.0 P < .0001 P < .001 0 2 4 6 8 10 12 14 P = .003 P = .25 Exemestane ATAC [1] (68 Ay ) IES [2] (58 Ay ) BIG 1-98 [3] (26 Ay ) MA.17 [4] (30 Ay ) 1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127. 3. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757. 4. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.

15. SABRE: Risedronate ile AI ilişkili Kemik Kaybının Önlenmesi * P values from paired t-test for open-label, noncomparative groups. † P values from ANCOVA in favor of anastrozole plus risedronate. Anastrozole Düşük Risk (n = 26) Orta Risk (n = 114) Anastrozole+ Pla s ebo Anastrozole + Risedronate Anastrozole + Risedronate Yüksek Risk (n = 33) % Değişiklik KMD Bazal değerlendirmeden 24 Ay P = .0109* P = .5988* P = .0006* P = .0104* P < .0001 † P < .0001 † -2.0 -1.0 0 1.0 2.0 3.0 4.0 5.0 -3.0 Lumbar vertebra Total Kalça Van Poznak C, et al. J Clin Oncol. 2010;28:967-975.

17. Adjuvan Endo krin Tedavi ± Zoledroni k Asit: KMD’de değişiklik Gnant M, et al. Lancet Oncol. 2008;9:840-849. 10 5 0 -5 -10 -15 Percent Change in Lumbar Spine BMD (g/cm 2 ) From Baseline Ay Ay Ay Ay Zoledroni k A sit YOK Tamoxifen Anastrozole 36 60 -9.0 P < .0001 -4.5 NS -13.6 P < .0001 -7.8 P = .003 36 60 36 60 36 60 Zoledroni k A s i t Tamoxifen Anastrozole +1.0 NS +5.2 P = .04 -0.1 NS +3.1 NS

18. Brufsky, A. M. Oncologist 2008;13:187-195 Figure 2. Patients with normal bone mineral density, osteopenia, or osteoporosis in the lumbar spine treated with goserelin and anastrozole without (A) or with (B) zoledronic acid, which resulted in significantly better T-scores than with hormone therapy alone ( p < .0001 )

20. Z-FAST: Up-front Z A Lomber vertebra ve kalça BMD (KMD) artırır (N = 602) 1.96% * P values correspond to intergroup comparisons. † Intragroup comparisons from baseline to all time points for all treatment groups were significant ( P ≤ .0003 for all). L omber Vertebra Mean (SEM) Percent Change in BMD Up-front Z A 4 mg/6 ay Delayed ZOL 4 mg/6 ay Brufsky A, et al. SABCS 2009. Abstract 4083. P < .0001, all time points* † 8 6 4 2 0 -2 -4 -6 Mos 12 24 36 48 61 3.14% 3.85% 4.64% 6.19% -2.33% -2.89% -2.99% -3.05% -2.42% ∆ 4.29% ∆ 6.03% ∆ 6.84% ∆ 7.69% ∆ 8.61% 1.26% Total Kalça P < .001, all time points* † 4 3 2 1 0 -1 -4 -6 Mos 12 24 36 48 61 1.41% 1.68% 1.70% 2.57% -1.88% -3.15% -3.46% -4.02% -4.12% ∆ 3.14% ∆ 4.56% ∆ 5.14% ∆ 5.72% ∆ 6.69% -2 -3 -5

22. ABCSG-12: Z A belirgin olarak DFS artırır ( %36 ) 100 90 80 70 60 50 40 30 20 10 0 0 12 24 36 48 60 72 84 Randomizasyon sonrası süre (Ay) DFS (%) HR (95% CI) Olay , n vs No ZOL P Value Z A 54 0.64 (0.46-0.91) .01 Z A YOK 83 Z A YOK Z A Gnant M, et al. N Engl J Med. 2009;360:679-691. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Ortanca takip süresi : 48 Ay Olaylar (n) 10 10 9 6 29* 41* 20 10 83 54 * ZA Yok grupta 23 , ZA grupta 16 kemik metastazını da içeriri 100 90 80 70 60 50 40 30 20 10 0 İkincil kanser Kontrolateral MK Uzak Lo korejyonel

23. ZO-FAST 48 Ay : Up-front Z A Belirgin olarak DFS olayları riskini %41 azaltır Gecikmiş Z A (n = 532) Up-front Z A (n = 532) 50 45 40 35 30 25 20 15 10 5 Patients (n) 3 5 20 30 10 2 Rekürrens (36 Ay ) [2] * 1. Coleman R, et al. SABCS 2009. Abstract 4082. 2. Eidtmann H, et al. Ann Oncol. 2010;[Epub ahead of print]. Lo kal Uzak L enf nodu 0 1.0 0.8 0.6 0.4 0.2 0 0 6 36 42 48 54 60 66 Study Mo Survival Distribution Function Z A 4 mg up-front Z A 4 mg gecikmiş 12 18 24 30 Up-front Gecikmiş Patients, n 532 533 Events/censored 32/500 53/480 Median follow-up 48.0 48.1 HR (95% CI) 0.59 (0.38-0.92) Up-front vs delayed log rank P value .0175 DFS at Median Follow-up 48 Mos [1] *Multiple sites of metastases may be reported for the same patient. Sites of distant metastases include bone, brain, liver, lung, skin, lymph node, and other.

25. AI- Bağlı Kemik Kaybının Denosumab ile Önlenmesi Ellis GK, et al. J Clin Oncol. 2008;26:4875-4882. Percent Change in BMD From Baseline at Lumbar Spine 8 7 6 5 4 3 2 1 0 -1 -2 -3 1 3 6 12 24 Mos 5.5% Fark 12 . Ay 7.4% Fark 24 . Ay * P < .0001 vs placebo Pla s ebo (n = 122) Denosumab (n = 123) * * * * *

26. Lack of evidence for fracture prevention in early breast cancer bisphosphonate trials: A meta-analysis Gynecologic Oncology 117 (2010) 139–145 n= 7461 Bifosfonat (n= 3691 ) vs Tedavi Yok (n= 3770 )

33. Meme Kanseri Bayanlarda KMD takibi için ASCO Klavuzu Önerileri ASCO: American Society of Clinical Oncology; AI: aromatase inhibitor. Reproduced with permission from: Pant, S, Shapiro, CL. Aromatase inhibitor-associated bone loss. Drugs 2008; 68:2591. Copyright ©2008 Adis Data Information BV. KMD için İndikasyonlar: > 65 yaş bayan 60 - 64 yaşında olan years with the one or more of the following: Ailede Osteoporoz öyküsü Düşük vücut ağırlığı( < 70 kg ) Travmatik olmayan kırık öyküsü Diğer risk faktörleri sedentar yaşam, sigara AI kullanan postmenopozal hasta Premenop o sal hasta tedaviye bağlı erken menopoz

36. Teşekkürler