Meme Kanserinde Fertilitenin Korunması Doç. Dr. L. Cem Demirel ACIBADEM HASTANESİ IVF Ünitesi İstanbul During the last three decades there has been a tremendous improvement in the success rates of cancer treatments and a continual rise in the survival rates. Unfortunately the treatment agents carry a risk for future fertility potential. The ovaries containing a limited number of germ cells are prone to irreversible damage as a result of chemotherpy. Ovaries may undergo follicular loss that may end up with the complete absence of follicles. Leading to premature ovarian failure. Young women are much more likely to retain some degree of ovarain function compared wih women in thier late 30s and 40s. Unfortunately, aggressive chemotherapy especially with alkylating agents and ionizing radiotherapy can destroy gonads and subsequently lead to a loss of fertility and premature menopause. While many physicians treating cancer in younger patients are sensitive to these issues, oncologists traditionally have focused on providing the most effective treatments available to help prolong life. With the growing number of cancer survivors, much attention is now focused on their quality of life and the physical, psychological, social, and spiritual issues which they confront (10). A high quality of life for younger survivors may include the ability to have and raise a family. With such great improvements in survival rates for younger patients, oncologists must also pay attention to the impact of treatment on fertility and ways to preserve it. xxxxxsedcrtfvgb jnkml,

Türkiye: Kanser İnsidansı 15-44 yaş/100,000 (2005) Meme Lösemi Over Kolon ve rektum SSS Serviks NHL Tiroid Mide Akciğer Stocholm çalışması.

Yeni Meme Kanseri Vakalarının Yaşa Göre Dağılımı (ABD, 2007) ABD’de Yeni Meme Kanseri Vakalarının Yaşa Göre Dağılımı (2007) Yaş İnvaziv Kanser <45 16.150 (%9) ≥45 162.330 (%91) Tümü 178.480 (%100) ACS Surveillance Research, 2007 Breast cancer is the leading cancer in reproductive age women. In the US alone, 15% of all women diagnosed with breast cancer are under the age of 45. Breast cancer is commonly treated with surgery followed 4–6 weeks later by gonadotoxic chemotherapy. ACS Surveillance Research, 2007

Meme Kanseri Primer Tedavi: Rezeksiyon – mümkünse meme koruyucu cerrahi ve sentinel LN Adjuvan kemoterapi Adjuvan radyoterapi Adjuvan hormonal tedavi

Kanser Tedavisinde Kalıcı Amenore Riski Risk Düzeyi Tedavi Şekli Yüksek (>%80) Kök hücre nakli için siklofosfamid + tüm vücut RT veya siklofosfamid/busulfan Overleri içine alacak şekilde eksternal radyoterapi CMF, CEF, CAF x6, ≥40 yaş (siklofosfamid, doksorubisin, epirubisin içeren kombinasyonlarla adjuvan meme kanseri tedavisi) Orta CMF, CEF, CAF x6, 30-39 yaş (siklofosfamid, doksorubisin, epirubisin içeren kombinasyonarla adjuvan meme kanseri tedavisi) AC x4, ≥40 yaş (doksorubisin/siklofosfamid ile adjuvan meme kanseri tedavisi) Düşük (<%20) ABVD (doksorubisin, bleomisin, vinblastin, dakarbazine; Hodgkin lenfoması) CHOP x4-6 çevrim (siklofosfamid, doksorubisin, vinkristin, prednizolon; NHL ve diğer hematolojik kanserler) AML tedavisi (antrasiklin + sitarabin) ALL tedavisi; Germ hücreli tümör tedavisi (BEP: bleomisin, etoposid, sisplatin) CMF, CEF, CAF x6, <30 yaş (siklofosfamid, doksorubisin, epirubisin içeren kombinasyonlarla adjuvan meme kanseri tedavisi) AC x4, <40 yaş (doksorubisin/siklofosfamid ile adjuvan meme kanseri tedavisi) Çok düşük Vinkristin Metotreksat 5FU Belirsiz Taksanlar (paklitaksel, dositaksel) Okzaliplatin (kolon ca) İrinotekan (kolon ca) Monoklonal antikorlar (trastuzumab, bevasizumab, cetuksimab) Tirozin kinaz inhibitörleri (erlotinib, imatinib) Bu liste ilk bakışta alfabe çorbası gibi görünse de, aslında CAF, ABVD ve benzeri kısaltmalara odaklanmaz ve onun yerine o kısaltmaların içerdiği ilaçlara odaklanırsanız, hepsinin ortak paydasında, sikofosfamid gibi alkilleyici bir ajan ve doksorubisin ya da epirubisin gibi antrasiklin grubu bir ilaç olduğunu görürsünüz. Çevrim sayısı arttıkça, ve verilen kümülatif doz arttıkça paralel olarak risk de artmakta.

For young single women with cancer, cryopreservation of mature oocytes offers the potential for achieving a pregnancy using their own oocytes. xxxxxsedcrtfvgb jnkml,

diğer stratejiler deneyseldir Cryopreservation of mature oocytes is an alternative to embryo storage. It still requires further investigation to become a routine clinical procedure, as the current pregnancy rates are significantly lower than those seen with embryo cryopreservation. Indeed, the prospects of pregnancy are very low if only one treatment cycle is available (11). As of December 2004, approximately 100 children had been born from oocyte freezing, but the number of offspring produced per number of oocytes frozen was seldom greater than 1% to 5% (12). Similarly, the Practice Committee of the American Society for Reproductive Medicine has concluded that at present neither oocyte (nor ovarian tissue preservation) should be offered or marketed as a means to defer reproductive aging Based on these reviews, we believe that the success rate is still too low to justify routine offering of oocyte cryopreservation as an established procedure to female cancer patients. Programs may, however, offer it experimentally as part of an IRB-approved protocol with full disclosure of risks and uncertainty of benefits to the participant xxxxxsedcrtfvgb jnkml,

for a young woman who recovered from Hodgkin’s lymphoma. For young single women with cancer, cryopreservation of mature oocytes offers the potential for achieving a pregnancy using their own oocytes. Here, we describe the outcome after the transfer of embryos generated from cryopreserved oocytes into a gestational carrier for a young woman who recovered from Hodgkin’s lymphoma. a 27-year-old single woman presented to Florida Institute for Reproductive Medicine (F.I.R.M.) with recurrent Hodgkin’s lymphoma requesting oocyte cryopreservation before chemotherapy. ASRM Practice commitee report: 2007: Oocyte cryopreservation is an experimental procedure that should not be offered or marketed as a means to defer reproductive aging, primarily because data relating to clinical outcomes are limited. Oocyte cryopreservation is not an established medical treatment. Women with cancer or other illnesses requiring immediate treatments that seriously threaten their future fertility who are considering oocyte cryopreservation should receive the same thorough counseling. However, unlike healthy women, they may have no viable options and therefore may be appropriate candidates for such treatment despite its experimental status. xxxxxsedcrtfvgb jnkml,

Fertilitenin Korunması ovarian tutulum hayır evet RT OT KT ? geciktirilebilir Mature oocytes can be harvested from the ovaries after COH allowing embryo and oocyte cryo. But disadvantages: 1. time interval needed for IVF (bw 2-6 weeks). May be too long to wait prior to starting chemo or radiotherapy due to the natural course of the malignant disease. 2. COH results in high estradio l levels that may not be safe in cases of estrogen sensitive tumors such as breast cancer, or in women with a high likelihood of thromboembolism, as well as for other patients wishing to avoid ovarian stimulation. geciktirilemez IVM oosit / embryo krio ovarian krio xxxxxsedcrtfvgb jnkml,

Fertilitenin Korunması oosit ve embryo kriyoprezervasyon KOH estrojen bağımlı olmayan kanser estrojen bağımlı kanser Issues to consider in stimulating cancer patients: - timing issues, - medical issues (wbc and platelet counts, medications, like anticoagulants and steroids). Still an experimental procedure. Moreover, exposure to a high estrogen milieu during ovarian stimulation with gonadotropin is undesirable when patients have estrogen-sensitive tumors such as breast cancer In patients with an estrogen-sensitive cancer such as breast or endometrial malignancies, specialized ovarian stimulation protocols have been developed that use aromatase inhibitors to keep the estrogen rise at minimum Letrozole / tamoksifen Konvansiyonel KOH xxxxxsedcrtfvgb jnkml,

Meme kanserli hastalarda IVF için tamoxifen hCG Tamoxifen 60 mg / gün Tamoxifen is an estrogen receptor antagonist 2 4 10 12 siklus günü Oktay, et al, F/S 2005 xxxxxsedcrtfvgb jnkml,

Meme kanserli hastalarda IVF için devamlı kombine tamoxifen / FSH protokolü antagonist hCG FSH 150 IU / gün Tamoxifen 60 mg / gün 2 4 10 12 siklus günü Oktay, et al, F/S 2005 xxxxxsedcrtfvgb jnkml,

Meme kanserli hastalarda IVF için devamlı kombine letrozole / FSH protokolü hCG FSH 150 IU / gün Letrozole 5 mg / gün Letrozole 5 mg / gün 2 4 10 12 siklus günü Oktay, et al, F/S 2005 xxxxxsedcrtfvgb jnkml,

Meme kanserli hastalarda IVF için devamlı kombine letrozole / FSH protokolü antagonist hCG FSH 150 IU / gün Letrozole 5 mg / gün Letrozole 5 mg / gün GnRH antagonist was administered when E2 > 50pg/mL. 2 4 10 12 siklus günü Oktay, et al, F/S 2005 xxxxxsedcrtfvgb jnkml,

Tam-IVF vs Tam FSH - IVF vs Letrozole FSH - IVF Değişken Tam - IVF Tam FSH - IVF Letrozole FSH - IVF P değeri Peak E2 (pg / mL) 419a,b 1182a 405a,b a< 0.01 b > 0.05 Toplam oosit 1.7a 6.9a,b 11a,b a< 0.001 Matür oosit 1.5a,c 5.1a,b,c 8a,b b , c < 0.05 2 PN embryo 1.3a 3.8a,b 5.3a,b b > 0.05 in breast cancer patients, Compared to Tam-IVF, both TamFSH-IVF and Letrozole-IVF patients had greater number of follicles (2 0.3 vs. 6 1 and 7.8 0.9, p0.0001), mature oocytes (1.5 0.3 vs. 5.1 1.1 and 8.5 1.6, p0.001) and embryos (1.3 0.2 vs. 3.8 0.8 and 5.3 0.8, p0.001) respectively per initiated cycle. Peak estradiol levels were lower with letrozole and tamoxifen stimulaton compared to TamFSH When combined with low dose follicle stimulating hormone stimulation, both tamoxifen and letrozole result in higher embryo yield compared to tamoxifen alone. Recurrence rates do not seem to be increased compared to controls but letrozole protocol maybe preferred as it yields higher number of embryos with lower peak estradiol levels. the combined letrozole-FSH protocol resulted in peak E2 levels close to those seen in unstimulated cycles, and breast cancer recurrence rates were not increased compared with control subjects. The letrozole-FSH treatment resulted in the cryopreservation of a higher number of embryos while maintaining peak E2 levels close to those of unstimulated cycles. Recurrence rate was similar to unstimulated control subjects with history of breast cancer. Oktay et al, J Clin Oncol 2005; 23: 4347-53 xxxxxsedcrtfvgb jnkml,

Letrozole IVF vs Uzun GnRH a protokolü Letrozole + FSH Kontrol p Peak E2 459 1453 < 0.001 Endometrial kalınlık 8.7 mm 10.8 mm Matür oosit sayısı 8.4 9.2 0.47 2 PN embryo sayısı 6.3 6.6 0.65 FR (%) 76 72 0.71 Total FSH dozu 1461 2355 Oktay, et al, JCEM 2006 Kontrol grubu uzun gnrh agonist grubu. Standard protocol group consisted of leuprolide suppression followed by gonadotropins (n68) Despite the significantly lower peak estradiol levels in the letFSH group, percent mature oocytes, fertilization rates and number of 2-pronuclei embryos were similar to standard-IVF patients (table). While letFSH resulted in higher number of 17 follicles, 46 % less FSH was required to achieve these results compared to all standard-IVF cycles. Continuous Combined Letrozole-FSH Stimulation Requires Less FSH With Similar Outcomes Compared To Standard Ovarian Stimulation Regimens for IVF. Moreover, we showed that stimulation with letrozole resulted in similar IVF outcomes in breast cancer patients compared with infertility patients undergoing IVF with standard protocols xxxxxsedcrtfvgb jnkml,

IVF (COH) yapılması meme kanserinde rekürrensi arttırıyor mu? 1. 00 0. 75 kontrol 0. 50 IVF 0. 25 No effect of stage...... Breast cancer recurrence or the incidence of invasive carcinoma in the contralateral breast does not appear to be increased after COH using letrozole and FSH for fertility preservation. 0. 00 1 2 3 4 yıllar Rekürrens için hazards ratio: 1.38 (% 95 CI. 0.28 – 6.9) Oktay et al, J Clin Oncol 2005; 23: 4347-53 xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 1 2 G, 2 A, 0Y Özgeçmiş: 9/2005 Laparoskopik bilateral endometrioma çıkartılması 16/10/2006: sağ parsiel mastektomi + sentinel lenf bezi bx Patoloji: ER (+), PR (+), c*erB-2 pr (HER-2/NEU) (-), invaziv duktal karsinom xxxxxsedcrtfvgb jnkml,

xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 1 OPU: 26 oosit, ICSI: 10 MII, 2PN: 7 x 2PN, Kriyo: 7 x D3 embryo 8 x MII oosit 2 x GV oosit toplam: 7 + 8 + 2 : 17 xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 2 0G, 0P Özgeçmiş: Özellik yok 05 /05/ 2007: Sol parsiel mastektomi ve sentinel lenf bezi bx Patoloji: İnvaziv duktal ca. xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 2 Operasyon: 5 / 5 / 2007 Son adet tarihi: 12 / 5 / 2007 IVF merkezine başvuru tarihi: 21 / 5 / 2007 xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 2 Operasyon: 5 / 5 / 2007 Son adet tarihi: 12 / 5 / 2007 IVF merkezine başvuru tarihi: 21 / 5 / 2007 KOH için zaman yok xxxxxsedcrtfvgb jnkml,

IVM Kararı Alındı ! xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 2 IVM / doğal siklus D11 (22 / 5 / 2007) hCG 10 000 IU 13 mm lead fol. Endo: 10.2 mm D 13 OPU 1 x MII 2 x MI 1 x GV xxxxxsedcrtfvgb jnkml,

Acıbadem Hastanesi Deneyimi Meme Ca. Vaka 2 IVM 24. saatte 2 MI oosit MII’e geçti 48. saatte 1 GV oosit MII’e geçti Kriyo: 1 x 2PN zigot 3 x D2 embryo Toplam: 1 + 3: 4 embryo xxxxxsedcrtfvgb jnkml,

Fertilitenin korunması: Kemoterapi sonrası IVF? In our study, we have tried to establish whether IVF with embryo cryopreservation could be performed in the course of a chemotherapy treatment. For women who have a steady partner, IVF with embryo cryopreservation is an applicable option. However, ovarian stimulation is time consuming, and chemotherapy cannot be delayed in most cancer patients. For this reason, some centers offer IVF and embryo cryopreservation in the interval between two chemotherapy regimens. Chemotherapy induces acute follicular damage, leading to a reduction in the number of follicles and also to chronic damage to the quality of the follicles as they easily undergo atresia. Electron microscopy studies after chemotherapy have demonstrated the cellular features that are typical of early atresia in primordial follicles, such as intracytoplasmic vacuoles, multivesicular bodies, altered mitochondria, and myelinic-like structures. On the other hand, when IVF was performed before chemotherapy (patients 5 through 11), between 4 and 11 embryos were obtained for cryopreservation per patient. In these seven patients, a total of 88 oocytes were obtained after pick-up (between 8 and 25 oocytes per patient, for a mean of 12.6); this represents an almost 10-fold increase over the women who had already received chemotherapy, from whom only six oocytes had been retrieved (between 0 and 6 oocytes per patient, for a mean of 1.5). This constitutes a statistically significant difference (P .05). The estradiol levels were significantly higher (P .05) in patients undergoing IVF before chemotherapy than after chemotherapy, reaching an average of 2658 pg/mL (range: 1202– 6750 pg/mL) compared with just 203 pg/mL (range: 10–671 pg/mL), The mean number of ampules required for stimulation per patient was 44 in the group undergoing IVF with embryo cryopreservation before chemotherapy compared with 84 in the group with previous chemotherapy, which was also a statistically significant difference (P .05). xxxxxsedcrtfvgb jnkml,

Overyan Doku Elde Edilmesi Doku elde edilmesi (L/S ile) Over medullasından temizlenen korteks dondurulur İdeal korteks fragmanları 6x6x1mm,10x5x1mm Ovarian kortex : % 95 primordial foliküülerden. I. Mayoz profazda arrest. Yüzey / hacim oranı yüksek, metaboliz hız yavaş ve zona pellusida yok

Konvansiyonel Dondurma - Vitrifikasyon Isachenko V, Cryobiology, 2007 n=14 hasta-overyan fragmanlar Grup 1 = Taze over dokusu Grup 2,3 = Hızlı dondurma-çözme Grup 4 = Konvansiyonel dondurma-çözme Doku canlılığı hormon üretimi ve folikül gelişimi ile değerlendiriliyor Isachenko V, Cryobiology, 2007

Konvansiyonel Dondurma - Vitrifikasyon Grup I Grup II Grup III Grup IV Estradiol (pg/ml) 358 275 331 345 Progesteron (ng/mL) 3.02 1.77 1.99 2.01 Normal folikül (%) 96 36 39 84 Isachenko V, Cryobiology, 2007

Ortotopik Transplantasyon

Heterotopik Transplantasyon Brakioradial fasyası üzerindeki subkutan doku Alt abdominal bölge, rektus fasyası üzerinde sukkütan aralık

İnsan Over Dokusu Transplantasyonu Klinik Sonuçları Hastalık Lokalizasyon Taze / Kriyo Gebelikyöntemi Sonuç Oktay, 2004 Meme Ca Heterotopik IVF Embryo (+), klin.gebelik(-) Meirow, 2005 Hodgkin Ortotopik, over üzeri Canlı doğum Donnez, 2005 Ortotopik Doğal Silber, 2005 POF Monozigotik ikizden taze transplant Taze Schmidt,2006 Biyo. gebelik Oktay, 2006 heterotopik Demeestere, 2006 Orto/hetero Klinik gebelik

Sonmezer&Oktay Textbook of Assisted Reproductive Technologies, 2005

Meme Ca Overyan Transplanatsyon Meme CA’da overyan transplantasyon ile sessiz tümör hücreleri aktive olabilir mi? Gerber B, Breast Cancer Res Treat, 2007

SABRINIZ İÇİN TEŞEKKÜRLER......... xxxxxsedcrtfvgb jnkml,