metastatik hastalıkta hormonal tedavi - Berna Öksüzoğlu
1. Metastatik Meme Kanserinde Hormonal Tedavi Dr. Berna Öksüzoğlu Ankara Onkoloji Eğitim ve Araştırma Hastanesi 2. Medikal Onkoloji Kliniği
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5. Zamanla MMK Daha Uzun Mu Yaşıyor Nedeni yeni ilaçlar; AI, taksan, trastuzumab Giordano SE, Buzdar AU Cancer 2004; 100: 44 Chia SK, Cancer 2007; 110: 973 Yıllar Ortanca Sağkalım 1991-1992 438 gün 1994-1995 450 gün 1997-1998 564 gün 1999-2001 667 gün
6. 1999-2009 arası randomize 1. basamak KT çalışmaları, PFS ve OS kaydı 36 çalışma (13.083 kadın) Ortanca PFS ve OS; 7.6 ve 21.7 ay ER(+) tm ve her2(+)herceptin kullanan çalışmalarda OS daha iyi
7. ESMO Kılavuzu Klinik Öneriler MMK risk değerlendirme ve tedavi kararını etkileyen faktörler
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12. Ö stro j en Yanıtlı Genlerin Transkripsiyonunda Östrojen Etkileri trans krips i y on trans k rip s i yo n co-act HSP kaybı f os f or i la sy on, dimeri z a sy on k onforma sy onal değişiklik ER + E H S P co-act E AF1 E AF1 AF2 E AF1 E AF1 AF2
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14. Meme Kanserinde Östrojen Bağımlı Büyümenin Antagonize Edilmesi Estro j en Ov erler Extragonadal Perifer a l yağ , cilt , kas , kemik , CNS, meme ve perit ü moral fibroblast, metasta zlar AI Tamoxifen , Fulvestran X Postmeno pozal OFS GnRH analogları veya o of erektomi Premenop ozal K an s er hücresi ER ER
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16. Antiöstrojenlerin Kimyasal Yapıları OH (CH 2 ) 9 SO(CH 2 ) 3 CF 2 CF 3 OH Fulvestrant ( steroidal ) HO 7 Ralo ks ifen HO S OH O O N Ös tr o diol HO Tamo ks ifen O NMe 2
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19. Ö stro j en Yanıtlı Genlerin Transkripsiyonunda Tamoksifen Etkileri trans k rip siy on t rans k rip s i y on yok co-act HSP kaybı f os f or i la sy on, dimeri z a sy on k onforma sy onal değişiklik ANTAGONI Z M A AGONI Z M A ER + T H S P T AF1 T AF1 AF2 T AF1 T AF1 AF2 co-act
23. Over Ablasyon Yöntemleri Radyoterapi , Kemoterapi , LHRH analogları ( Goserelin Leuprolide) Cerrahi kastrasyon (o oferektomi)
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25. GnRH Analoglarının Etki Mekanizması LHRH ( hipotalamus) Pitüiter bez Ö stro j en ler Progesteron Ov er LHRH re s ept ö r downregülasyonu Gonadotropin ler (FSH + LH)
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27. Goseralin Etki Mekanizması Şekil A ( tumor flare ) Goseralin akut uygulama sonrası LH hip erse kresyonu ve androjen artışı Şekil B Goseralin kronik uygulama sonrası LH hipo se kresyonu goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin Pit üi t e r Hücre LH Pit ü it e r Hücre LH goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin
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29. Östrojen Biyosentezi Aromata z İ nhibit örleri Etki Mekanizması 20,22-L i ya z 11 -H i dro ksi la z 18-H i dro ksi la z 17,20 Lyase Farmakolojik Hedef Ko lesterol Pregnenolone Progesteron 11-Deoxycorticosterone K orti k osteron 17 -H i dro ksi la z 21 -H i dro ksi la z 11-Deo ksik orti z ol Testosteron Deh i droepiandrosteron Androstenedion Ko rti z ol Aldosteron aromata z Ö stron Ö stradiol 17 - Hydro ksi pregnenolon 17 - Hydro ksi progesteron
38. Pre-/perimenop oz al MMK F a z III Çalışmalar Goseralin vs Ooferektomi Goseralin vs Goseralin + tmx Obje k ti f yanıt oranı (%) Ortanca sağkalım Taylor CW, et al ‘Zoladex’ 3.6mg Cerrahi o fe re k tom i ‘Zoladex’ 3.6mg Cerrahi J Clin Oncol o ferek tom i 1998; 16: 994 – 9. ( n =29*) ( n =30*) ( n =69) ( n =67) 31 27 37 months 33 months Boccardo F, et al ‘Zoladex’ 3.6mg Cerrahi oferektomi ‘Zoladex’ 3.6mg Cerrahi Ann Oncol veya over radyoterapi o ferektomi 1994; 5: 337 – 42. veya ov e r rad yoterapi ( n =22*) ( n =15*) ( n =24) ( n =18) 27 ( + 19) 47 ( + 25) 36 months 38 months Jonat W, et al ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg + + tamo ks ifen (40mg) tamo ks ifen (40mg) Eur J Cancer Part A ( n =159) ( n =159) ( n =159) ( n =159) 1995; 31A: 137 – 42. 31 38 29 months 32 months Kombine (goser+tamoks) kolda ortanca TTP farkı ( 5.3 vs 6.5 ay) Sadece kemik met olanlarda objektif yanıt, TTP ve OS farkı * Değerlendirilebilen hastalar
1973-82 arası 1581 hasta antrasiklinli tedavi almış (en fazla 2 yıl)- %16.6 (263 hasta) tam yanıt, %3.1 (49 hasta)>5 yıl tam yanıt devam, premenap, genç ortanca yaş, iyi PS. İlk 3 yıl hızla çoğu progrese sonra progresyon riski sabitleniyor 1988-93 arası 315 hastadan 40 hasta tam yanıt ve DFS> 5yıl – krc. met yok, iyi PS, düşük met bölge sayısı 40. Breast Cancer: Stage IV Stage IV, or metastatic, breast cancer is a lethal disease. The most common sites of metastases are soft tissue (skin or draining lymph nodes), bone, and viscera (eg, liver, lung).
LHRH = Luteinising Hormone Releasing Hormone EBCTCG = Early Breast Cancer Trialists’ Collaborative Group
ER proteini sadece çekirdekte değil plazma mebranında da bulunur. Bu ER.ü nongenomik fonksiyonlara sahiptir ve nukleustaki gen ekspresyoundaki transkripsiyonel aktiviteden farklıdır. Bu non-genomik aktiviteler bazı büyüme faktörlerinin (EGFR, her2-neu ve IGF gibi) aktivasyonunu içerir. Östrojenle bu reseptörlerin aktivasyonu tm büyümesini arttırabilir (aynı büyüme faktörü ligandı gibi). Sonra büyüme faktör yolağındaki aktive kinazlar ER ve koaktivatör proteinleri fosforilleyip daha da aktive edebilir ve nükleustaki transkripsiyonel etki güçlenir (cross-talk) Prolif ve sağkalım için kısır döngü oluşur
AI, aromatase inhibitor; CNS, central nervous system; ER, estrogen receptor; GnRH, gonadotropin-releasing hormone; OFS, ovarian function suppression; OVX, ovariectomized. In premenopausal women, estrogen primarily comes from the ovaries with a smaller contribution from extragonadal aromatization, predominantly emanating from fat, skin, and muscle, but also from other areas such as bone and the central nervous system. Interestingly, breast and peritumoral fibroblasts also contribute to estrogen synthesis both at the site of primary breast tumors and at the site of metastases. Suppressing ovarian function minimizes the contribution of the primary source of estrogen in premenopausal women, but adding tamoxifen or an aromatase inhibitor would be required to completely block the entry of estrogen into breast cancer cells. In patients in whom ovarian function ceases (because of menopause or cancer therapy), peripheral aromatization requires suppression or estrogen antagonism. This can be accomplished with monotherapy using aromatase inhibitors or with tamoxifen. Importantly, aromatase inhibitors cannot be given as monotherapy to premenopausal women but must be administered in conjunction with ovarian function suppression. This is because as single agents, aromatase inhibitors are unable to fully suppress ovarian estrogen synthesis and cause a reflex rise and increased risk of fertility and unwanted pregnancy.
Toremifen vs Tamoksifen meta-analizi; 5 çalışma: fark yok, RR %24 vs TTP 25.3 ve 4.9 vs 5.3 ay Pyrhonen S, Breast Cancer Res Treat 1999; 56: 133-43
Fulvestrant (‘Faslodex’) has a steroidal structure similar to that of the naturally occurring hormone estradiol, differing by the addition of a long side-chain at the 7- position, which is responsible for its antagonistic properties. This steroidal structure of fulvestrant is markedly different from that of two typical SERMs ( S elective E strogen R eceptor M odulators), tamoxifen and raloxifene.
İlk 3 ay sıcak basması sonra plato Keikleri koruma premenapozlarda belirgin değil Flush için venlafaxine, gabapentin, düşük doz megesterol (paroksetin kullanmamalı-CYP2D6yı inhibe eder ve tamoks metabolize olamaz Tamoksifen ER.ye bağlandığında hücre siklusu G1de arrest olur, prolif durur. Bir miktar apoptozis olur.. IGF-I konsantrasyonunda azalma diğer bir mekanizma ancak esas mekanizma ER aracılıklı olan. A beneficial effect of tamoxifen citrate (Nolvadex ® ) is seen in pre- and postmenopausal patients, in ER-positive and ER-negative cases, as well as node-negative and node-positive cases, although the greatest benefit is seen in postmenopausal, ER-positive patients † Tamoxifen is the only endocrine therapy indicated in the treatment of early disease In addition to the survival benefits associated with adjuvant therapy, tamoxifen also reduces the incidence of contralateral tumours compared with controls (no treatment/placebo) Tamoxifen is well tolerated and has proven efficacy benefits; however, it is associated with a small increased risk of endometrial cancer ER = oestrogen receptor Nolvadex ® is a trade mark, the property of Zeneca Limited † In the US, Nolvadex ® is not indicated for premenopausal node-positive patients
Daha nadir direnç mekanizmaları; ER mutasyonu, ER fosforilasyonu %7-10 CYP2D6yı kötü metabolize edenler ve tamok yararı az
ICI 182,780 (‘Faslodex’) has a steroidal structure similar to that of the naturally occurring hormone, oestradiol, differing by the addition of a long side-chain at the 7- position, which is responsible for its antagonistic properties This steroidal structure of ICI 182,780 is markedly different from those of two typical SERMs ( S elective E strogen R eceptor M odulators), tamoxifen and raloxifene
Surgical oophorectomy , results in immediate and permanent reduction in ovarian steroid production. The current laparoscopic surgical techniques are associated with less operative morbidity and are the usual means of removing the ovaries in the standard surgical situation. However, women who have a genetic predisposition to ovarian cancer—for example, women who carry mutations in the BRCA1 or BRCA2 genes—require open surgery with removal of the uterus. Node sampling and peritoneal washing are often recommended at the time of surgery for these women. Women who choose to have their uterus removed at the time of surgery would also have an open procedure. The removal of the ovaries permanently prevents the production of ovarian steroids such as estrogen and alleviates the burden of continued, expensive monthly injections (ie, with GnRH agonists). One of the difficult aspects of treatment in women who have received chemotherapy is the need for continued injections throughout the duration of their hormone therapy in order to reduce and prevent the production of estrogen by the ovaries. The use of a surgical oophorectomy can prevent the need for continued intervention. However, surgery induces early menopause and renders the recovery of ovarian estrogen production impossible. Therefore, this procedure is a difficult decision for most young women facing a diagnosis of breast cancer and the implications of early menopause.
The normal stimulus for the release of gonadotrophins, follicle stimulating hormone (FSH) and luteinising hormone (LH), from the pituitary gland is pulsatile secretion of LHRH by the hypothalamus In the premenopausal female, LH induces the secretion of oestrogens from the ovary, the most important of which is oestradiol ‘ Zoladex’ acts on the hypothalamic-pituitary axis by a process known as ‘receptor downregulation’
A third, popular way to cause ovarian suppression in premenopausal women with early‑stage breast cancer is through the use of GnRH analogues, or GnRH agonists. These agents suppress ovarian function through agonist properties. High doses of GnRH agonists flood the body with hormone-releasing agent and prompt suppression of ovarian function. These agents are given as monthly or every-3-month injections and were first used in the treatment of metastatic prostate cancer. Available GnRH agonists include goserelin, leuprolide, and triptorelin. Monthly injection is the most appropriate administration schedule because data indicate it is more effective than injection every 3 months. When GnRH agonists are discontinued, particularly in young women, the effects are generally reversible, and menses may restart. This reversibility is likely to be age related: Suppression of menses is less likely to be reversible in women older than 40 years of age compared with women younger than 40 years of age. The duration of GnRH agonist therapy and its relationship to recoverability of ovarian function in not fully understood. Most studies have investigated 2 years of therapy and recovery. Whether 5 years of therapy affects the recoverability of ovarian function or not is unknown. The extent to which fertility is preserved in women receiving long-term ovarian suppression with GnRH agonists is also unknown. Isolated reports of breakthrough ovarian function in women who have substantial residual ovarian function (eg, in women younger than 35 years of age) have been reported. Breakthrough ovarian function in these women is managed through the regular monitoring of estradiol levels, which can help ensure continued ovarian suppression, as opposed to assuming that an amenorrhea state is equivalent to full ovarian suppression. Gonadotropin‑releasing hormone agonists possess fairly modest side effects that are similar to the effects of menopause. All individual side effects from GnRH agonists are associated with suppression of ovarian function. This can benefit patients by allowing them to experience the effects of menopause while still retaining a chance that ovarian function will return once treatment is stopped, in contrast to the immediate and final ovarian suppression with surgery. Although patients treated with GnRH agonists will not require surgery, it is necessary that they return to clinic monthly for injections during a long treatment course.
Following initial administration of ‘Zoladex’ 3.6mg depot, all the LHRH receptors on the surface of the pituitary cell become occupied by goserelin (Figure A) This results in a transient increase in serum LH, but the occupied LHRH receptors form clusters and gradually disappear into the cell, leading to a profound suppression of LH and, subsequently, of oestradiol New receptors are constantly resynthesised but, once again, they become occupied by the goserelin, which is continually released from the ‘Zoladex’ 3.6mg depot Hence, on chronic administration of ‘Zoladex’ 3.6mg, the continuous presence of goserelin prevents a sufficiently large amount of LHRH receptors from being stimulated by the pituitary gland to produce a normal amount of LH and, therefore, the production of oestrogens is suppressed to postmenopausal levels, essentially producing a ‘medical castration’ (Figure B) Reference Furr BJA. Hormone Res 1989; 32 (Suppl1): 86–92.
Oestrogens are the end-products of a complex sequence of steroid intermediates, involving the key cytochrome P-450 enzyme, aromatase The aromatase enzyme converts the androgens, androstenedione and testosterone, into the oestrogens, oestrone and oestradiol, respectively Non-selective aromatase inhibitors, such as aminoglutethimide, have actions on other cytochrome P-450 enzymes, such as 20,22-lyase, 17 -hydroxylase, 21 -hydroxylase, 11 -hydroxylase, 18-hydroxylase and 17,20-lyase. These result in unwanted side effects Selective aromatase inhibitors, such as formestane and anastrozole, inhibit only the aromatase enzyme
DeVita 2008
CR = Complete response PR = Partial response
The results of the studies by Taylor et al and Boccardo et al show that ‘Zoladex’ 3.6mg is an effective alternative to oophorectomy for the treatment of advanced breast cancer in premenopausal women with ER+/unknown tumours
Avrupa ve amerika çalışması
(AI hafif daha iyi)
third-generation aromatase inhibitors and inactivators (vorozole, letrozole, examestane, and anastrazole
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