Cancer in Women after Menopause

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1 Cancer in Women after Menopause BELGIAN MENOPAUSE SOCIETY SEPTEMBER 19, 2009 A. Pintiaux ULg

2 Gynaecological Uses of a New Class of Steroids : the Selective Progesterone Receptor Modulators BELGIAN MENOPAUSE SOCIETY SEPTEMBER 19, 2009 A PINTIAUX ULG

3 Definition Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on various progesterone target tissues in vivo

4 Selective Action At the tissue level At the cellular level At the gene level

5 Mechanisms of Action

6 PR binding an agonist

7 PR Ligands : mechanism of action Agonist/antagonist Agonist COACTIVATORS PR PRE PR Pol II Transcription activation Stop transcription Antagonist COREPRESSORS

8 First compounds from this new class of steroids CH 3 H 3 C N H 3 C OH CH 3 C H 3 NH O Mifepristone (RU 486) C H 3 H 3 C OH OH O Onapristone (ZK )

9 New Compounds HO N H H 3 C O CH 3 O CH 3 CH 3 O Asoprisnil (J 867) H 3 C N H 3 C H 3 C O O O CH 3 O Ulipristal (VA2914)

10 Gynaecological uses of a new class of steroids : the selective progesterone receptor modulators Axelle Pintiaux, Nathalie Chabbert-Buffet, Jean-Michel Foidart Medical Abortion Management of Miscarriage Emergency Contraception Long Term Contraception Treatment of Uterine Leiomyomata Treatment of Endometriosis Breast Cancer Gynecological Endocrinology, February 2009 ; 25(2) : 67-73

11 Why the need of a new class of steroids? To develop an estrogen-free contraception To avoid progestin To treat gynaecological diseases (myoma, endometriosis) To treat or to prevent breast cancer

12 Avoid The Progestins Breast effect Bloating Breakthrough bleeding Mood changes Acne, hirsutism Cardiovascular effects

13 Breast and Progesterone Agonists Role of progestins in the developement of breast cancer WHI 2002, MWS 2003, HABITS 2004 Increased cell proliferation, decreased apoptosis Alteration in ratio of PR isoforms Genes (VEGF, thymidine kinase, EGF, EGFR, TGF, IGF1) activated via PR Rapid signaling with direct activation of protein kinase pathways by PR Wiebe 2006, Mote PA 2007, Moore 2005, Lange and Yee 2008

14 Breast and SPRMs Progesterone and progestins increase VEGF production from many PR + breast cancer cells. Inhibition by mifepristone (Hyder, 2001) Rat breast cancer model with DMBA with mifepristone, ZK98299, CBD 4124 : decrease in tumor load and size (Wiehle, 2007) Xenograft (from T47-D ; BT-474) inoculation in nude mice : tumor growth blocked by mifepristone or agents inhibiting synthesis or action of VEGF or disrupting VEGF-VEGFR2 interaction (Liang, 2007)

15 Breast and SPRMs Mifepristone administrated to BRCA1/P53 deficient mice : inhibition of tumorigenesis by decreasing ductal branching and alveolar proliferation + increased survival (Poole 2006) CDB4124 administrated to rats : Ki 67 decreases and apotosis increases (Wiehle and Christov in press)

16 Breast and SPRMs (clinical studies) Mifepristone and onapristone used as first, second and third line treatment of BC : poor responses (the best response observed : 67% of partial response when onapristone was used as first line) Different response between mifepristone & onapristone explained by the antiglucocorticoid potency, the stimulation of adrenals (increase of cortisol, androgens and estradiol) +++ with mifepristone Currently : studies conducted with lonaprisan Mifepristone 50mgr on alternate days for 3 months in normal women : reduced Ki67 ( Engman 2008)

17 Endometrium under SPRMs GL Mutter 2008

18 Endometrium under SPRMs GL Mutter 2008

19 Endometrium under SPRMs GL Mutter 2008

20 PRM - Associated Endometrial Changes Dyssynchronous growth between glands and stroma Interspersed cysts throughout all the endometrium Glands showing non physiological combination of inactivity, secretory changes, mitosis and apoptosis Fibrous stroma with mitotic figures Vascular aspects (thick wall vessels, anastomosing capillary network, ectatic stromal blood vessels)

21 Conclusions SPRM limited actually to short term use Ideal SPRM : reduced antiglucocorticoid properties Intermittent therapy? Place in breast cancer prophylaxis? Place in breast cancer treatment? Long term endometrial safety?

22 Symptomatic uterine leiomyomata

23 SPRMs and Symptomatic uterine leiomyomata To avoid surgical treatment in pre or perimenopausal women To avoid gonadotropin releasing hormone agonists and their side effects due to hypo estrogenism

24 Deleterious effect of progesterone receptor agonist on proliferation of leiomyomata cells Maximal mitotic activity during luteal phase, up regulation of PR in leiomyomata compared to normal adjacent myometrium Increased Ki 67(proliferation marker) in leiomyomata compared to the normal myometrium and up-regulation by progesterone Increased expression of EGF, a proliferative cytokine, and Bcl2, an apoptosis-inhibiting protein in fibroids relative to the adjacent myometrium Progesterone increases Bcl2 protein expression in primary leiomyomata cell cultures Progestins finally attenuate or even reverse the inhibitory effects of GnRHa on leiomyomata size when used as add-back therapy

25 Cell type specific action of SPRM Mifepristone : decreases proliferation of smooth muscle cells Asoprisnil : (mixed progesterone agonist/antagonist with no antiglucocorticoid effect) : inhibits proliferation and induces apoptosis in cultured uterine leiomyoma cells (absence of comparable effects on cultured normal myometrial cells) VA 2914 :down regulation of VEGF and its receptors in cultured human uterine leiomyoma cells (not observed in the surrounding normal myometrial cells)

26 Clinical studies : Mifepristone (5 to 50 mg/d for 3 to 6 months Reduction in uterus and leiomyoma volumes, ranging from 27% to 49% and 26% to 74% respectively. Reduced prevalence and severity of dysmenorrhoea, menorrhagia and pelvis pressure. Recurrence rate after cessation : and 17,8% after mifepristone (40% after GnRHa)

27 Clinical studies : Asoprisnil ( 5, 10 or 25 mg/d, 12weeks) Reduced uterine volume as well as the volume of the largest leiomyoma in a dose dependant manner. Suppressed pelvis pressure after 12 weeks treatment in contrast to placebo which was inactive. Reduced uterine bleeding (both duration and intensity) in a dose dependant manner No decrease of plasma estradiol or increase of cortisol

28 Endometriosis

29 Endometriosis Mifepristone (5 or 50 mg/day for 6 months or 100 mg/day for 3 months), improved the clinical symptoms associated to endometriosis. The 50 mg daily dose elicited a mean 55% regression of visible endometriosis after 6 months of treatment. Asoprisnil (5,10 and 25 mg versus placebo for 12 weeks) were significantly effective on pain scores, on bleeding pattern( dose dependence) at all treatment months compared with placebo.

SPRMs, androgens and breast cancer

SPRMs, androgens and breast cancer Dr Joëlle Desreux BMS 04/06/2016 WHI : the nuclear explosion Looking for the perfect menopause treatment Hot flushes relieve Osteoporosis prevention Cardio-vascular health