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Hormonale substitutie na kanker: do’s and don’t’s PROF. DR. H. DEPYPERE

Hormonale substitutie na kanker: do’s and don’t’s PROF. DR. H. DEPYPERE Menopauze kliniek en borstkliniek, Universitair Ziekenhuis, Gent.

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Hormonale substitutie na kanker: do’s and don’t’s PROF. DR. H. DEPYPERE

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  1. Hormonale substitutie na kanker: do’s and don’t’s PROF. DR. H. DEPYPERE Menopauze kliniek en borstkliniek, Universitair Ziekenhuis, Gent.

  2. CA: A Cancer Journal for CliniciansVolume 56, Issue 2, pages 106-130, 24 FEB 2009 DOI: 10.3322/canjclin.56.2.106http://onlinelibrary.wiley.com/doi/10.3322/canjclin.56.2.106/full#fig5

  3. Quid nemen van hormonen ? Afhankelijk van: Type en ernst van klachten Type van kanker Expressie van hormoonreceptoren Type van adjuvante hormonale therapie

  4. Pons Locus coeruleus Hypothalamus Raphe nucleus Brain stem Type klacht 1: Vasomotore klachten

  5. Ernstige³ !!!! vasomotore klachten Hormoon receptor negatief: HRT bespreekbaar indien alle alternatieven niet helpen. Hormoon receptor positief: Indien Tamoxifen behandeling: hrt bespreekbaar indien alle alternatieven niet helpen. Adjuvante aromatase behandeling: absolute contraindicatie. Alternatief: poging twee jaar AI te nemen dan conversie naar tamoxifen en indien persiteren van de klachten HRT bespreekbaar.

  6. RATIONALE VOOR EVENTUELE HT BEHANDELING BIJ VROUWEN ONDER TAMOXIFEN LANCET 2007 369 1711-23

  7. Oestrogeen concentraties onder tamoxifen kunnen op tot 300 pg/gram weefsel. Bloodvessels Estrogen synthesisin the breast Peripheral estrogen production Tumor Peripheral estrogen Estrogen concentrationin the breast Miller W et al.

  8. Literatuur Veel case control studies: mogelijks bias Liberate: nefast Habits trial: nefast – onderbehandeling met tamoxifen Stockholm trial: geen toename van recidieven. Recent rapport na 10 j opvolging: geen toename van recidieven. 8

  9. Liberate:Lancet oncology 2009 Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52.7 years (SD 7.3) and mean time since surgery was 2.1 years (SD 1.3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6.5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6.4 (SD 5.1). After a median follow-up of 3.1 years (range 0.01-4.99), 237 of 1556 (15.2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10.7%) on placebo (HR 1.40 [95% CI 1.14-1.70]; p=0.001). Results in the per-protocol population were similar (209 of 1254 [16.7%] women in the tibolone group had a recurrence vs 138 of 1213 [11.4%] women in the placebo group; HR 1.44 [95% CI 1.16-1.79]; p=0.0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone. 9

  10. « previous figurenext figure » 10

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  12. Habits trial: Hormonal replacement After Breast cancer – Is it Safe ? Lancet 2004 HRT No HRT Number with follow-up 174 171 Median follow-up in years 2.1 2.1 Interval prim treatment-random 2.6 2.7 Node positive 26 % 21 % Receptor positive 56 % 48 % On tamoxifen 21 % 21 % 12

  13. Habits trial: Lancet 2004 RR (95 % CI) All women 3.5 (1.5-8.1) ER pos 4.8 (1.1-21.4) ER neg 1.9 (0.4-9.6) Tamoxifen 2.8 (0.3-27.4) No Tamoxifen 3.7 (1.5-9.0) 13

  14. Stockholm trial: geen toename van recidieven. Recent rapport na 10.8 j opvolging: geen toename van recidieven. European Journal of Cancer, 2013. HRT (n=188) No HRT (n=190) HR = 1.3 (0.9-1.9) Death: 19 (10 from breast cancer) in HRT group en 18 (11 from breast cancer) in non HRT group 14

  15. Type klacht 2: Osteoporose: Hormoon therapie (HT), gegeven voor vasomotore klachten, beschermen tegen osteoporose (level 1). Bewezen osteoporose is geen indicatie om HT te geven. Er zijn voldoende alternatieven (level 1). Bewezen osteoporose na kanker. Er is evidentie voor bisfosfonaten (level 1) en contraindicatie voor HT.

  16. Klacht: verandering RR, lipiden RR medicatie en cholesterolverlagende medicatie

  17. Type klacht 3: urogenitale atrofie: Komt frequent voor. Indien lubrifiërende producten niet effectief zijn: oestriol crème. 17

  18. Maubach J, Bracke M, Heyerick A, Depypere H, Serreyn R, Mareel M, De Keukeleire D. Quantitation of soy-derived phytoestrogens in human breast tissue and biological fluids by high-performance liquid chromatography. J Chromotography B 2003 ;784 :137-144. (I.F. = 2.085) J. Maubach, H.T. Depypere, J. Goeman, J. Van der Eycken, A. Heyerick, M.B. Bracke, P. Blondeel and D. De Keukeleire. Distribution of soy-derived phytoestrogens in human breast tissue and biological fluids. Obstetrics and Gynecology . Obstetr Gynecol 2004; 103, 892-898. (I.F. = 3.512) B. Vanhoecke, A. Heyerick, H. Depypere, F. Delporte, E. Van Braeckel, M. Nuytinck, D. De Keukeleire and M. Bracke. A safety study of oral tangeretin and xanthohumol administration to laboratory mice. Clin. Chem. Lab. Med. Vanhoecke, B.; Depypere, H.; De Keukeleire, D.; Bracke, M.; “Cellular activities related to growth and invasion: Targets for flavonoids”, Recent Res. Devel. Cell. Sci., 2004, 1, 165-192. Familial male lethal incontinentia pigmenti: a rare cause of recurring spontaneous abortions. De Coen K., Lissens W., De Cuyper C., Depypere H., De Praeter C. Journal of Maternal-Fetal & Neonatal Medicine 2004, 16 suppl 1, p253. (peer reviewed en geïndexeerd voor Medline). M.E. Bracke, B.W. Vanhoecke, H.T. Depypere, H.J. Kloosterboer. Tibolone and its metabolites inhibit the invasion of human breast cancer cells. EJC Supplements, 2004, 2(9): 105-112. Van Slambrouck S, Parmar V, Sharma S, De Bondt B, Flore F, Coopman P, Van hoecke B, Boterberg T, Depypere H, Leclercq G, Bracke M. Tangeretine inhibits extracellular-signal-regulated kinase phorphorylation. FEBS Letters, 2005, 579:1665-1669. (I.F. = 3.415)B. Vanhoecke, F. Delporte, E. Van Braeckel, A. Heyerick, H. Depypere, M. Nuytinck, D. De Keukeleire, and M. Bracke. A Safety study of oral tangeretin and xanthohumol administration to laboratory mice. In Vivo, 2005, 19: 103-108. (I.F. = 1.037)B. Vanhoecke, H. Depypere, A. De Beyter, S. Sharma, V. Parmar, D. De Keukeleire, and M. Bracke. New anti-invasive compounds: results from the Indo-Belgian screening program. Pure Appl. Chem., 2005, 77(1):65-74. (I.F. = 1.679)

  19. Derycke L, Van Marck V, Depypere H, Bracke M. Molecular targets of growth, differentiation, tissue integrity and ectopic cell dath in cancer cells. Cancer Biother Radiopharmac. 2005, 20:579-588. (I.F. = 1.669) B. Vanhoecke, L. Derycke, V. Van Marck, H. Depypere, D. De Keukeleire, and M. Bracke. The anti-invasive effect of xanthohumol, a prenylated chalcone present in hops (Humulus lupulus L.) and beer. Int. J. Cancer 2005, 889-895. (I.F. = 4.700)Depypere, H., Bracke, M., Vanhoecke, B., De Keukeleire, D., Heyerick, A., Bolca, S., Verstraete W. Are phytoestrogens of any help? International Journal of Gynecological Cancer, 2006; 16[S2], 580-580. B.W. Vanhoecke, M.E. Bracke, H.J. Kloosterboer en H.T. Depypere. Tibolone and its metabolites inhibit invasion of human mammary carcinoma cells in vitro. Maturitas 2006; 54: 229-237. (I.F. 2005 = 2.004) Heyerick A, Vervacke S, Depypere H, Bracke M, De keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2005; 54: 164-175. (I.F. 2005 = 2.004) Bolca, S., Possemiers, S., Maervoet, V., Huybrechts, I., Heyerick, A., Vervarcke, S., Depypere, H., De Keukeleire, D., Bracke, M., De Henauw, S., Verstraete, W., Van de Wiele, T. Microbial and dietary factors associated with the 8-prenylnaringenin producer phenotype: a dietary intervention trial with fifty healthy post-menopausal. British Journal of Nutrition, 2007; 98[5], 950-959. Bolca, S., Possemiers, S., Herregat, A., Huybrechts, I., Heyerick, A., De Vriese, S., Verbruggen, M., Depypere, H., De Keukeleire, D., Bracke, M., De Henauw, S., Verstraete, W., Van de Wiele, T. Microbial and dietary factors are associated with the equol producer phenotype in healthy postmenopausal women. Journal of Nutrition, 2007; 137[10], 2242-2246. Possemiers, S., Bolca, S., Eeckhaut, E., Depypere, H., Verstraete, W. Metabolism of isoflavones, lignans and prenylflavonoids by intestinal bacteria: producer phenotyping and relation with intestinal community. FEMS Microbiology Ecology, 2007; 61; 372-383. Bracke, M., Vanhoecke, B., Dercycke, L., Bolca, S., Possemiers, S., Heyerick, A., Stevens, C.V., De Keukeleire, D., Depypere, H.T., Verstraete, W., Williams, C.A., McKenna, S.T., Tomar, S., Sharma, D., Prasad, A.K., DePass, A.L., Parmar, V.S. Plant polyphenolics as anti-invasive cancer agents. Anti-Cancer Agents in Medicinal Chemistry, 2008; 8[3], 171-185.

  20. Phytoestrogens are a diverse group of polyphenolic non steroidal plant compounds

  21. Individual phytoestrogens SHIME run Twin 1: Inoculated as a strong END and ENL producer Twin 2: Inoculated as a strong END and weakENL producer Agreement Nr. RT-05/02-FYTOES-1 Ghent, January12th 2009

  22. control (C); 0.25 mg estradiol (E2) implant (E); E2 implant + 2.5 mg TAM implant (2.5 TE); E2 implant + 2.5 mg TAM implant + 1000 ppm genistein (2.5 TEG); E2 implant + 5 mg TAM implant (5 TE), and E2 implant +5 mg TAM implant +1000 ppm genistein (5 TEG). Dietary Genistein Negates the Inhibitory Effect of Tam on Growth of Estrogen-dependent Human Breast Cancer (MCF-7) Cells Implanted in Athymic Mice Ju, et al Cancer Research 2003

  23. Tam Tang Tam Tang Contr Bracke M, Depypere H et al. JNCI 2000 Tumor volume (mm3) 1000 weeks 2 4 8 6 10 12 14

  24. Proliferation and cell cell adhesion SLOW AGGREGATION ASSAY

  25. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet oncol, 2012 Mar 6. [Epub ahead of print] Anderson GL, Chlebowski RT, Aragaki AK, Kuller LH, Manson JE, Gass M, Bluhm E, Connelly S, Hubbell FA, Lane D, Martin L, Ockene J, Rohan T, Schenken R, Wactawski-Wende J. 25

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  29. Oestradiol (valeraat, hemihydraat,.. Dosis) Progestagenen (dosis, duur, regime) Progesterone derivaten C-19 nortestosterone Spironolactone [Estranes] [Gonanes] [Pregnanes] Dienogest Norgestrel Drospirenone Megestrol acetaat Norethindrone Levonorgestrel Cyproterone acetaat Norethisterone acetaat Norgestimate Medroxyprogesterone acetaat Ethynodiol diacetaat Desogestrel Lynestrenol Gestodene Norethynodrel Schindler et al. Maturitas 2008;61:171–80; Sitruk-Ware R. Maturitas 2004;47:277–83

  30. Hormonal replacement after endometrial cancer no indication of higher recurrence rates Chapman et al. Am J Obstet Gynecol 1996 Suriano et al. Obstet Gynecol 2001 Barakat et al. J Clinical oncol 2006 Hormonal replacement after ovarian carcinoma Few data One study with 130 women: no neg influence Guidozzi and Daponte. Cancer 1999

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