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Roberta Ness, MD, MPH University of Pittsburgh

Roberta Ness, MD, MPH University of Pittsburgh. Ovarian Cancer: Reproductive Factors and Beyond. Ovarian Cancer Descriptive Statistics Highlights. Most frequent cause of death from gynecologic malignancy 40% five year survival

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Roberta Ness, MD, MPH University of Pittsburgh

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  1. Roberta Ness, MD, MPHUniversity of Pittsburgh Ovarian Cancer: Reproductive Factors and Beyond

  2. Ovarian Cancer Descriptive Statistics Highlights • Most frequent cause of death from gynecologic malignancy • 40% five year survival • 75% of patients have cancer spread beyond the ovary by the time of clinical detection • Mortality has decreased only slightly in past 30 years • Current guidelines do not support screening either pre- or post- menopausal women in whom there is no history of ovarian cancer

  3. Prevention of Ovarian Cancer • Secondary: Screening for early disease • Primary: Preventing cancer development

  4. Does Anything Prevent Ovarian Cancer? • Oral contraceptives • Pregnancies • Breast feeding (long duration) • Tubal ligation • Oophorectomy and hysterectomy

  5. Oral Contraceptives and Ovarian Cancer • Risk 30-40%  • Longer use, more protection • Protection 20 or more years after last use • New OCs protective

  6. Pregnancies and Ovarian Cancer Whittemore 1992

  7. Breast Feeding and Ovarian Cancer 0 6 12 18 24 Whittemore 1992

  8. Tubal Ligation

  9. Oophorectomy Salpingo-oophorectomy (n=98) 1.0 0.9 Cumulative Proportion without Breast or BRCA-Related Gynecologic Cancer 0.8 0.7 Surveillance (n=72) 0.6 0 12 24 36 48 60 72 84 Months Kauff ND, et al. N Engl J Med 2002;346:1609-15.

  10. Etiologic Hypotheses • Ovulation hypothesis: Ovulation exposes ovarian epithelium to minor trauma which allows promotion of cells containing allele loss. • Pituitary gonadotropin hormone hypothesis: High gonadotropin levels have direct toxic effect.

  11. Gonadotropin Hypothesis Pro Parity Breastfeeding OC use Con HRT Fertility drugs Prospective measures

  12. Fertility Drug Use Variable Cases Controls Adjusted OR (95% CI) Fertility Drugs (all) No 911 1137 1.0 Yes 149 200 0.97 (0.76, 1.25) Fertility Drugs Never pregnant No 191 147 1.0 Yes 54 22 1.60 (0.90, 2.87) Ever pregnant No 720 990 1.0 Yes 95 178 0.82 (0.62, 1.09) Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs and ovarian cancer: a pooled analysis of case-control studies. Am J Epid 2002:155:217-24.

  13. Odds Ratios (95% CI) for Ovarian Cancer according to Estrogen Replacement (ERT), Estrogen + Progestin Sequential (HRT SP), and Estrogen + Progestin Continuous (HRT CP) Cases Controls OR (95%CI) ERT No 583 3531 Yes 59 259 1.43(1.02-2.0) HRT SP No 550 3434 Yes 57 348 1.54(1.15-2.05) HRT CP No 583 3494 Yes 55 280 1.02(0.73-1.43) Riman T, et al. J Natl Cancer Inst 2002;94:497-504.

  14. Relative Odds (95% CI) of Ovarian Cancer by Thirds of Serum Hormone Levels. Helzsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-1930.

  15. ? Ovulation Involves Inflammation Parity  Breastfeeding  Oral contraceptive use  Reduced Ovarian Cancer Risk

  16. Ovulation Elevates Inflammation Mediators • TNF, IL-6, IL-1 • Cell proliferation • Oxidative stress • Prostaglandins and leukotrienes • Vascular permeability

  17. Talc Use and Ovarian Cancer

  18. Aspirin Use Risk 1.0 0.90.9 0.75 X X X 0.7 0.6 0.5 X X X Tzonou Cramer Rosenberg Tavani Akhmedkhanov Moysich 1984 1998 2000 2000 2001 2001

  19. Host-invader Interactions Promote Carcinogenesis • Treatment of ovarian ascites with TNF  promotes solid nodule formation in nude mice • Nude mice with macrophages lacking gene for MMP-9 developed fewer ovarian tumors. Addition of macrophages with MMP-9 allowed ovarian neoplastic growth

  20. ? Reduced Unopposed Estrogen Parity  Breastfeeding  Oral contraceptive use  Reduced Ovarian Cancer Risk

  21. Unopposed Estrogen: Epidemiology of Risk • Early menarche, short cycle length • Reduced exercise • ERT, but not necessarily HRT

  22. Odds Ratios and 95% Confidence Intervals of Ovarian Cancer Risk in Relation to Lifetime Leisure Physical Activity. Cottreau CM, Ness RB, Kriska AM. Physical activity and reduced risk of ovarian cancer. Obstet Gynecol 2000;96:609-14. Physical activity Level Cases Controls OR (95% CI) Low 289 444 1.00 Moderate 321 576 0.85 (0.69, 1.06) High 154 344 0.73 (0.56, 0.94) P for Trend .01

  23. Unopposed Estrogens • Estrogen receptors in normal ovarian epithelium, ovarian cancer cells • Estrogen stimulates ovarian cancer in vitro • Elevated local and serum estrogen levels in ovarian cancer • Ovulation may elevate serum estradiol levels

  24. Progesterone Apoptotic Effect of Hormonal Treatment on Macaque Ovarian Epithelium Median percent of Range of percent of Study group Number apoptic cell counts apoptotic cell counts Control 20 3.9% 0.1-33.0 % Hormone treated Ethinyl – Estradiol 20 1.8% 0.1-28.6 % Combination pill 17 14.5% 3.0-61.0 % Levonogestrel 18 24.9% 3.5-61.8 % Rodriguez G. Ovarian cancer and high risk women: implications of prevention, screening and early detection. May, 2002, Pittsburgh, PA.

  25. Adjusted Odds Ratios for Ovarian Cancer According to Oral Contraceptive (OC) Potency Progesterone/Estrogen Cases Controls Adjusted OR(95%CI) High/High 22 334 1.0 High/Low 0 17 0.0 (0.0-n/e) Low/High 49 497 2.1(1.2-3.7) Low/Low 33 306 1.6(0.9-3.0) Nonusers 286 1711 2.9(1.8-4.5) Schindkraut JM, Calingert B, Marchbanks PA, et al. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. JNCI 2002;94:32-8.

  26. Barriers to Understanding the Pathophysiology of Ovarian Cancer • Lack of a relevant animal model • Absence of a recognized premalignant lesion

  27. Endometriosis • Endometrial implants (ectopic)/outside the endometrium • Occurs in 3-8% of reproductive age women • Thought to arise from retrograde menstruation • Almost all women have retrograde menstruation

  28. Epidemiology: Brinton, et al. 20,686 women hospitalized for endometriosis 11.4 Years Ovarian Breast Non-Hodgkin’s Cancer Cancer Lymphoma SIR 1.9 SIR 1.3 SIR 1.8 SIR 4.2 for longstanding ovarian disease

  29. Epidemiology: Ness et al. • SHARE analysis: 767 cases, 1367 controls • Pooled analysis: 5207 cases, 7705 controls

  30. Endometriosis 1.9 X 1.7 1.7 X X Risk 1.0 Brinton Ness Ness 2000 2002

  31. Ovarian Cancer Studies • Endometriosis among 20-50% of endometrioid and clear cell tumors • Endometriosis among 3-9% of serous, mucinous, and other histologic subtypes

  32. Immune Abnormalities in Endometriosis • Reduced peritoneal NK activity • Elevated numbers and activity of peripheral/ peritoneal macrophage and T cell activity • TGF  NK activity • MMP-9, VEGF   extracellular matrix and  angiogenesis

  33. Macrophages, T cells, NK cells • Cytokines • TGF •  NK activity • VEGF • MMPs Genetics Endometriosis Cytokines Estradiol Prostaglandins Aromatase COX-2 X X Aromatase 17HSD-1 Progesterone Aromatase Estrone Androstenedione Estrogens

  34. Estrogen-Related Risk Factors for Ovarian Cancer and Endometriosis Association to Association to Variable Ovarian Cancer Endometriosis Nulliparity ++ ++ Lack of oral contraception ++ + Lack of breast feeding ++ +? Early age at menarche + ++ Short or long menstrual cycles + + Body Mass Index - +? Height + + Caffeine use + + Alcohol use - +? Lack of exercise +? ++

  35. Macrophages, T cells, NK cells • Cytokines • TGF •  NK activity • VEGF • MMPs Genetics Endometriosis Cytokines Estradiol Prostaglandins Aromatase COX-2 X X Aromatase 17HSD-1 Progesterone Aromatase Estrone Androstenedione Estrogens

  36. Synthesis Retrograde Menstruation Endometriosis Ovarian Cancer • Androgens • Estrogens • Progesterone Cytokines Prostaglandins MMP-9

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