Ovarian Cancer Reproductive Factors and Beyond[1]

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  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 Prevention of Ovarian Cancer  Secondary:  Primary: Screening for early disease Preventing cancer development Does Anything Prevent Ovarian Cancer?  Oral contraceptives  Pregnancies  Breast feeding (long  Tubal duration) ligation  Oophorectomy and hysterectomy Oral Contraceptives and Ovarian Cancer Risk 30-40%   Longer use, more protection  Protection 20 or more years after last use  New OCs protective  Pregnancies and Ovarian Cancer 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 Whittemore 1992 Risk 1 2 3 4 5 6 Number of pregnancies Breast Feeding and Ovarian Cancer 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Risk 0 6 12 18 Number of months breastfeeding 24 Whittemore 1992 Tubal Ligation Oophorectomy 1.0 0.9 0.8 0.7 Salpingo-oophorectomy (n=98) 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. 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. Gonadotropin Hypothesis Pro Parity Breastfeeding Con HRT Fertility drugs OC use Prospective measures Fertility Drug Use Variable Cases Controls Adjusted OR (95% CI) Fertility Drugs (all) No Yes Fertility Drugs Never pregnant No Yes Ever pregnant No Yes 911 149 1137 200 1.0 0.97 (0.76, 1.25) 191 54 147 22 1.0 1.60 (0.90, 2.87) 720 95 990 178 1.0 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. Odds Ratios (95% CI) for Ovarian Cancer according to Estrogen Replacement (ERT), Estrogen + Progestin Sequential (HRT SP), and Estrogen + Progestin Continuous (HRT CP) Cases ERT Controls 3531 259 3434 348 OR (95%CI) No Yes HRT SP No Yes HRT CP No Yes 583 59 550 57 1.43(1.02-2.0) 1.54(1.15-2.05) 583 55 3494 280 1.02(0.73-1.43) Riman T, et al. J Natl Cancer Inst 2002;94:497-504. Relative Odds (95% CI) of Ovarian Cancer by Thirds of Serum Hormone Levels. Hormone Low Medium High P (Trend) LH FSH 1.0 1.0 0.6 (0.1-2.8) 0.5 (0.1-2.8) 0.4 (0.1-2.0) 0.1 (0.0-1.0) .25 .02 Androstenedione 1.0 Progesterone Estrone 2.3 (0.4-12.6) 3.5 (0.4-31.5) 3.0 (0.9-10.3) 7.6 (1.2-48.7) .008 1.0 1.0 5.8 (0.2-167.3) .58 1.7 (0.4-7.6) NA Estradiol 1.0 2.1 (0.54-7.8) 3.0 (0.6-14.9) .26 Helzsouer KJ, Alberg AJ, Gordon GB, et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-1930. ? Ovulation Involves Inflammation Parity Breastfeeding   Reduced Ovarian Cancer Risk Oral contraceptive use  Ovulation Elevates Inflammation Mediators   TNF, IL-6, IL-1 Cell proliferation    Oxidative stress Prostaglandins and leukotrienes Vascular permeability Talc Use and Ovarian Cancer Aspirin Use Risk 1.0 0.75 X 0.9 X 0.9 X 0.7 X 0.6 X 0.5 X Tzonou Cramer Rosenberg Tavani Akhmedkhanov Moysich 1984 1998 2000 2000 2001 2001 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  ? Reduced Unopposed Estrogen Parity Breastfeeding   Reduced Ovarian Cancer Oral contraceptive use  Risk Unopposed Estrogen: Epidemiology of Risk  Early menarche, short cycle length Reduced exercise   ERT, but not necessarily HRT Odds Ratios and 95% Confidence Intervals of Ovarian Cancer Risk in Relation to Lifetime Leisure Physical Activity. Physical activity Level Low Moderate High P for Trend Cases 289 321 154 Controls 444 576 344 OR (95% CI) 1.00 0.85 (0.69, 1.06) 0.73 (0.56, 0.94) .01 Cottreau CM, Ness RB, Kriska AM. Physical activity and reduced risk of ovarian cancer. Obstet Gynecol 2000;96:609-14. 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 Progesterone Apoptotic Effect of Hormonal Treatment on Macaque Ovarian Epithelium Study group Number Control 20 Hormone treated Ethinyl – Estradiol 20 Combination pill 17 Levonogestrel 18 Median percent of apoptic cell counts 3.9% Range of percent of apoptotic cell counts 0.1-33.0 % 1.8% 14.5% 24.9% 0.1-28.6 % 3.0-61.0 % 3.5-61.8 % Rodriguez G. Ovarian cancer and high risk women: implications of prevention, screening and early detection. May, 2002, Pittsburgh, PA. Adjusted Odds Ratios for Ovarian Cancer According to Oral Contraceptive (OC) Potency Progesterone/Estrogen High/High High/Low Low/High Low/Low Nonusers Cases Controls 22 0 49 33 286 334 17 497 306 1711 Adjusted OR(95%CI) 1.0 0.0 (0.0-n/e) 2.1(1.2-3.7) 1.6(0.9-3.0) 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. Barriers to Understanding the Pathophysiology of Ovarian Cancer  Lack of a relevant animal model Absence of a recognized premalignant lesion  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 Epidemiology: Brinton, et al. 20,686 women hospitalized for endometriosis 11.4 Years Ovarian Cancer SIR 1.9 SIR 4.2 for longstanding ovarian disease Breast Cancer SIR 1.3 Non-Hodgkin’s Lymphoma SIR 1.8 Epidemiology: Ness et al.  SHARE analysis: 767 cases, 1367 controls  Pooled analysis: 5207 cases, 7705 controls Endometriosis 1.9 X 1.7 X 1.7 X Risk 1.0 Brinton Ness 2000 Ness 2002 Ovarian Cancer Studies  Endometriosis among 20-50% of endometrioid and clear cell tumors  Endometriosis among 3-9% of serous, mucinous, and other histologic subtypes 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  Genetics Macrophages, T cells, NK cells Cytokines Endometriosis Cytokines  TGF  NK activity  VEGF  MMPs Estradiol X Aromatase Prostaglandins X Progesterone Androstenedione Estrone Estrogens Estrogen-Related Risk Factors for Ovarian Cancer and Endometriosis Association to Variable Ovarian Cancer 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 +? Association to Endometriosis ++ + +? ++ + +? + + +? ++ Genetics Macrophages, T cells, NK cells Cytokines Endometriosis Cytokines  TGF  NK activity  VEGF  MMPs Estradiol X Aromatase Prostaglandins X Progesterone Androstenedione Estrone Estrogens Synthesis Retrograde Menstruation Endometriosis Ovarian Cancer Androgens Estrogens Progesterone Cytokines Prostaglandins MMP-9