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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

Roberta Ness, MD, MPHUniversity of Pittsburgh

Ovarian Cancer: Reproductive Factors and Beyond


Ovarian cancer descriptive statistics highlights
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
Prevention of Ovarian Cancer

  • Secondary: Screening for early disease

  • Primary: Preventing cancer development


Does anything prevent ovarian cancer
Does Anything Prevent Ovarian Cancer?

  • Oral contraceptives

  • Pregnancies

  • Breast feeding (long duration)

  • Tubal ligation

  • Oophorectomy and hysterectomy


Oral contraceptives and ovarian cancer
Oral Contraceptives and Ovarian Cancer

  • Risk 30-40% 

  • Longer use, more protection

  • Protection 20 or more years after last use

  • New OCs protective



Breast feeding and ovarian cancer
Breast Feeding and Ovarian Cancer

0 6 12 18 24

Whittemore 1992



Oophorectomy
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.


Etiologic hypotheses
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
Gonadotropin Hypothesis

Pro

Parity

Breastfeeding

OC use

Con

HRT

Fertility drugs

Prospective measures


Fertility drug use
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.


Roberta ness md mph university of pittsburgh 1323997

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.


Relative odds 95 ci of ovarian cancer by thirds of serum hormone levels
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.


Roberta ness md mph university of pittsburgh 1323997

? Ovulation Involves Inflammation Hormone Levels.

Parity 

Breastfeeding 

Oral contraceptive use 

Reduced

Ovarian Cancer

Risk


Ovulation elevates inflammation mediators
Ovulation Elevates Inflammation Mediators Hormone Levels.

  • TNF, IL-6, IL-1

  • Cell proliferation

  • Oxidative stress

  • Prostaglandins and leukotrienes

  • Vascular permeability



Aspirin use
Aspirin Use Hormone Levels.

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


Host invader interactions promote carcinogenesis
Host-invader Interactions Promote Carcinogenesis Hormone Levels.

  • 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


Roberta ness md mph university of pittsburgh 1323997

? Reduced Unopposed Estrogen Hormone Levels.

Parity 

Breastfeeding 

Oral contraceptive use 

Reduced

Ovarian Cancer

Risk


Unopposed estrogen epidemiology of risk
Unopposed Estrogen: Epidemiology of Risk Hormone Levels.

  • Early menarche, short cycle length

  • Reduced exercise

  • ERT, but not necessarily HRT


Roberta ness md mph university of pittsburgh 1323997

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


Unopposed estrogens
Unopposed Estrogens Risk in Relation to Lifetime Leisure Physical Activity.

  • 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
Progesterone Risk in Relation to Lifetime Leisure Physical Activity.

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.


Adjusted odds ratios for ovarian cancer according to oral contraceptive oc potency
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.


Barriers to understanding the pathophysiology of ovarian cancer
Barriers to Understanding the Pathophysiology of Ovarian Cancer

  • Lack of a relevant animal model

  • Absence of a recognized premalignant lesion


Endometriosis
Endometriosis Cancer

  • 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
Epidemiology: Brinton, et al. Cancer

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


Epidemiology ness et al
Epidemiology: Ness et al. Cancer

  • SHARE analysis: 767 cases, 1367 controls

  • Pooled analysis: 5207 cases, 7705 controls


Endometriosis1
Endometriosis Cancer

1.9

X

1.7 1.7

X X

Risk 1.0

Brinton Ness Ness 2000 2002


Ovarian cancer studies
Ovarian Cancer Studies Cancer

  • 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
Immune Abnormalities in Endometriosis Cancer

  • 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


Roberta ness md mph university of pittsburgh 1323997

Genetics

Endometriosis

Cytokines

Estradiol Prostaglandins

Aromatase

COX-2

X

X

Aromatase

17HSD-1

Progesterone

Aromatase

Estrone

Androstenedione

Estrogens


Estrogen related risk factors for ovarian cancer and endometriosis
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 +? ++


Roberta ness md mph university of pittsburgh 1323997

Genetics

Endometriosis

Cytokines

Estradiol Prostaglandins

Aromatase

COX-2

X

X

Aromatase

17HSD-1

Progesterone

Aromatase

Estrone

Androstenedione

Estrogens


Synthesis
Synthesis Endometriosis

Retrograde Menstruation

Endometriosis

Ovarian Cancer

  • Androgens

  • Estrogens

  • Progesterone

    Cytokines

    Prostaglandins

    MMP-9