Roberta Ness, MD, MPHRoberta Ness, MD, MPHUniversity of PittsburghUniversity of Pittsburgh

Ovarian Cancer: Reproductive Factors and Beyond

Ovarian Cancer Descriptive Ovarian Cancer Descriptive Statistics HighlightsStatistics Highlights

Most frequent cause of death from gynecologic malignancy

40% five year survival75% of patients have cancer spread beyond the

ovary by the time of clinical detectionMortality has decreased only slightly in past 30

yearsCurrent guidelines do not support screening

either pre- or post- menopausal women in whom there is no history of ovarian cancer

Prevention of Ovarian Prevention of Ovarian CancerCancer

Secondary: Screening for early disease

Primary: Preventing cancer

development

Does Anything Prevent Does Anything Prevent Ovarian Cancer?Ovarian Cancer?

Oral contraceptivesPregnanciesBreast feeding (long duration)Tubal ligationOophorectomy and

hysterectomy

Oral Contraceptives and Oral Contraceptives and Ovarian CancerOvarian Cancer

Risk 30-40% Longer use, more protectionProtection 20 or more years after last useNew OCs protective

Pregnancies and Ovarian Pregnancies and Ovarian CancerCancer

00.10.20.30.40.50.60.70.80.9

1

0 1 2 3 4 5 6

Number of pregnancies

Ris

k

Whittemore 1992

Breast Feeding and Ovarian Breast Feeding and Ovarian CancerCancer

00.10.20.30.40.50.60.70.80.9

1

Number of months breastfeeding

Ris

k

Whittemore 1992

0 6 12 18 24

Tubal LigationTubal Ligation

OophorectomyOophorectomy

Kauff ND, et al. N Engl J Med 2002;346:1609-15.

0 12 24 36 48 60 72 84

1.0

0.9

0.8

0.7

0.6

Salpingo-oophorectomy (n=98)

Months

Cum

ulat

i ve

Pro

port

ion

with

out B

reas

t or

BR

CA

-Rel

ated

Gyn

ecol

ogic

Can

cer

Surveillance (n=72)

Etiologic HypothesesEtiologic 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 HypothesisGonadotropin Hypothesis

Pro

Parity

Breastfeeding

OC use

Con

HRT

Fertility drugs

Prospective measures

Fertility Drug UseFertility Drug UseVariable 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.

Odds Ratios (95% CI) for Ovarian Cancer Odds Ratios (95% CI) for Ovarian Cancer according to Estrogen Replacement (ERT), according to Estrogen Replacement (ERT),

Estrogen + Progestin Sequential (HRT SP), and Estrogen + Progestin Sequential (HRT SP), and Estrogen + Progestin Continuous (HRT CP)Estrogen + Progestin Continuous (HRT CP)

Cases Controls OR (95%CI)ERT

No 583 3531Yes 59 259 1.43(1.02-2.0)

HRT SPNo 550 3434Yes 57 348 1.54(1.15-2.05)

HRT CPNo 583 3494Yes 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 Relative Odds (95% CI) of Ovarian Cancer by Thirds of Serum Hormone Levels.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.

Hormone Low Medium High P (Trend)

LH 1.0 0.6 (0.1-2.8) 0.4 (0.1-2.0) .25

FSH 1.0 0.5 (0.1-2.8) 0.1 (0.0-1.0) .02

Androstenedione 1.0 2.3 (0.4-12.6) 7.6 (1.2-48.7) .008

Progesterone 1.0 3.5 (0.4-31.5) 5.8 (0.2-167.3) .58

Estrone 1.0 3.0 (0.9-10.3) 1.7 (0.4-7.6) NA

Estradiol 1.0 2.1 (0.54-7.8) 3.0 (0.6-14.9) .26

Parity

Breastfeeding

Oral contraceptive use

? Ovulation Involves Inflammation

Reduced

Ovarian Cancer

Risk

Ovulation Elevates Ovulation Elevates Inflammation MediatorsInflammation Mediators

TNF, IL-6, IL-1

Cell proliferation

Oxidative stress

Prostaglandins and leukotrienes

Vascular permeability

Talc Use and Ovarian Talc Use and Ovarian CancerCancer

Aspirin UseAspirin Use

Risk 1.0

Tzonou Cramer Rosenberg Tavani Akhmedkhanov Moysich

1984 1998 2000 2000 2001 2001

0.9 0.9

0.75 X X

X 0.7 0.6

0.5 X X

X

Host-invader Interactions Host-invader Interactions Promote CarcinogenesisPromote 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

Parity

Breastfeeding

Oral contraceptive use

? Reduced Unopposed Estrogen? Reduced Unopposed Estrogen

Reduced

Ovarian Cancer

Risk

Unopposed Estrogen: Unopposed Estrogen: Epidemiology of RiskEpidemiology of Risk

Early menarche, short cycle length

Reduced exercise

ERT, but not necessarily HRT

Cottreau CM, Ness RB, Kriska AM. Physical activity and reduced risk of ovarian cancer. Obstet Cottreau CM, Ness RB, Kriska AM. Physical activity and reduced risk of ovarian cancer. Obstet Gynecol 2000;96:609-14.Gynecol 2000;96:609-14.

Odds Ratios and 95% Confidence Intervals of Ovarian Cancer Risk in Relation to Lifetime Leisure Physical Activity.

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 EstrogensUnopposed Estrogens

Estrogen receptors in normal ovarian epithelium, ovarian cancer cells

Estrogen stimulates ovarian cancer in vitroElevated local and serum estrogen levels in

ovarian cancerOvulation may elevate serum estradiol levels

ProgesteroneProgesterone

Rodriguez G. Ovarian cancer and high risk women: implications of prevention, screening and early detection. May, 2002, Pittsburgh, PA.

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 %

Adjusted Odds Ratios for Ovarian Adjusted Odds Ratios for Ovarian Cancer According to Oral Cancer According to Oral

Contraceptive (OC) PotencyContraceptive (OC) Potency

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.

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)

Barriers to Understanding the Barriers to Understanding the Pathophysiology of Ovarian CancerPathophysiology of Ovarian Cancer

Lack of a relevant animal model

Absence of a recognized premalignant lesion

EndometriosisEndometriosis

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.

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.

SHARE analysis: 767 cases, 1367 controls

Pooled analysis: 5207 cases, 7705 controls

EndometriosisEndometriosis

Risk 1.0

1.9

X 1.7 1.7

X X

Brinton Ness Ness 2000 2002

Ovarian Cancer StudiesOvarian 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 Immune Abnormalities in EndometriosisEndometriosis

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

Endometriosis

Estradiol Prostaglandins

Cytokines

Estrone

Genetics

Macrophages, T cells, NK cellsCytokines

TGF

NK activity

VEGF

MMPs

Androstenedione

Progesterone

X

Aromatase

Aromatase

Aro

mat

ase

17HSD

-1

X

Estrogens

COX-2

Estrogen-Related Risk Factors for Estrogen-Related Risk Factors for Ovarian Cancer and EndometriosisOvarian Cancer and Endometriosis

Association to Association toVariable Ovarian Cancer EndometriosisNulliparity ++ ++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 +? ++

Endometriosis

Estradiol Prostaglandins

Cytokines

Estrone

Genetics

Macrophages, T cells, NK cellsCytokines

TGF

NK activity

VEGF

MMPs

Androstenedione

Progesterone

X

Aromatase

Aromatase

Aro

mat

ase

17HSD

-1

X

Estrogens

COX-2

SynthesisSynthesis

Retrograde Menstruation

Endometriosis Ovarian Cancer

Androgens

Estrogens

Progesterone

Cytokines

Prostaglandins

MMP-9