Download Epidemiology: Ness et al. - 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
 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:
Screening for early disease
 Primary:
Preventing cancer development
Does Anything Prevent
Ovarian Cancer?
 Oral
contraceptives
 Pregnancies
 Breast feeding (long duration)
 Tubal 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

Risk
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
1
2
3
4
Number of pregnancies
5
6
Risk
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
0
Whittemore 1992
6
12
18
Number of months breastfeeding
24
Tubal Ligation
Oophorectomy
Salpingo-oophorectomy (n=98)
1.0
0.9
0.8
0.7
Surveillance (n=72)
0.6
0
12
24
36
Months
Kauff ND, et al. N Engl J Med 2002;346:1609-15.
48
60
72
84
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
Con
Parity
HRT
Breastfeeding
Fertility drugs
OC use
Prospective measures
Fertility Drug Use
Variable
Cases
Controls
Adjusted OR (95% CI)
Fertility Drugs (all)
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)
Fertility Drugs
Never pregnant
No
Yes
Ever pregnant
No
Yes
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
Controls
OR (95%CI)
583
59
3531
259
1.43(1.02-2.0)
550
57
3434
348
1.54(1.15-2.05)
583
55
3494
280
1.02(0.73-1.43)
ERT
No
Yes
HRT SP
No
Yes
HRT CP
No
Yes
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
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
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

Oral contraceptive use 
Reduced
Ovarian Cancer
Risk
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
0.5
0.9
0.9
X
X
0.7
0.6
X
X
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

Oral contraceptive use 
Reduced
Ovarian Cancer
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
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
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%
1.8%
14.5%
24.9%
Range of percent of
apoptotic cell counts
0.1-33.0 %
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
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

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
Breast
Non-Hodgkin’s
Cancer
Cancer
Lymphoma
SIR 1.9
SIR 4.2 for
longstanding
ovarian disease
SIR 1.3
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
1.7
X
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
Macrophages,
T cells, NK cells
Genetics
Cytokines
 TGF
Endometriosis
 NK activity
Cytokines
 VEGF
 MMPs
Aromatase
Estradiol
Prostaglandins
X
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
++
+
+?
++
+
+?
+
+
+?
++
Macrophages,
T cells, NK cells
Genetics
Cytokines
 TGF
Endometriosis
 NK activity
Cytokines
 VEGF
 MMPs
Aromatase
Estradiol
Prostaglandins
X
X
Progesterone
Androstenedione
Estrone
Estrogens
Synthesis
Retrograde
Menstruation
Endometriosis
Androgens
Estrogens
Progesterone
Cytokines
Prostaglandins
MMP-9
Ovarian Cancer