Presented July 9, 2016 at the Ovarian Cancer National Conference in Washington, DC

1. STRESS AS A POTENTIALLY
MODIFIABLE RISK FACTOR
FOR OVARIAN CANCER
Liz Poole
Assistant Professor of Medicine
Harvard Medical School and Brigham and Women’s Hospital
Department of Defense Ovarian Cancer Academy Early Career Investigator
7/9/2016

2. Most ovarian cancer risk factors are not
modifiable
Established Probable Suspected
Age Early menarche Dietary fat
BRCA/HNPCC Late Menopause NSAIDs (protective)
Family history Infertility Pelvic diseases
Oophorectomy
(protective)
Hysterectomy
(protective)
Adiposity
(premenopausal)
Tubal ligation
(protective)
Lactation
(protective)
Flavonoids
(protective)
OC use (protective) HT Vitamin D
Nulliparity Talc use Others

3. Is chronic stress a modifiable risk factor for
ovarian cancer?
• Mouse models suggest a role of chronic stress in tumor
progression
Thaker PH et al, Nature Medicine, 2006; Moreno-Smith M et al, Clin Cancer Res, 2011

4. Is chronic stress a modifiable risk factor for
ovarian cancer?
• Mouse models suggest a role of chronic stress in tumor
progression
• Epidemiologic studies suggest a role of stress in cancer
risk and survival
Chida Y et al, Nature Clinical Practice, 2008

5. • Mouse models suggest a role of chronic stress in tumor
progression
• Epidemiologic studies suggest a role of stress in cancer
risk and survival
• In ovarian cancer patients, stress associated with
• Higher levels of circulating angiogenic factors (MMPs, ,
inflammatory markers (IL-6), stress markers (norepinephrine,
diurnal cortisol)
• Poorer quality of life
• Worse survival
Lutgendorf SK et al, J Clin Oncol, 2012
Is chronic stress a modifiable risk factor for
ovarian cancer?

6. A multi-faceted approach
• Self-reported stress
• Depression, anxiety, social support, job strain, caregiving stress
• Biologic markers of stress in plasma
• Telomeres, prolactin
•
• Developing new scales and markers
• Other self-reported sources of stress
• Novel biomarkers (metabolomics profiling)

7. A multi-faceted approach
• Self-reported stress
• Depression, anxiety, social support, job strain, caregiving stress
• Biologic markers of stress in plasma
• Telomeres, prolactin, metabolomics
• Developing new scales and markers
• Other self-reported sources of stress
• Novel biomarkers

8. We have a wealth of data in the Nurses’
Health Studies
76
Questionnaire (diseases, medications, hormones, many others!)
78 80 82 84 86 88 90 92 94 96 98 00 02 04 06 08 10 12 14
Blood collection
NHSI
89 91 93 95 97 99 01 03 05 07 09 11 13NHSII
Q + questions related to stress

9. Exposures
• Depression
• Any of depressive symptom scale (MHI-5<52), anti-depressant use,
or physician diagnosed depression
• At least two asked every 2-4 years since 1992/1993
• Anxiety
• Crown-Crisp phobic anxiety scale (1988/1989)
• In validation study, correlated with generalized anxiety
• Social support
• Asked every 4 years since 1992 in NHS
• Berkman-Syme index: marital status, # close friends & relatives,
attendance at religious & other groups
• Relative telomere length, measured by qPCR

10. 1.00
1.35
1.17
1.38
0.0
0.5
1.0
1.5
2.0
2.5
No Yes Yes, one episode Yes, chronic
RelativeRisk
Depression Status
Depression is associated with a modest
increased risk of ovarian cancer
Huang et al, Gynecol Oncol, 2015

11. 1.07
0.91
1.09
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
All women Pre-menopausal Post-menopausal
RelativeRiskIncreasing anxiety levels are suggestively
associated with ovarian cancer, particularly for post-
menopausal women
Poole et al, CCC, 2016

12. Moderate isolation suggestively associated
with risk, but not total isolation
1.00
1.11
1.28
0.91
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
1.80
Socially integrated Moderately integrated Moderately isolated Socially isolated
Relativerisk
Poole et al, submitted

13. Widowhood is associated with a modest increased
risk of ovarian cancer and a modest increased risk
of dying from ovarian cancer
1.00 1.00
1.18
1.05
1.41
1.63
0.00
0.50
1.00
1.50
2.00
2.50
3.00
Ovarian cancer risk Ovarian cancer survival
Relativerisk
Married/domestic partner Divorced/separated Widowed
Poole et al, submitted

14. 1.00
0.85 0.83
0.68
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
Relativerisk
Quartiles of telomere length (short to long)
Longer telomeres are associated with
decreased ovarian cancer risk
Yang et al, CEBP, in press

15. Strengths and limitations
Strengths
• Prospective design
• Large number of women
• Long follow-up
• Same measures asked
multiple times
• Many potential
confounders assessed
Limitations
• Few ovarian cancer cases
• No clinical information
(treatment, surgery)
• Biomarkers are indirect
measures of HPA and
SNS activation

16. Summary and next steps
• Consistent, but modest signal across multiple measures
of stress
• Need to replicate in other large, prospective studies
• Development of new markers of stress
• Metabolomics profiling in mouse models and humans
• Comprehensive assessment of many stressors in NHSII

17. Acknowledgements
• Psychosocial Stress and Ovarian Cancer Risk:
Metabolomics and Perceived Stress (Ovarian Cancer
Academy Early Career Investigator Award: DOD
W81XWH-13-1-0493)
• Shelley Tworoger
• Tianyi Huang
• Laura Kubzansky
• Olivia Okereke
• Anil Sood
• Susan Hankinson
• Meng Yang

18. THANK YOU!
Questions?