Post on 13-Feb-2017
STRESS AS A POTENTIALLY MODIFIABLE RISK FACTOR FOR OVARIAN CANCER
Liz PooleAssistant Professor of Medicine Harvard Medical School and Brigham and Women’s HospitalDepartment of Defense Ovarian Cancer Academy Early Career Investigator7/9/2016
Most ovarian cancer risk factors are not modifiable
Established Probable SuspectedAge 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
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
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
• 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?
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)
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
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
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
No Yes Yes, one episode Yes, chronic0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.00
1.351.17
1.38
Depression Status
Rela
tive
Ris
kDepression is associated with a modest increased risk of ovarian cancer
Huang et al, Gynecol Oncol, 2015
All women Pre-menopausal Post-menopausal0.80
0.85
0.90
0.95
1.00
1.05
1.10
1.15
1.07
0.91
1.09
Rela
tive
Ris
kIncreasing anxiety levels are suggestively associated with ovarian cancer, particularly for post-menopausal women
Poole et al, CCC, 2016
Moderate isolation suggestively associated with risk, but not total isolation
0.00
2.00
4.00
6.00
8.00
10.00
12.00
Rela
tive
risk
Poole et al, submitted
Widowhood is associated with a modest increased risk of ovarian cancer and a modest increased risk of dying from ovarian cancer
Ovarian cancer risk Ovarian cancer survival0.00
0.50
1.00
1.50
2.00
2.50
3.00
1.00 1.00
1.18
1.05
1.41
1.63
Married/domestic partner Divorced/separated Widowed
Rela
tive
risk
Poole et al, submitted
Series10.00
0.20
0.40
0.60
0.80
1.00
1.20
1.00
0.85 0.83
0.68
Quartiles of telomere length (short to long)
Rela
tive
risk
Longer telomeres are associated with decreased ovarian cancer risk
Yang et al, CEBP, in press
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
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
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
THANK YOU!Questions?