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?