1. DOES STRESS CAUSE CANCER?
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2. IS STRESS ASSOCIATED WITH INCREASED RISK OF BREAST CANCER?
Presented by
Professor Phyllis Butow
School of Psychology, University of Sydney

3. COMMON BELIEFS
“Well, my husband left me for a younger woman in August, and I was diagnosed with breast cancer in September. Go figure…”
“I had had a year of bullying at work, which really ground me down. I had no resistance left in me! No wonder I got diagnosed with testicular cancer!”
“I was diagnosed about 2 months after my husband had his heart attack. I was worn out looking after him!”

4. COMMON BELIEFS
1109 women with breast cancer and 1633 unaffected women in WA
Thompson AK et al, BMC 2014

5. PRESENTATION OUTLINE Some definitions Potential biological mechanisms
What good research looks like
Summary of evidence to date
New research from the University of Sydney: breast cancer study

6. WHAT IS STRESS? Number and severity of life events Death of a spouse
Divorce
Marital separation
Jail term
Death of close family member
Personal injury or illness
Marriage
Retirement
Change in health of family member
Moving house
Pregnancy
Sex difficulties
Business readjustment
Change in financial state
More or fewer arguments with spouse
A large mortgage or loan
Change in responsibilities at work
Son or daughter leaving home
Trouble with in-laws
Holmes & Rahe Stress Scale

7. SYMPTOMS OF STRESS Physical and psychological symptoms
Physiological markers
High blood pressure
High cortisol levels
Immune function (activated natural killer cells)
Psychological / somatic markers
Anxiety, depression
Not sleeping
Belly ache

8. COPING WITH STRESS Actual Stress Perceived: Demand Impact on Self
Capability
Support
Stress Felt

9. MEASURING STRESS IS COMPLEX
Life events should not be considered in isolation
Need to also consider:
Impact of life events
Coping
Social support

10. HOW DO YOU PROVE STRESS CAUSES INCREASED RISK OF BREAST CANCER?
Biologic plausibility
Strong research designs
Strength and consistency of association

11. BIOLOGICAL PLAUSIBILITY – A MECHANISM
Research has identified hormonal and immune system changes in response to stress, which could predispose to malignant growth
Antoni et al, Nat Rev Cancer 2006;
Thaker et al, Nat Med 2006;
Kemeny et al, Brain Behav Immun 2007

12. MECHANISMS: IMPACT OF STRESS ON CANCER
Stressors
Psychological Responses
Autonomic Nervous System
Antoni et al, Nat Rev Cancer 2006; 6(3):

13. MECHANISMS: IMPACT OF STRESS ON CANCER
Noradrenalin/Adrenalin & Cortisol
Viruses
Immune Cells
Cancer Cells
Blood Vessels
Antoni et al, Nat Rev Cancer 2006; 6(3):

14. POTENTIAL STRESS-GENE INTERACTION
Animal research found:
Down regulation of the BRCA1 gene after exposure to chronic cortisol excess (mimicking chronic, unremitting stress in humans)
Effect was dependent on cortisol excess being high, and continuous, suggesting that chronic stress may be required to have an impact
Antonova et al, Gene Chromosome Canc 2008

15. INDIRECT EFFECTS OF STRESS
Psychosocial factors might:
impact directly on endocrine, immune and nervous systems OR
impact indirectly, by affecting behaviours
diet, exercise and disturbed sleep
themselves linked to endocrine and immune functioning

16. HOW DO YOU PROVE STRESS CAUSES INCREASED RISK OF BREAST CANCER?
Biologic plausibility
Strong research designs
Strength and consistency of association

17. RETROSPECTIVE CASE-CONTROL STUDIES
Ask people with cancer (cases), and those without cancer (controls), to remember back, stress from last 3 years
CONTROL
GROUP
Control Group
Vs.
Do cases remember more stress than controls?

18. RETROSPECTIVE CASE-CONTROL STUDIES
Potential Confounds?
Suffer from recall bias; people look for explanations of their cancer
Patients recall more life events, and that they were more stressful
Do cases remember more stress than controls?

19. CASE CONTROL STUDIES Compare cases and controls
By linking pre-existing registry data
Cancer registry, linked to other registries, eg Births, deaths, marriages, divorces
More objective
Limited by the stress data available (usually little)
Do people with cancer have more pre-existing
stressful life events, eg deaths, divorces,
than people without cancer

20. IDEAL DESIGN: PROSPECTIVE COHORT
Very large sample of people without cancer
Stressful life events, coping, social support
No bias
Lots of detail
about stress
Time
Stressful life events, coping, social support
Stressful life events, coping, social support
Cancer diagnosis at follow-up,
controlling for other likely causes of cancer

21. “WITHOUT DATA YOU’RE JUST ANOTHER PERSON WITH AN OPINION”
SHOW ME THE EVIDENCE …
“WITHOUT DATA YOU’RE JUST ANOTHER PERSON WITH AN OPINION”
W. Edwards Deming
Data Scientist

22. SHOULD WE STRESS ABOUT STRESS?
Primarily retrospective, case-control studies – varying findings, but studies are of low quality
Data linkage studies exploring impact of single life events (eg divorce) have found NO relationship with cancer
Two large prospective studies in breast cancer have conflicting findings

23. PROSPECTIVE STUDY 1
Surtees PG et al, Breast Cancer Res Treat (2010) 120:169–174
11,467 women aged (residents of Norfolk, UK) followed for 10 years
313 cancers by end of study
No relationship found between any of the social adversity variables measured and breast cancer diagnosis

24. PROSPECTIVE STUDY 2
Lillberg K et al, Am. J. Epidemiol. (2003) 157 (5):
10,808 women from the Finnish Twin Cohort, followed for 20 years
180 cancers by end of study
Divorce/separation
Death of a husband
Death of a close relative or friend
All associated with increased risk of breast cancer
On average, doubled the risk

25. SYSTEMATIC REVIEWS AND META-ANALYSES
Look at all the available evidence
Summarise it as a whole
Come to a conclusion

26. SYSTEMATIC REVIEWS AND META-ANALYSES
Nielsen NR. Nat Clin Pract Oncol, 2006; 3(11): p
Stress measured in very heterogeneous ways
Quality of studies too poor on the whole
Remains an open question
Chida et al Nat Clin Pract Oncol 2008; 5:466–475
Stressful life events NOT related to cancer incidence
Stress-prone personality, poor coping and negative emotion
ARE related to higher cancer incidence
Santos et al 2009; 25 Suppl 3:S453-63
High Intensity, frequent stress IS related to cancer
Trend: (HR=1.73, p = 0.059) ? X

27. USYD COMPREHENSIVE STUDY [15 YEARS]
Aim: In women at high risk of breast cancer, to prospectively investigate the role of:
life event stress
excluding events / chronic stressors related to personal or familial cancer risk
social support
psychological distress
anxiety and depression
personality characteristics
optimism, anger control, anti-emotionality
in the development of primary breast cancer

28. HYPOTHESES
Women with high levels of acute and chronic stressors will be at increased risk of developing primary breast cancer (BCa)
There will be a dose-response, such that more severe and prolonged stressors will be associated with a greater increased risk of developing BCa
Psychosocial factors (anxiety and depression, optimism, anger repression, anti-emotionality and social support), will be associated with increased risk of developing BCa
Controlling for psychosocial factors, higher levels of stressors will still be associated with an increase in risk of developing BCa

29. RECRUITMENT BASE: kConFab
The Kathleen Cunningham Foundation Consortium established in
Brings together geneticists, clinicians, surgeons, genetic counsellors, psychosocial researchers, pathologists and epidemiologists from Australia and New Zealand
Recruits families with a strong history of breast and breast/ovarian cancer through Family Cancer Clinics

30. INCLUSION CRITERIA
a mutation in BRCA1, BRCA2 or another breast cancer pre- disposition gene in the family OR
family member high-risk according to national guidelines
and
4+ cases of BCa/OvCa on one side of the family and
2+ living family members with BCa/OvCa and
4+ living first/second-degree unaffected females 18+

31. RECRUITMENT PROCESS
Once key family member recruited, all members of family invited
On entry: collection of bloods (mutation status) and risk factors such as family history, parity and weight
Every three years: breast cancer diagnoses, risk-reducing surgery and chemo-prevention, screening, and cancer risk factors
All unaffected women invited into the psychosocial study  

32. DESIGN: PSYCHOSOCIAL STUDY
Start study
LEDS interview + Questionnaires
Prospective Cohort study
Unaffected women from kconfab registry
Measured stressful life events, coping, social support, 3-yearly
Followed them for 15 years or until the woman developed cancer
Cancer status checked at the end
LEDS interview + Questionnaires
15 yrs
LEDS interview + Questionnaires
LEDS interview + Questionnaires
Br cancer
diagnoses

33. MEASURING STRESS
Brown and Harris (1978) – Life Events and Difficulties Interview (LEDS)
Person is prompted for life event stressors in the past 3 years, within different categories
health, relationships, work, etc
Context is recorded
Severity of each stressor independently rated, taking into account context
4 levels: mild, moderate, high, severe
Avoids mood impacts on ratings of life events
Allows a constant reference point for rating stressors across people

34. ACUTE AND CHRONIC STRESSORS
Acute stressors (short-term)
Death of an aunt
Car crash, no ongoing injury
Loss of work for short period
Chronic stressors (6+ months)
Looking after handicapped child
Protracted divorce and settlement
Ongoing illness or depression

35. QUESTIONNAIRES Variables Valid Measures Anxiety and depression HADS
Optimism Life Orientation Test
Anger control Courtauld Emotional Control Scale
Not expressing feelings Anti-Emotionality Scale
Social support Duke-UNC

36. ANALYSIS
Explored impact of stressful life events and psychosocial variables in each round
On breast cancer diagnoses in the following 3 years
Cox regression analysis
Start
study
LEDS interview + Questionnaires
3 yearly
Cancer
Breast
cancer
diagnoses

37. ANALYSIS Excluded all events related to cancer in individual or family
Otherwise, stress could be a proxy for a strong family history!
Looked separately at numbers of:
Total acute stressors; Mild, moderate, high severe, acute stressors
Total chronic stressors; Mild, moderate, high severe, chronic stressors

38. ANALYSIS
Looked at the impact of events, over and above family history / genetic / risk behaviour, and psychosocial variables
E.g. Stress could cause smoking
Smoking could cause breast cancer
E.g. Stress could cause social isolation
Social isolation could cause breast cancer

39. POTENTIAL CONFOUNDER BRCA1 and BRCA2 mutation status
family history of breast cancer
risk-reducing bi-lateral salpingo-oopherectomy
age at study entry
age at menarche
number of live births
history of benign breast disease (time varying)
HRT use
hormonal contraceptive use in last round
body mass index
smoking status
exercise status in last round
breast feeding
Breast cancer diagnoses reported by women and confirmed by clinical follow-up study

40. Between May 2001 and December 2010
OUR PARTICIPANTS
Between May 2001 and December 2010
3,595 women invited and 3,054 (85%) consented
2,739 (89%) with adequate data included in the analyses
Average follow-up time was 7.2 years
103 women from 97 families diagnosed with breast cancer

41. BREAST CANCER DIAGNOSES IN 2,739 PARTICIPANTS

42. SAMPLE CHARACTERISTICS
Breast cancer diagnosed
Variable
Yes
(n=103) No
(n=2636)
Mean
Mean Age at study entry 47 45
No. 1st and 2nd degree relatives:
Breast cancer
Ovarian cancer
3.3
0.4
3.0

43. SAMPLE CHARACTERISTICS
Breast cancer diagnosed
Variable
Yes
(n=103) No
(n=2636)
N (%)
Person mutation***
Positive
44 (43)
672 (26)
Family mutation **
54 (52)
1004 (38)
** p<0.01; *** p<0.001

44. SAMPLE CHARACTERISTICS
Breast cancer diagnosed
Variable
Yes
(n=103) No
(n=2636)
N (%)
BSO **
Oophorectomy
25 (24)
302 (11)
History of benign disease*
53 (52)
1066 (41)
* p<0.05 ** p<0.001

45. ARE YOU READY?

46. ACUTE STRESSORS [3 YEAR PERIOD]
% Of women

47. MILD-MODERATE ACUTE STRESSORS
% Of women

48. HIGH-SEVERE ACUTE STRESSORS
% Of women

49. CHRONIC STRESSORS [3 YEAR PERIOD]
% Of women

50. MILD-MODERATE CHRONIC STRESSORS
% Of women

51. HIGH-SEVERE CHRONIC STRESSORS
% Of women

52. MEAN LEVELS OF PSYCH. VARIABLES
% Of women

53. HAZARD RATIOS OF BREAST CANCER DIAGNOSIS Adjusted for risk / behavioural confoundersHR
95% CI
P-value
Total Acute Stressors
1.03
0.19
Total Chronic stressors
1.00
0.98
P should be less than 0.05

54. HAZARD RATIOS OF BREAST CANCER DIAGNOSIS Adjusted for risk / behavioural confoundersHR
95% CI
p-value
Mild-Mod Acute
1.05
0.10
High-Sev Acute
0.93
0.57
Mild-Mod Chronic
1.00
0.96
High-Sev Chronic
1.36
0.13

55. PSYCHOSOCIAL VARIABLES
In individual models, controlling for risk and behavioural confounders, none of the psychosocial variables were significantly associated with breast cancer risk
Multivariate models - none of the psychosocial variables associated with risk
Multivariate models - none of the interactions between stressor and psychosocial variables associated with risk

56. HAZARD RATIOS OF BREAST CANCER DIAGNOSIS Adjusted for risk / behavioural confoundersHR
95% CI
p-value
Mild-Mod Acute
1.05
0.10
High-Sev Acute
0.93
0.57
Mild-Mod Chronic
1.00
0.96
High-Sev Chronic
1.36
0.13
Social Support
0.97
Optimism
1.03
0.23
Anti-emotionality
0.75
0.17
Anger control
0.99

57. CONCLUSION …
This large-scale prospective cohort study evaluating the association between acute and chronic stressors, social support, optimism, anti-emotionality and anger control, and breast cancer risk…
…did not demonstrate an association between these psychosocial factors (or their interactions), and the development of primary breast cancer

58. important methodological issues
STRENGTHS
Designed to address
important methodological issues
These included:
Distinguishing between ‘stressors’ (the external event) and ‘stress’ (the individual’s perception of the stressor)
Including chronic stressors and the timing of stressors
Assessing stressors prior to BCa diagnosis to avoid recall bias
Controlling for established BCa risk factors

59. STRENGTHS Controlling for disease and demographic factors
Controlling for anxiety, depression when stress was assessed
Controlling for potential behavioural consequences of stressors, such as increased eating or smoking or social isolation
Excluding stressors related to breast cancer risk, including their own and familial risk

60. LIMITATIONS
It is possible that we lacked power to detect effects, given the modest number of breast cancer events
It is also possible that our sample choice of women from high-risk breast cancer families was flawed
We don’t know if our results generalise to other cancers

61. CLINICAL IMPLICATIONS
Reassurance
Regardless
Relief

62. Good News!
Stress Will Not Give You Cancer

63. RELAXATION AND MEDITATION HELP
Stress: What helps?
RELAXATION AND MEDITATION HELP

64. ACCEPT WORRY, BUT DON’T GET CAUGHT UP IN IT …
Mindfulness
Think of your thoughts and feelings as passers by – they come and go
Accept them – they are there
Don’t judge them, or react to them, or try to get rid of them
Like leaves passing down a stream
Or clouds in the sky

65. ACCEPT WORRY, BUT DON’T GET CAUGHT UP IN IT …
The cat task
Imagine a cat
Watch the cat , does it move?
Don’t make it move, just watch
Simply a thought in your mind
Not real
You can watch it

66. ACKNOWLEDGEMENTS
kConFab Investigators Clinical Follow-up Study Investigators: Prof Phyllis Butow Dr Melanie Price Prof Chris Tennant Dr Kathy Tucker A/Prof Bettina Meiser Prof Kelly-Anne Phillips
Staff
Dr Joe Coll
Judy Wilson
Louise Heiniger
Brandi Baylock
Tracey Bullen
Collaborators
Joe Coll
Roger Milne
Pru Weiderman

67. ACKNOWLEDGEMENTS kConFab families
Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff of the Family Cancer Clinics for their contributions to the kConFab resource.
The kConFab Psychosocial Study funded by NHMRC Project Grants No , , and ,
kConFab supported by grants from the National Breast Cancer Foundation, NHMRC, Cancer Councils NSW, VIC, TAS, SA, WA, QLD.
The kConFab Follow-Up Study funded by NHMRC, National Breast Cancer Foundation and Cancer Australia.

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