1.
Dr Craig Hassed
Monash University Dept. of General Practice
The Essence of Managing
Breast Cancer

2.
The first thing
• “You need to keep an open
mind, but not so open that
your brain falls out.”
–Prof MacLennan

3.
Medical ‘facts’
• During grand rounds and medical
conferences ‘bold statements’ frequently
made regarding medical facts
– Expert opinion frequently voiced with great conviction
and assimilated by junior staff as fact
• 1/3 statements were evidence-based
• ½ available literature contradicted the
statement
• 1/6 no literature on the subject could be
located
– Senior staff less likely to review evidence for opinion
> Linthorst G, Daniels J, Van Westerloo D. The majority of bold
statements expressed during grand rounds lack scientific merit.
Medical Education 2007;41(10):965–967.

4.
Chemotherapy and 5-year survival
• “… it is very clear that cytotoxic
chemotherapy only makes a minor
contribution (2%) to cancer survival. To
justify the continued funding and availability
of drugs used in cytotoxic chemotherapy, a
rigorous evaluation of the cost-effectiveness
and impact on quality of life is urgently
required.”
– Morgan G, Ward R, Barton M. Clin Oncol
2005;16(8):549-60.

5.
Integrative Medicine
• Integrative medicine incorporates:
– Evidence-based and safe therapies
> Conventional medical care
> Lifestyle interventions
> Complementary therapies
– Holistic approach
> Physical, mental, emotional, spiritual, social,
environmental
• Not ‘alternative practice’ but ‘best practice’

6.
6
The ESSENCE of health
• Education
• Stress management
• Spirituality
• Exercise
• Nutrition
• Connectedness
• Environment

7.
Education
• Education is more than giving factual
information
• Education is also about enabling
strategies e.g.:
– Mindfulness and stress management
– Behaviour change strategies
– Goal setting
– Cycle of change
– Self

8.
The mind and body
• “You ought not to attempt to cure
the body without the soul (psyche)
for this is the great error of our day
(400BC), in the treatment of the
human body, that physicians
separate the soul from the body.”
– Attributed to Socrates by Plato in Charmides

9.
9
The role of meaning
• The lack of meaning in life is a
soul sickness whose full extent
and full import our age has not yet
begun to comprehend.
>Carl Jung
• Many different ways of exploring
and expressing meaning
–Philosophy, religion, science, altruism,
environmentalism, art …

10.
10
“Religious commitment” and health
• Religious commitment is widely used in the
medical and psychological studies
– Most common interpretation of spirituality / easy to
measure
• Protective for:
– Depression and suicide
– Substance abuse
– Physical illness
– Longer life expectancy
• Links hold even when controlled for other risk
factors
> Arch Fam Med 1998;7:118-24.

11.
Spirituality and cancer
• Spiritual wellbeing demonstrated significant positive
association with QOL and Fighting spirit
• Significant, negative relationship with
Helplessness/hopelessness and Anxious
preoccupation
• “By failing to assess spiritual wellbeing, the 'true'
burden of cancer is likely to be miscalculated.
However, at this stage, the exact clinical utility of
spirituality assessment is unclear.”
> Whitford HS, Olver IN, Peterson MJ. Spirituality as a core domain in the
assessment of quality of life in oncology. Psychooncology. 2008
Nov;17(11):1121-8.

12.
Spirituality and cancer
• Perceived/self-reported ‘Religiousness’ associated with
reduced risk of colo-rectal cancer
– RR 0.70 (p=0.002)
– Controlled for other risk factors
– Median survival time greater - 62 vs 52 months (p=0.42)
> Kune G. et al. The Melbourne Colorectal Cancer Study
Journal of the Royal Society of Medicine 1993;86:645-7
• Religiosity and spiritual well-being positively
associated with positive mood states and hope
> Fehring R. et al. Oncology Nursing Forum 1997, 24(4):663-
71

13.
13
Inactivity and health
• Chronic conditions related to inactivity
– Heart disease
– Hypertension
– Type II diabetes
– Cancer
– Depression
– Anxiety
– Osteoporosis
– Obesity
– Poor immunity
– Parkinson’s Disease
– Dementia…

14.
Physical exercise and cancer survival
• 2987 women with breast cancer
followed for up to 18y
– Halved the risk of death for those who
engaged in regular exercise (~walking
3-5 hr/wk)
> JAMA. 2005;293(20):2479-86.
• 47620 men, ~3000 with prostate
cancer, 14y follow-up
– In men >65 risk of advanced prostate
cancer 0.33
> Arch Int Med 2005;165:1005-10.
• 526 patients with colorectal cancer
followed for over 5y
– Risk of death 0.49 for stage II&III
> Gut 2006;55:62-67.

15.
Exercise and cancer survival
• Women with breast cancer or people with
brain cancer who regularly walk or jog even
to a moderate extent reduce mortality over 11
year follow-up by over 40% and have better
quality of life compared to those who don't.
> Williams PT. Breast Cancer Mortality vs. Exercise and Breast
Size in Runners and Walkers. PLoS One. 2013 Dec
9;8(12):e80616. doi: 10.1371/journal.pone.0080616.
eCollection 2013.
> Williams PT. Reduced Risk of Brain Cancer Mortality from
Walking and Running. Med Sci Sports Exerc. 2013 Oct 1.
[Epub ahead of print]

16.
Lung cancer survival and exercise
Association between exercise behavior [MET-hrs wk−1(<9 MET-hrs wk−1 vs. >9 MET-hrs
wk−1)] and survival. Prognostic significance of functional capacity and exercise behavior in
patients with metastatic non-small cell lung cancer. Lung Cancer. 2012 May;76(2):248-252.

17.
Cancer survival and physical exercise
• “Consistent evidence from 27 observational studies
that physical activity is associated with reduced all-
cause, breast cancer–specific, and colon cancer–
specific mortality.”
• Exercise results in beneficial changes in the
circulating level of insulin, insulin-related pathways,
inflammation, and immunity
> Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM,
McTiernan A, Alfano CM. Physical Activity, Biomarkers, and
Disease Outcomes in Cancer Survivors: A Systematic Review. J
Natl Cancer Inst. 2012 June 6; 104(11): 815–840. doi:
10.1093/jnci/djs207

18.
Physical exercise and cancer survival
• 15 studies found a significant inverse relationship between
exercise and prognosis (cancer-specific or all-cause mortality)
• Range of risk reduction between 15% to 67% and 18% to 67% for
cancer-specific mortality and all-cause mortality, respectively
• The dose of exercise required for mortality reduction ranged
from ≥9 metabolic equivalent time (MET)-hours per week of
exercise (MET-h wk−1) of moderate intensity exercise (equivalent
to approximately 180 min wk−1 of moderate intensity exercise) to
≥27 MET-h wk−1 (equivalent to ≥500 min wk−1 of moderate
intensity exercise)
> Betof AS, Dewhirst MW, Jones LW. Effects and potential mechanisms of
exercise training on cancer progression: A translational perspective. Brain
Behav Immun. Author manuscript; available in PMC 2014 March 1. Published
in final edited form as: Brain Behav Immun. 2013 March; 30(0): S75–S87.
Published online 2012 May 17. doi: 10.1016/j.bbi.2012.05.001

19.
Exercise has many health benefits
• Physical fitness
• Vitality
• Reduced pain
• Reduced anxiety and depression
• Better cognitive function
• Reduced side-effects of treatment
– Bones, N&V, pain …
• Reduced risk of other illnesses

20.
Exercise, stress and telomeres
• For non-exercisers a one unit increase in the
stress scale related to a 15-fold increase in
the odds of having short telomeres (a marker
of rapid ageing and chronic illnesses)
• For exercisers, perceived stress was
unrelated to telomere length (i.e. exercise
buffered against the effects of emotional
stress on ageing)
> Puterman E, Lin J, Blackburn E, et al. The power of exercise:
buffering the effect of chronic stress on telomere length. PLoS One.
2010 May 26;5(5):e10837.

21.
Perceived stress, telomere length and
exercise
• Physical activity categories
are based on whether the
participant met CDC
recommended levels of
exercise per week.
Perceived stress ratings
are based on the Perceived
Stress Scale. The
relationship between
perceived stress and
telomere length was
significant in sedentary
participants only.

22.
Exercise and mental health
• Evidence supports inclusion of Physical Activity as
an adjunct to treatment for conditions including:
– Depression
– Schizophrenia
– Anxiety disorders
– Post-traumatic stress disorder
– Substance abuse
• “PA is a feasible, effective and acceptable adjunct to
usual care for a variety of mental disorders. There is
a clear need for greater investment in initiatives
aiming to increase PA among people experiencing
mental illness, given the benefits to both mental and
physical health outcomes.”
> Rosenbaum S, Tiedemann A, Stanton R, Parker A, Waterreus A, Curtis J,
Ward PB. Implementing evidence-based physical activity interventions for
people with mental illness: an Australian perspective. Australas Psychiatry.
2015 Jul 2. pii: 1039856215590252.

23.
Lifestyle and cancer: WCRF
1. Be as lean as possible without becoming underweight
2. Be physically active for at least 30 minutes every day
3. Calorie restriction: avoid sweet drinks and limit energy-dense
foods particularly processed foods high in added sugar, low
in fibre, or high in fat
4. Eat more of a variety of vegetables, fruits, whole-grains and
pulses such as beans
5. Limit red meat, e.g. beef, pork and lamb, and avoid processed
meat
6. Limit alcoholic drinks to 2 for men and 1 for women a day
7. Limit consumption of salty foods and food processed with salt
8. Don’t use supplements to protect against cancer
http://www.wcrf-uk.org/research_science/recommendations.lasso

24.
25
Calorie restriction
• Caloric (or dietary) restriction (CR) extends
lifespan and lowers risk for age associated
diseases including cancer and heart disease
> Willcox DC, Biogerontology. 2006 Jun 30; [Epub ahead of
print]
• CR is not under-nutrition but having a diet
which does not contain calories excess to
requirements
– Most westernised diets are calorie-dense (empty
calories with little nutritional value)

25.
Nutrition and breast cancer
• Women in the highest quarter of intake of vegetables
and fruit had a 43% reduction in risk and controlled for
other factors influencing prognosis.
> Rock CL, et al. J Clin Oncol. 2005;23(27):6631-8.
• Phytoestrogens: risk estimate (breast cancer) for the
highest versus the lowest third was 0.68
> Verheus M, van Gils CH, Keinan-Boker L, et al. J Clin Oncol. 2007
Jan 2; [Epub ahead of print]
• RCT on women with 2437 women with breast cancer
found that a low-fat diet was associated with a 24%
reduction in recurrence and 19% improvement in
survival after 5 years
> Chlebowski RT, Blackburn GL, Elashoff RE, et al. J Natl Cancer Inst.
2006 Dec 20;98(24):1767-76.

26.
Antioxidants and cancer
• “Vegetable and, particularly, fruit
consumption contributed to the
decreased risk … These results
indicate the importance of diet, rather
than supplement use, in concert with
endogenous antioxidant capabilities,
in the reduction of breast cancer
risk.”
> Ahn J, Gammon MD, Santella RM, et al. Am J
Epidemiol. 2005;162(10):943-52.

27.
Cancer and cruciferous vegetables
• Bioactive constituents of plants have cancer-
preventive properties
• The consumption of fruits and vegetables leads
to a reduced frequency of certain cancers and
has therapeutic effects
• Cruciferous vegetables (e.g. broccoli, brussel
sprouts, cabbage ...) contain chemicals such as
glucosinolates and isothiocyanates which have
anti-carcinogenic potential
> Herr I, Büchler MW. Dietary constituents of broccoli and other cruciferous vegetables: Implications
for prevention and therapy of cancer. Cancer Treat Rev. 2010 Feb 19. [Epub ahead of print]

28.
Fruit, vegies and illness
• Study on association b/w fruit and vegetable consumption and all-
cause, cancer and cardiovascular mortality
– Adjusting for age, sex, social class, education, BMI, alcohol consumption and physical
activity: over 8 years in 65 226 participants aged 35+ years in UK
• Fruit and vegetable consumption associated with:
– Decreased all-cause mortality when excluding deaths within a year of baseline (HR:
0.58)
– Reduced cancer (0.75) and cardiovascular mortality (0.69)
– Vegetables had a stronger association with mortality than fruit (HR for 2 to 3 portions
0.81 and 0.90 respectively)
– Consumption of vegetables (0.85) per portion or salad (0.87) per portion were most
protective
– Frozen/canned fruit consumption associated with increased mortality (1.17) per
portion)
> Oyebode O, Gordon-Dseagu V, Walker A, Mindell JS. Fruit and vegetable
consumption and all-cause, cancer and CVD mortality: analysis of Health Survey
for England data. J Epidemiol Community Health doi:10.1136/jech-2013-203500

29.
Soy and breast cancer
• 4 year f/up on 5042 breast cancer patients
• Those with the highest intake of soy protein had a
29% lower risk of death and a 32% lower risk of
breast cancer recurrence c/w patients with the lowest
intake of soy protein
> Xiao Ou Shu, Ying Zheng, Hui Cai, et al. Soy Food Intake and
Breast Cancer Survival. JAMA. 2009;302(22):2437-2443.

30.
Soy and breast cancer
• Soy foods are the major source of isoflavones – believed to play
important roles in genesis of breast cancer and its progression
• Prospective study to evaluate the association of soy isoflavone food
consumption with breast cancer prognosis in China
• Median follow up of 52.1 months: 79 breast cancer related deaths
• Risk inversely associated with a high intake of soy isoflavone
• Average intake of soy isoflavone above 17.3 mg/day, the mortality of
breast cancer reduced by 38-36%
• Decreased breast cancer death with high soy protein intake, with a HR
of 0.71
• Stratified analysis with reference to the ER status, further
demonstrated a better prognosis of ER positive breast cancer with a
high intake of soy isoflavone (HR 0.59)
– Zhang YF, Kang HB, Li BL, Zhang RM. Positive effects of soy isoflavone food on survival of
breast cancer patients in China. Asian Pac J Cancer Prev. 2012;13(2):479-82.

31.
Dietary patterns
• Mediterranean Diet: includes nine components: vegetables (excluding
potatoes), fruits, nuts, whole grains, legumes, fish, monounsaturated:saturated
fatty acid ratio, red and processed meats, and moderate alcohol intake
• Prudent dietary pattern: characterized by high intakes of fruits, vegetables,
legumes, fish and other seafood, poultry, and whole grains
• Western dietary pattern: high intakes of red and processed meats, butter,
high fat dairy products, eggs, sweets and desserts, French fries, and refined
grains
• The Alternative Healthy Eating Index: adherence to a dietary pattern based
on foods and nutrients most predictive of risk for chronic disease. Each of the
11 components of the score (vegetables, fruits, whole grains, sugar sweetened
drinks, nuts and legumes, red and processed meat, trans fat, long chain (n-3)
fats, polyunsaturated fatty acids, sodium, and alcohol) has a minimum score of
0 (worst) and a maximum score of 10 (best), according to component specific
criteria

32.
Mediterranean diet and telomeres
BMJ. 2014; 349: g6674. Published online Dec 2, 2014. doi: 10.1136/bmj.g6674
All dietary patters are represented: prudent pattern, Western pattern, Alternative Healthy
Eating Index (AHEI) score, and Alternate Mediterranean Diet (AMED) score.

33.
Mediterranean diet and telomere length
• “The difference in TL for each one point change in the Alternate
Mediterranean Diet score corresponded on average to 1.5 years of
aging. A three point change in the Alternate Mediterranean Diet
score would correspond to on average 4.5 years of aging, which
is comparable to the difference observed when comparing
smokers with non-smokers (4.6 yrs) (1), highly active women with
less active women (4.4 yrs) (2), and women with high phobic
anxiety scores with women with low phobic anxiety (6 yrs) (3).”
– Crous-Bou M, Fung TT, Prescott J, Julin B, Du M, Sun Q, Rexrode KM, Hu FB, De Vivo I.
Mediterranean diet and telomere length in Nurses’ Health Study: population based cohort study.
BMJ. 2014; 349: g6674. Published online 2014 December 2. doi: 10.1136/bmj.g6674
1. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, et al. Obesity,
cigarette smoking, and telomere length in women. Lancet 2005;366:662-4.
2. Du M, Prescott J, Kraft P, Han J, Giovannucci E, Hankinson SE, et al. Physical activity,
sedentary behavior, and leukocyte telomere length in women. Am J Epidemiol
2012;175:414-22.
3. Okereke OI, Prescott J, Wong JY, Han J, Rexrode KM, De Vivo I. High phobic anxiety is
related to lower leukocyte telomere length in women. PLoS One 2012;7:e40516.

34.
Social support and cancer
• Social support important e.g.
– Better mental health
– Reduced stress
– Better immunity
– Lower cortisol
– Better coping
– Less cognitive decline

35.
Breast cancer and social support
• Women with metastatic (advanced)
breast cancer divided into two groups
– One had support group (communication,
relaxation, dealing with difficult emotions)
plus usual care
– Control group had usual care alone
> Spiegel D et al. Effect of psychosocial
treatment on survival of patients with
metastatic breast cancer. Lancet. 1989 Oct
14;2(8668):888-91.

36.
Breast cancer and social support
• Results 1 year later
– Support group had better adjustment, coping,
dealing with pain, QoL, mood, relaxation
• 10 years later
• Average doubling of survival time in
support group
– 3 long term survivors in support group
> None in control group
– Divergence began at about 20 months after
commencement of study

37.
Stress management and melanoma
• 68 patients with early stage malignant
melanoma divided into two groups
– Usual care vs. usual care plus stress management
• Intervention - 6 weeks of stress
management
• Immune function monitoring showed that
after being originally comparable the stress
management group significantly improved
by 6 months
> Fawzy F. et al. Arch Gen Psych 1993;50:681-89.

38.
Stress management and melanoma
• 6-year follow-up: halving of recurrence
and much lower death rate (p=0.03)
> Fawzy F. et al. Arch Gen Psych 1993;50:681-89.
Recurrence Deaths
Intervention 7/34 3/34
Control 13/34 10/34

39.
Psychosocial support and cancer survival
• LONGER SURVIVAL
• Metastatic breast cancer
– Spiegel D. Lancet 1989;2:888-
891*
• Malignant melanoma
– Fawzy F. Arch Gen Psych
1993;50:681-89*
• Liver and other GI
malignancies
– Kuchler T Hep Gast
1999;46(25):322-35*
• Lymphoma
– Richardson J J Clin Oncol
1990;8:356-64.*
– Ratcliffe M Psychooncology
1995;4:39-45.*
• NO LONGER SURVIVAL
• Various cancers
– Cunningham A Psycho-Oncology.
2000;9(4):323-39
– Ilnyckyj A Ann R Coll Physicians
Surg Can 1994;27:93-6*
– Linn M Cancer 1982;49:1048-55
• Breast cancer
– Edelman SPsycho-Oncology.
1999;8(6):474-81
– Goodwin P N Engl J Med
2001;345:1719-26*
• *studies where program
effective (associated with
showed improved QOL or
mental health)

40.
Psychosocial treatment and
survival
• Not all psychosocial interventions work
• 9 out of 12 studies have followed the rule
that psychosocial interventions which
improve mental health and quality of life
also improve survival but psychosocial
interventions that are ineffective in
improving mental health and quality of
life do not improve survival

41.
Possible biological mechanisms
1. Chemical mediators via the HPA-axis
a. Cortisol
b. Cytokines and other stress hormones
a. Accelerate cancer cell replication
b. Promote angiogenesis
2. Genetic mutation, repair, ageing and
expression
3. Effects on immune (NK) cells
4. ‘Anti-cancer’ hormones (e.g. melatonin)
5. Better compliance with treatment
6. Healthier lifestyle
7. Others?

42.
Social isolation, stress and cancer
• Effects of stress and psychosocial processes on
the tumor microenvironment. The stress
response results in activation of the autonomic
nervous system and the hypothalamic-pituitary
adrenal axis. Factors released from these
pathways can have direct effects on the tumor
microenvironment, resulting in a favorable
environment for tumor growth and progression.
These dynamics can also adversely affect patient
quality of life. CRH, corticotropin releasing
hormone; ACTH, adrenocorticotrophic hormone;
NK natural killer; T-regs, regulatory T-cells; TAM,
tumor associated macrophages; MMP, matrix
metalloprotinease; VEGF, vascular endothelial
growth factor; IL, interleukin; STAT3, signal
transducer and activator of transcription factor-
3; QOL, quality of life.
– Lutgendorf S., et al. J Clin Oncology, 28 (26) 2010, 4094-9.
– Lutgendorf SK, Sood AK. Biobehavioral factors and cancer
progression: physiological pathways and mechanisms.
Psychosom Med. 2011 Nov-Dec;73(9):724-30. doi:
10.1097/PSY.0b013e318235be76.
43

43.
Melatonin and cancer
• Melatonin has anti-tumour effects
• Mechanism still under investigation
– antiproliferative
– intra-nuclear down regulation of gene
expression
– inhibition of release and activity of growth
factors
Reiter R. in ‘Melatonin’, Bantam Books -1995

44.
Melatonin and cancer
• 10 trials on melatonin for solid tumours
• Melatonin reduced the risk of death at 1 yr (RR: 0.66)
• Effects consistent across melatonin dose and type of
cancer
• No severe adverse events reported
• “The substantial reduction in risk of death, low
adverse events reported and low costs related to this
intervention suggest great potential for melatonin in
treating cancer.”
> Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of
cancer: a systematic review of randomized controlled trials and
meta-analysis. J Pineal Res. 2005;39(4):360-6.
• Things that affect melatonin (e.g. nurses on shift-
work) may also be risk factors for cancer (e.g. breast)
> Franzese E, Nigri G. Night work as a possible risk factor for breast
cancer in nurses. Correlation between the onset of tumors and
alterations in blood melatonin levels. Prof Inferm. 2007;60(2):89-93.

45.
Sunlight and cancer
• Regular moderate sun exposure associated with
less cancer, less heart disease, less depression,
better immunity, better sleep, less MS…
• Risk in areas of low sun exposure nearly twice as
high as high exposure areas
– Reduced risk of breast, colon, ovary, and prostate cancer,
lymphoma and eight other cancers
– 23,600 annual premature deaths from cancer due to lower
UV-B exposure in USA
• “Many lives could be extended through increased
careful exposure to solar UV-B radiation and
more safely, vitamin D3 supplementation,
especially in non-summer months.”
> Grant WB. Cancer 2002;94(6):1867-75.

46.
Vitamin D and breast cancer survival
• “Higher serum concentrations of
25(OH)D (Vitamin D) were
associated with lower case-fatality
rates after diagnosis of breast
cancer. Specifically, patients in the
highest quintile (20%) of 25(OH)D
had approx. half the death rate from
breast cancer as those in the
lowest.”
• Overall dose–response relationship
between serum 25-hydroxyvitamin D
and death from breast cancer, with
coefficient of determination, all
studies combined.
> From: Mohr SB, Gorham ED, KIM J, et al.
Meta-analysis of Vitamin D Sufficiency for
Improving Survival of Patients with Breast
Cancer. Anticancer Research March
2014;34(3):1163-1166.

47.
Ornish program for cancer
• Men with early prostate cancer (biopsy
and raise PSA) who chose not to have
treatment (watch and wait)
• 92 patients randomised to lifestyle
(experimental) group vs. usual
treatment (control) group
> Ornish D. Weidner G. Fair WR. et al. Intensive
lifestyle changes may affect the progression of
prostate cancer. Journal of Urology.
2005;174(3):1065-9.

48.
Ornish lifestyle intervention
• Vegan diet
– Fruits, vegetables, whole grains, legumes and soy
– 10% calories from fat
– Supplemented by soy (tofu), fish oil (3gm daily),
vitamin E (400IU daily), selenium (200mcg daily),
vitamin C (2gm daily)
• Exercise
– Walking 30min 6 times weekly
• Stress management
– Gentle yoga, meditation, breathing and PMR
• Support group 1 hour weekly
> Ornish et al. Journal of Urology 2005;174:1065-70.

49.
PSA readings
• Mean changes in
PSA (ng/ml) after 1
year
• PSA decreased by
4% in experimental
group and
increased by 6% in
control group
(p=0.016)
• Ornish et al. Journal of
Urology 2005;174:1065-70.

50.
Level of lifestyle change and PSA
Ornish et al. J Urology
2005;174:1065-70.

51.
Ornish lifestyle intervention
• 2-year follow-up
– 27% (13/49) patients in control group have gone on to
require cancer treatment because of disease
progression but only 5% (2/43) patients in lifestyle
group
– Frattaroli J, et al. Urology 2008 July 2 Epub ahead of print.
• Ornish program down-regulated prostate
cancer gene expression
– Ornish D, et al. PNAS 2008;105(24):8369-74.
• Comprehensive lifestyle change increased
genetic repair (telomerase activity)
– Ornish D, et al. Lancet Oncology 2008 Sept 15 Epub

52.
Lifestyle change and telomeres
• Telomere shortness is a prognostic marker of ageing, disease,
and premature illness
• 5 year follow-up study to investigate long-term effects of
lifestyle change on telomere length on men who had biopsy-
proven low-risk prostate cancer
• Intervention group followed a programme of comprehensive
lifestyle changes (low fat vegan diet, exercise, stress
management, meditation and social support)
• Control group underwent active surveillance alone
• At 5 years compared relative telomere length and telomerase
activity and their relation to the degree of lifestyle change
> Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ,
Magbanua MJ, Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR,
Blackburn EH. Effect of comprehensive lifestyle changes on telomerase activity and
telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up
of a descriptive pilot study. Lancet Oncol. 2013 Sep 16. doi:pii: S1470-
2045(13)70366-8. 10.1016/S1470-2045(13)70366-8

53.
Lifestyle change and telomeres
• Relative telomere length increased from baseline in the
lifestyle intervention group, but decreased in the control group
• Adherence to lifestyle change significantly associated with
relative telomere length after adjustment for age and the
length of follow-up
• “Our comprehensive lifestyle intervention was associated with
increases in relative telomere length after 5 years of follow-up,
compared with controls, in this small pilot study. Larger
randomised controlled trials are warranted to confirm this
finding.”
> Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJ,
Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR, Blackburn EH. Effect of
comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-
proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol. 2013
Sep 16. doi:pii: S1470-2045(13)70366-8. 10.1016/S1470-2045(13)70366-8

54.
Stress and mental health
• The stress of modern life is increasing at an
alarming rate
– E.g. 45% increase over the last 30 years[i]
– Could be explained by increased awareness of
stress and also more stressful and busy lives
• Mental health issues, particularly
depression, are soon predicted to be the
major burden of disease[ii]
> [i] Miller M., Rahe R. J Psychosom Res 1997;43(3):279-92.
> [ii] Mathers CD et al. MJA 2000;172(12):592-6.

55.
Mathers CD, Loncar D. Projections of global mortality and burden of disease
from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442.

56.
Allostatic load
• Prolonged stress leads to wear-and-tear on
the body (allostatic load)
– Mediated through the Sympathetic Nervous System
• Allostatic load leads to:
– Impaired immunity (immune dysregulation),
atherosclerosis, metabolic syndrome, bone
demineralization
– Atrophy of nerve cells in the brain
> Hippocampal formation: learning and memory
> Prefrontal cortex: working memory, executive function
– Growth of Amygdala mediates fear response
• Many of these processes are seen in
chronic depression and anxiety
> McEwen BS. Ann N Y Acad Sci. 2004;1032:1-7.

57.
Stress and genetics
• Mental state effects genetic function
• Stress increases genetic mutations
• Impairs the body’s ability to repair genes
– DNA repair capacity
– Implications for carcinogenesis and other illnesses
• Changes genetic expression
• Accelerates genetic ageing
> Adachi S et al. Cancer Research 1993;53(18):4153-5.
> Fischman H et al. Int J Neurosciences 1996;84(1-4):219-27.
> Kiecolt-Glaser J. et al. Psychosom Med 1999;61(3):271-2.
> Cohen L et al. J Behavioural Medicine 2000;23(6):531-45.
> Epel ES et al. Proc Natl Acad Sci U S A. 2004;101(49):17312-5.

58.
Stress and telomere shortening
• Study on healthy premenopausal women showed
that psychological stress associated with:
– higher oxidative stress
– lower telomerase activity (telomerase repairs DNA
telomeres) leading to shorter telomere length
• These are known determinants of cell death/longevity
• Women with highest levels of perceived stress c/w
low stress women have shorter telomeres
– Average equivalent at least 9-17 years of additional
ageing
• Implications for how, at the cellular level, stress may
promote earlier onset of age-related diseases
> Epel ES et al. Proc Natl Acad Sci U S A. 2004;101(49):17312-5.

59.
Genetic ageing and pessimism
• The combination of lower optimism and higher
pessimism increases risk for disease and early
mortality
– Sample of healthy post-menopausal women
• Pessimism is independently associated with
over 10 years accelerated ageing
– Shorter Telomere length and higher Interleukin-6
concentrations
> Lin J,Dhabhar FS, Wolkowitz O, Tillie JM, Blackburn E, Epel
E.Pessimism correlates with leukocyte telomere shortness and
elevated interleukin-6 in post-menopausal women. Brain Behav
Immun. 2009 May;23(4):446-9.

60.
Hostility and telomere length
• High-hostile men had significantly shorter leukocyte TL than
their low-hostile counterparts
• The relationship between hostility and disease is stronger in
men than in women, and men generally have a shorter life
expectancy than women
Brydon L, Lin J, Butcher L, Hamer M,
Erusalimsky JD, Blackburn EH, Steptoe A.
Hostility and cellular aging in men from the
Whitehall II cohort. Biol Psychiatry. 2012
May 1;71(9):767-73. doi:
10.1016/j.biopsych.2011.08.020.

61.
Depression, ageing and telomeres
• Patients with major depressive disorder (MDD) have increased risk
of aging-related illness (e.g. heart disease, diabetes, obesity,
cancer)
• Study on whether MDD associated with accelerated aging
– 1095 current MDD patients, 802 remitted MDD patients and 510 control subjects
• TL shorter among remitted MDD patients and current MDD
patients
– Adjustment for health / lifestyle variables did not reduce associations
• Higher depression severity and longer symptom duration in the
past 4 years were associated with shorter TL
• Depressed patients show accelerated cellular aging according to a
'dose-response' gradient
> Verhoeven JE, Révész D, Epel ES, Lin J, Wolkowitz OM, Penninx BW. Major depressive
disorder and accelerated cellular aging: results from a large psychiatric cohort study. Mol
Psychiatry. 2013 Nov 12. doi: 10.1038/mp.2013.151.

62.
Mind wandering and ageing
• The greater the
level of mind
wandering, the
greater the level
of telomere
shortening (a
marker of
biological age)
Epel ES, Puterman E, Lin J, Blackburn E, et al. Wandering Minds
and Aging Cells. Clinical Psychological Science 2012, in press.

63.
Breast cancer and telomeres

64.
Psychoneuroimmunology
1. Lowered immune markers (WBC and Ig)
2. Increased susceptibility to infections
3. Increased severity and progression of
infections
4. Increased relapse of chronic and latent
infections
5. Increased activity of inflammatory illnesses
6. Increased activity of autoimmune conditions
7. Poor response to immunisation
8. Effects on the activity of allergic conditions
9. Lowered defences against some cancers

65.
Stress and immunity
• Changes in immune cell numbers and
function start to occur within five minutes
of the stressful event.
> Herbert T et al Psychosomatic Medicine
1994;56:337-44.

66.
Stress and immunity
• Those who have higher sympathetic
nervous system reactivity to stress
(increased blood pressure, heart rate,
catechol hormones related to adrenaline)
also have the greatest disturbance to
immunity and greatest susceptibility to
infection.
> Marsland A et al. Physiology & Behavior. 2002;77(4-
5):711-6.

67.
Stress and immunity
• Depending on the reaction to the stressor,
immunosuppression can remain for up to 72
hours afterwards.
– Those who perceived being in control had no
negative effect
– Those who perceived no control had prolonged
negative effect
> Sieber W et al. Brain, Behaviour and Immunity
1992;6:141-56.

68.
• A good laugh and a
long sleep are the best
cures in the doctor’s
book.
–IRISH PROVERB

69.
Laughter and immunity
• Increases were found in:
– Leukocyte numbers and NK cell activity
– Immunoglobulins G, A, and M (effects lasting 12
hours)
– WBC cell numbers
– The cytokine interferon-gamma
• Has an anti-inflammatory affect
> Cousins N. N Engl J Med. 1976;295:1458-1463.
> Yoshino S, Koyama T. Ryumachi. 2000 Jun;40(3):651-8
> Berk LS et al. Altern Ther Health Med. 2001 Mar;7(2):62-72,
74-6.
> Bennett MP et al. Altern Ther Health Med. 2003 Mar-
Apr;9(2):38-45.

70.
Melatonin and cancer
• Hormone produced by pineal gland
• Highest concentration at night
• Biologic effects:
– Setting the body clock
– Antioxidant
– Immunomodulator
– Antitumor, anticytokine, anti-insomnia, anticachexia
– Improves survival in advanced cancer
– Reduces radiation and chemotherapy-induced toxicity
> Am J Hospice & Palliative Care. 2005;22(4):295-309.
• Taking (high dose) supplements may not be
advisable

71.
Melatonin and cancer
• Enhanced by:
– meditation
– sunlight
– subdued lighting
after sunset
– calorie restriction
– exercise
– foods rich in Ca, Mg,
B6, niacinamide
– tryptophane rich
foods
• Inhibited by:
– Caffeine, beta +/-
alpha blockers,
sedatives, alcohol,
tobacco
– electro-magnetic
radiation
– night shift and jet-lag
– excessive calories
– inactivity

72.
Emotions and inflammation
• Immune dysregulation is a core mechanism for
conditions associated with aging
– E.g. CVD, osteoporosis, arthritis, Type 2 diabetes, certain
cancers, and frailty and functional decline
• Production of pro-inflammatory cytokines that
influence these conditions can be stimulated directly
by negative emotions
• Depression (stress) can down-regulate the immune
response, prolong infection and delay wound healing
– Kiecolt-Glaser JK, et al. Depression and immune function:
central pathways to morbidity and mortality. J Psychosom Res.
2002;53(4):873-6.
– Kiecolt-Glaser JK, et al Psychoneuroimmunology: psychological
influences on immune function and health. J Consult Clin
Psychol. 2002;70(3):537-47.

73.
Emotions and inflammation
• These inflammatory chemicals can accelerate
cell replication and new blood vessel growth
– Thus inflammation can accelerate cancer cell growth
• These chemicals are increased by ‘negative
emotions’ and reduced by ‘positive emotions’
• What are positive and negative emotions
– E.g. an appropriate expression of sadness or anger
could be a positive emotion and suppressing them
could be negative

74.
Does ‘stress’ cause cancer?
• Yes and no depending on how you define it,
measure it and the person experiencing it
• Meta-analysis to verify association b/w stressful
life events and primary breast cancer incidence
• 618 studies (1982-2007): 8 case control and
cohort studies selected and 3 analyses for
Relative Risk
– Widowhood: RR1.04
– Divorce: RR1.03
– Self-rated intensity/frequency of stress: RR1.73
> Santos MC, Horta BL, do Amaral JJ, et al. Association between stress and
breast cancer in women: a meta-analysis. Cad Saude Publica. 2009;25
Suppl 3:S453-63.

75.
Stress and cancer
• Review evaluated longitudinal associations between
stress and cancer using meta-analytic methods (165
studies)
• Stress-related psychosocial factors associated with
higher cancer incidence in initially healthy populations (P
= 0.005)
• Poorer survival in patients with diagnosed cancer
• Higher cancer mortality
• Stressful life experiences related to poorer cancer
survival and higher mortality but not to an increased
incidence
• Stress-prone personality or unfavourable coping styles
and negative emotional responses or poor quality of life

76.
Depression and risk of cancer
• “After adjustment for age, sex, race, disability, hospital
admissions, alcohol intake, and smoking, the hazard ratio
for cancer associated with chronically depressed mood was
1.88. The excess risk of cancer associated with chronic
depression was consistent for most types of cancer and
was not specific to cigarette smokers. ... When present for
at least 6 years, depression was associated with a
generally increased risk of cancer.”
> Penninx BW, Guralnik JM, Pahor M, Ferrucci L, Cerhan JR, Wallace RB, et al.
Chronically depressed mood and cancer risk in older persons. J Natl Cancer
Inst 1998;90:1888-93.

77.
Depression and cancer
• Immune activation and inflammation play a role in the
pathophysiology of both depression and cancer
• Cancer patients experience a threefold higher rate of
depression within the first five years of diagnosis
• Chronic depression associated with increased (approx.
doubled) cancer risk and shortened survival
– Elevated concentrations of proinflammatory cytokines associated with
depression may mediate the neuroendocrine, neural, and immune pathways
that account for the relationship
– Proinflammatory cytokines are known to modulate key neurobiological
correlates of depression including hypothalamic-pituitary-adrenal (HPA) axis
dysregulation, monoamine neurotransmitter metabolism, and limbic system
activity
> Penninx BW, Guralnik JM, Pahor M, Ferrucci L, Cerhan JR, Wallace RB, et al.
Chronically depressed mood and cancer risk in older persons. J Natl Cancer Inst
1998;90:1888-93.
> Currier MB, Nemeroff CB. Depression as a Risk Factor for Cancer: From
Pathophysiological Advances to Treatment Implications. Annu Rev Med. 2013 Nov
11. [Epub ahead of print]

78.
Depression and breast cancer survival
• Randomized trial of supportive-expressive group therapy on 125 women
with metastatic breast cancer (MBC)
• Completed a depression symptom measure [CES-D] at baseline and
were randomly assigned to a treatment group or to a control group that
received educational materials.
• Median survival time was 53.6 months for women with decreasing CES-
D scores over 1 year and 25.1 months for women with increasing CES-D
scores
• There was a significant effect of change in CES-D over the first year on
survival out to 14 years
• Neither demographic nor medical variables explained this association.
• “Decreasing depression symptoms over the first year were associated
with longer subsequent survival for women with MBC in this sample.”
> Giese-Davis J, Collie K, Rancourt KMS, Neri E, Kraemer HC, Spiegel D. Decrease in
Depression Symptoms Is Associated With Longer Survival in Patients With Metastatic
Breast Cancer: A Secondary Analysis. J Clin Oncol. 2011 February 1; 29(4): 413–420.

79.
Purpose, happiness, self-gratification,
genetics and immunity
• Immune cells in individuals with
high levels of hedonic wellbeing
(pleasure seeking / gratification)
were characterized by:
– an increased expression of genes
involved in inflammation (implicated in
diseases such as arthritis and heart
disease), and
– decreased expression of genes involved
in antiviral responses
• This immune response (known as
CTRA) is also associated with
chronic stress and uncertainty
• The opposite effect was found for
eudaimonic wellbeing (meaning /
engagement)
• Both forms of wellbeing were
associated with similar self-
Fredrickson BL, Grewen KM, Coffey KA, et al. A
functional genomic perspective on human well-being.
Proc Natl Acad Sci U S A. 2013 Jul 29. [Epub ahead of
print]

80.
Healthy lifestyle and NK-cell activity
Kusaka Y. et al. Preventive Medicine 1992;21:602-15.
• Behaviour
– Exercise
– Managing stress
– Enough sleep
– Balanced meals
– Not smoking
– Eating breakfast
– Not overworking
– Avoiding alcohol
• Adv. NK-cell activity
– 47%
– 45
– 44
– 37
– 27
– 21
– 17
– 0

81.
• “The faculty of
voluntarily bringing
back a wandering
attention over and
over again, is the very
root of judgment,
character, and will. No
one is compos sui if
he have it not. An
education which
should improve this
faculty would be the
education par
excellence.”
– William James,
Principles of Psychology,
1890

82.
Applications of mindfulness
• Mental health: E.g. therapeutic for depression, anxiety, panic disorder, stress,
emotional regulation, addiction, sleep problems, eating disorders, psychosis,
ADHD, autism, reduced burnout
• Neuroscience: E.g. structural and functional changes in the brain,
neurogenesis, (dementia prevention), down-regulating the amygdala, improved
executive functioning and working memory, reduced default mental activity,
improved self-monitoring and cognitive control
• Clinical: E.g. pain management, symptom control, coping with chronic illness,
metabolic and hormonal benefits, facilitating lifestyle change (e.g. weight
management, smoking cessation), improved immunity, enhanced genetic
function and repair
• Performance: E.g. sport, academic, leadership, mental flexibility
• Education: E.g. improved problem-solving, improved executive functioning
and working memory, focus, better behaviour
• Relationships: E.g. emotional intelligence, communication, empathy
• Spiritual 83

83.
Default mode network
• Default mental activity flourishes in various forms of
psychopathology including depression, anxiety,
schizophrenia and autism
• Default activity decreased or deactivated when
paying attention (e.g. experienced meditators)
• In experienced meditators but not novices, even
when the default mode network is active, brain
regions associated with self-monitoring and
cognitive control are co-activated
– Reduces vulnerability to default thinking
> Brewer JA, Worhunsky PD, Gray JR, et al. Meditation experience is
associated with differences in default mode network activity and
connectivity. Proc Natl Acad Sci U S A. 2011 Dec
13;108(50):20254-9.

84.
MBCT and depression
• RCT investigated the effects of Mindfulness-based cognitive
therapy (MBCT) on the relapse in depression, time to first
relapse and the quality of life
– 106 recovered depressed patients with a history of at least 3 depressive
episodes
– Treatment as usual (TAU) vs MBCT plus TAU 1 year f/up
• Relapse/recurrence significantly reduced and the time until first
relapse increased in the MBCT plus TAU c/w TAU
• MBCT plus TAU group also showed a significant reduction in
both short and longer-term depressive mood, better mood states
and quality of the life
> Godfrin KA, van Heeringen C. The effects of mindfulness-based cognitive
therapy on recurrence of depressive episodes, mental health and quality of
life: A randomized controlled study. Behav Res Ther. 2010 Aug;48(8):738-46.

85.
Godfrin KA, van Heeringen C. Behav Res Ther. 2010 Aug;48(8):738-46.

86.
Godfrin KA, van Heeringen C. Behav Res Ther. 2010 Aug;48(8):738-46.

87.
Acceptance and quality of life
• “After controlling for sociodemographic and
medical variables, self-blame, rumination, and
catastrophizing negatively affected QOL, whereas
acceptance and positive reappraisal had positive
effects.”
> Li L, Zhu X, Yang Y, He J, Yi J, Wang Y, Zhang J. Cognitive
emotion regulation: characteristics and effect on quality of life in
women with breast cancer. Health Qual Life Outcomes. 2015
May 6;13(1):51. doi: 10.1186/s12955-015-0242-4.

88.
Yogic meditation, genes and immunity
• Study on effect of Yogic meditation on genetic
expression
• 68 genes were found to be differentially expressed
(19 up-regulated, 49 down-regulated) after adjusting
for potentially confounded differences in sex, illness
burden, and BMI
• Up-regulated genes included immunoglobulin-related
genes
• Down-regulated genes included pro-inflammatory
cytokines
> Black DS, Cole SW, Irwin MR, et al. Yogic meditation reverses NF-κB and
IRF-related transcriptome dynamics in leukocytes of family dementia
caregivers in a randomized controlled trial. Psychoneuroendocrinology.
2013 Mar;38(3):348-55. doi: 10.1016/j.psyneuen.2012.06.011.

89.
Meditation and inflammation
• Novice meditators’ Inflammatory markers (serum
interleukin (IL)-6 levels) were 41% higher than those
of expert meditators
• The odds of a novice having detectable C-reactive
protein (CRP) (a marker of inflammation) were 4.75
times as high as that of an expert
• Differences in stress responses between experts and
novices provided one plausible mechanism for their
divergent inflammatory response to stress
> Kiecolt-Glaser JK, Christian L, Preston H, et al. Stress, inflammation, and
yoga practice. Psychosom Med. 2010 Feb;72(2):113-21. doi:
10.1097/PSY.0b013e3181cb9377.

90.
Mindfulness and cancer
• Controlled trial demonstrated:
– Significantly lower scores on Total Mood Disturbance
and subscales of Depression, Anxiety, Anger, and
Confusion but more Vigor
– Fewer overall physical and stress symptoms
– 65% reduction in mood disturbance and a 31%
reduction in stress
> Speca M, et al. Psychosom Med. 2000;62(5):613-22.
• Associated with decrease in afternoon cortisol level
– Cortisol one of the stress hormones: a prognostic
factor for outcomes for cancer patients
> Carlson LE. Et al. Psychoneuroendocrinology. 2004;29(4):448-74.

91.
Mindfulness and cancer
• At the first assessment (i.e., before MBSR start), reductions in
peripheral blood mononuclear cell NK cell activity (NKCA) and
IFN-gamma production with increases in IL-4, IL-6, and IL-10
production and plasma cortisol levels were observed for both
the MBSR and Non-MBSR groups of breast cancer patients
• Women in the MBSR group
– Re-established their NKCA and cytokine production levels
– Reduced cortisol levels
– Improved QOL, and increased coping effectiveness
• Breast cancer patients in the Non-MBSR group exhibited
continued reductions in NKCA and IFN-gamma production with
increased IL-4, IL-6, and IL-10 production
> Witek-Janusek L, Albuquerque K, Chroniak KR, et al. Effect of mindfulness
based stress reduction on immune function, quality of life and coping in
women newly diagnosed with early stage breast cancer. Brain Behav
Immun. 2008 Aug;22(6):969-81. doi: 10.1016/j.bbi.2008.01.012.

92.
Mindfulness, telomeres and breast cancer
• Telomere length (TL) associated with breast cancer prognosis
• RCT compared effects of a mindfulness program and Supportive
Expressive Therapy with control intervention on TL in 88
distressed stage I-III breast cancer survivors
– Intervention focused on training in mindfulness meditation and gentle Hatha yoga:
SET focused on emotional expression and group support
• TL in the intervention group was maintained whereas it was
found to decrease for control participants
• “Psychosocial interventions providing stress reduction and
emotional support resulted in trends toward TL maintenance in
distressed breast cancer survivors, compared with decreases in
usual care.”
> Carlson LE, Beattie TL, Giese-Davis J, Faris P, Tamagawa R, Fick LJ, Degelman ES,
Speca M. Mindfulness-based cancer recovery and supportive-expressive therapy
maintain telomere length relative to controls in distressed breast cancer survivors.
Cancer. 2014 Nov 3. doi: 10.1002/cncr.29063

93.
Brain Behav Immun. 2008 Aug;22(6):969-81. doi: 10.1016/j.bbi.2008.01.012.

94.
Mindfulness and cellular ageing
• Meditation may slow
genetic ageing and
enhance genetic repair
– “...we propose that some
forms of meditation may have
salutary effects on telomere
length by reducing cognitive
stress and stress arousal and
increasing positive states of
mind and hormonal factors
that may promote telomere
maintenance.”
> Epel E, Daubenmier J, Moskowitz JT,
Folkman S, Blackburn E. Can meditation
slow rate of cellular aging? Cognitive
stress, mindfulness, and telomeres. Ann N
Y Acad Sci. 2009 Aug;1172:34-53.

95.
Mindfulness, telomeres and breast cancer
• Short telomere length (TL) associated with poor breast cancer
prognosis
• RCT compared effects of a mindfulness program and
Supportive Expressive Therapy with a minimal intervention
control intervention on TL in 88 distressed stage I-III breast
cancer survivors
– Intervention focused on training in mindfulness meditation and gentle Hatha
yoga: SET focused on emotional expression and group support
• TL in the intervention group was maintained whereas it was
found to decrease for control participants
> Carlson LE, Beattie TL, Giese-Davis J, Faris P, Tamagawa R, Fick LJ, Degelman ES,
Speca M. Mindfulness-based cancer recovery and supportive-expressive therapy
maintain telomere length relative to controls in distressed breast cancer survivors.
Cancer. 2014 Nov 3. doi: 10.1002/cncr.29063