Integrative Strategies For Supporting Patients

Integrative Strategies for Supporting
Patients Diagnosed with Breast Cancer:
Part 1
Lise Alschuler, ND, FABNO
Genova Diagnostics LiveGDX
May 28, 2014
Christine Stubbe, ND
Medical Education Specialist - Asheville
Lise Alschuler, ND, FABNO
http://www.drlise.net
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Integrative Strategies for Supporting
Patients Diagnosed with Breast Cancer:
Part 1
Lise Alschuler, ND, FABNO
May 28, 2014
6
7
Today’s presentation
• Due to the positive response from our listeners and length of
the presentation, Dr. Lise Alschuler will be presenting again
next month, June 25 for part 2
8
Outline of Topics
• Integrative Management
• Prognostic and Biomarker testing
• Lifestyle (diet, exercise, sleep,
alcohol, psychological wellbeing)
• Natural therapies
Prognosis is adversely affected by:
– ER negative
– PR negative
– Her2neu positive (however, this provides a target for highly
effective monoclonal antibody, tratuzamab (Herceptin)
– Elevated Ki-67 (proliferative index)
• Ki-67 > 25% = highly proliferative
– Higher tumor grade (1-3; Grade 3 = highest)
– Lower albumin concentration (indirect indication of
inflammation)
– Lymphovascular invasion
– BRCA status – minimal contributor to prognosis
• Premenop. women with stages I-III BrCA: 10yr survival rate for BRCA1
mutation carriers = 80.9% vs. 82.2% in non-carriers
Murri A, et al. Br J Cancer. 2008; 99(7):1013-9
Huzarski T et al. J Clin Oncol. 2013;31(26):3191-6
9
10
Most important prognostic markers
• The two most important prognostic markers are tumor size and
presence of malignant disease in regional lymph nodes.
– For women with tumors of equivalent size, lethality increases with
increasing number of positive lymph nodes, such that there is an extra
approximately 6% chance of death associated with each positive lymph
node.
– For women with equivalent lymph node status, tumor size is associated
with increased lethality, such that each millimeter of tumor diameter is
associated with an additional approximately 1% chance of death.
• The overall lethality is equal to the sum of the contribution from
lymph node status and the contribution from tumor size
• Tumor size + lymph node involvement are stronger predictors than
tumor grade.
Hughes K. et al. Cancer. 2003 Nov 15;98(10):4276
11
Prognostic biomarkers: vitamin D
• Serum 25-hydroxyvitamin D3 at diagnosis:
(n=1800 women with early breast cancer)
– Low 25-OHD (<20 ng/mL) is correlated with larger tumor size at
diagnosis, but not with lymph node invasion, receptor status or tumor
grade.
– High 25-OHD (>30 ng/mL) at diagnosis is significantly correlated with
improved Overall Survival (p=0.0101) and DFS (0.0192) up to 3 years
from diagnosis.
• Inverse correlation between low vit. D and risk of death; HR = 0.79.
– Relapse rate at median follow-up of 4.7y = 7.8% for low Vit. D vs. 5.6%
for high Vit. D – difference was noted in postmenopausal women only.
– Risk of distance metastasis in postmenopausal women decreased by
66% in women with 25OHD >30ng/mL vs. less than 30ng/mL.
Hatse S. et al. Carcinogenesis. 2012 Jul;33(7):1319-26.
12
Catechol-O-methyltransferase (COMT
polymorphisms)
• COMT adds methyl groups to catechol estrogens, thereby stabilizing
these estrogen metabolites and reducing the likelihood of their
causing DNA damage.
• Thus, COMT SNPs would be predicted to increase breast cancer risk.
• SNP, particularly in the 3’ UTR region of COMT is associated with
increased risk
– This SNP is associated with a 29% increase in breast cancer risk (odds ratio,
1.29; 95% confidence interval, 1.06-1.58) compared with the most common
haplotype TGAA; however, the global test for haplotype associations was
not significant (P = 0.09).
• COMT Val158Met polymorphism does not contribute to BrCA risk
• Bottom Line: In the presence of COMT 3’UTR SNP: increase
methylation support and reduce exogenous estrogen exposure
Gaudet M. et al. Cancer Res. 2006;66(19):9781-5.
Qin X et al. Diagn Pathol. 2012;7:136.
13
IGF-1
•
Adipocyte = primary source of
– IGF-1 stimulates cancer cell
proliferation and is
factor in
cell growth
•
•
•
•
IGF-1.
survival and
considered a pivotal
adipocyte regulation of cancer
Adipocytes transcribe and secrete Insulin-like growth factor-1 in response to elevated
blood (and tissue) levels of glucose and fatty acids.
This effect is most significant in obese individuals.
IGF-1 lowering interventions: Low glycemic load diet; blood sugar balancing nutrients and
herbs, metformin
Bottom line: Measure IGF-1 in TN BrCA and in obese women
–
Of note, BRCA1 mutation carriers have a higher incidence of IGF1-IR (IGF-1 insulin receptors) and are therefore
more sensitive to the effects of elevated IGF-1
D’Esposito et al. Diabetologia. 2012;55(10):2811-22
Maor S et al. Cancer Lett. 2007;257(2):236-43.
14
C-peptide [insulin]
•
•
c-peptide is associated with an approximately 50% increased risk of invasive breast cancer [top vs.
bottom quartile, that was robust to adjustment for plasma-free estradiol and sex hormone–binding
globulin. The association was stronger for ER-negative disease (adjusted OR 2.0).
C-peptide also worsens prognosis. A prospective observational study of 604 women without diabetes
in the HEAL study.
–
–
•
•
•
•
A 1-ng/mL increase in C-peptide was associated with a 31% increased risk of any death (HR = 1.31;
95% CI, 1.06 to 1.63; P = .013) and a 35% increased risk of death as a result of breast cancer (HR =
1.35; 95% CI, 1.02 to 1.87, P = .048).
Women with the highest C-peptide levels at the time of breast cancer diagnosis had almost 2x risk of
death compared to women with lower C-peptide levels.
In women with invasive breast cancer and high C-peptide levels, their risk of death was 3 times that
of women with lower C-peptide levels.
Associations between C-peptide and death from breast cancer was strongest in women with:
–
–
–
–
•
All women were diagnosed with breast cancer and were followed until death or 2006, whichever came
first.
C-peptide levels were assessed.
type 2 diabetes
body mass index less than 25 kg/m(2)
diagnosed with a higher stage of disease
tumors were estrogen receptor positive
Bottom Line: In women with elevated C-peptide, employ strategies to lower insulin:
–
–
–
–
Physical activity
Weight loss
Blood sugar lowering strategies (diet, supplement, botanical)
Insulin-lowering medications (metformin)
Ahern T. et al. Cancer Epid Biomarkers Prevention. 2013;22(10):1786-96.
Irwin M. et al J Clin Oncol. 2011;29(1):47-53
15
Galectin-3
• Galectin-3 is elevated 31-fold in patients with cancers of the breast, GI,
lung, ovarian, melanoma and NHL.
• Galectin-3 is correlated with metastasis:
– Promotes adhesion of disseminating tumor cells to vascular endothelium
– Increases endothelial IL-6 secretion
– Decreases dendritic cell differentiation and T-cell Ag presentation
• Values > 17.8 ng/mL are considered elevated (and associated with a 35%
HR of all cause mortality and all-cause hospitalization in heart failure
patients over 30m study)
– Note patients with high gamma-globulins (over 2.5g/dL) may have falsely
elevated results
• Bottom Line: Elevated galectin-3 indicate the need for modified citrus
pectin, cytotoxic immunity enhancement (mushrooms, beta-glucan, AHCC,
melatonin)
Iurisci I, et al. Clin Cancer Res. 2000;6:1389.
Chen C, et al. Clin Cancer Res. 2013;19:1693.
Chung A, et al. J Infect Dis. 2013;207(6):947-56.
De Boer R, et al. Eur J Heart Fail. 2009;11:811-7
16
a.m. cortisol and 4-point cortisol
• Elevated cortisol and flattened diurnal variation are
associated with decreased immunity and increased breast
cancer progression
– Some breast cancer cells express corticoid receptors, the activation of
which increases transcription of genes involved in proliferation and
invasiveness
• Morning (6a – 8a) is the most sensitive single draw to assess
overall cortisol influence.
– Normal: 6-23 mcg/dL
• Diurnal cortisol x 4 with DHEA-sulfate x 1 (salivary) provides a
more sensitive measurement of overall cortisol along with
stress patterns.
Sephton S, et al. JNCI. 2000;92(12):994-1000
17
Thyroid function
• Low thyroid function is associated with decreased
cell repair and increased breast cancer risk
• There is an increased prevalence of autoimmune
thyroid disease in patients with breast cancer
• Normal ranges:
– TSH: 0.4 - 4.0 mIU/L
– Free T4: 0.9 and 1.8 ng/dL
– total T3: 100 - 200 ng/dL.
• If abnormal, run TPO
antibodies
Smyth P. Breast Cancer Res. 2003;5(5):235-38
18
Inflammation biomarker ‘panel’
• Homocysteine: elevated homocysteine is associated with increased risk of
breast cancer
– <8.0 mol/L is optimal
• hsCRP: marker of acute inflammatory stress
– <1.0mg/L is ideal
• Ferritin: elevated ferritin can occur with iron overload, but can also be the
result of liver disease, cancer and inflammation
– <150ng/mL is optimal
• Fibrinogen: clotting factor that increases with inflammation, IR,
malignancy. Fibrinogen is the precursor for fibrin which coats cancer cells
creating immune camouflage and which facilitates angiogenesis
– Fibrinogen Ag <400mg/dL is optimal
• IL-6: secreted by tumor cells and associated fat and stromal cells;
correlates with increased invasiveness and angiogenesis
– < 7pg/mL is optimal
• IL-8: associated with angiogenesis and invasiveness
– < 11 pg/ml is optimal
19
Breast Cancer and IL-6
• Serum and plasma concentrations of VEGF and
serum concentration of IL-6 were measured in 87
patients with a fully documented history of
metastatic breast cancer using an enzyme-linked
immunoassay.
• All patients had detectable levels of VEGF, whereas
39% patients had detectable serum levels of IL-6.
Bachelot T, et al. Br J Cancer, 2003 Jun;88(11):1721-6.
20
IL-6 and VEGF
• Interleukin 6 expression is induced by hypoxia and,
in turn, is able to upregulate VEGF transcription.
• IL-6 has been shown to correlate with platelet count
and platelet VEGF content.
• As circulating VEGF is mostly transported by
platelets, IL-6 could be regarded as an indirect
angiogenic factor that facilitates the production and
the distribution of VEGF to metastatic sites.
21
Prognostic significance of IL-6
• There was a positive correlation between IL-6 levels
and the theoretical VEGF load of platelets (P<0.001).
• The presence of high levels of serum IL-6, but not
VEGF, was significantly correlated to a shorter
survival.
• These results indicate that serum IL-6 levels correlate
to poor survival in patients with hormone-refractory
metastatic breast cancer.
22
IL-6 and survival in Breast Cancer
Bachelot et al. Br J Cancer, 2003.
23
Immune assessment: NK cell assay
• Absolute number and percentage of CD16+ and CD56+
(standard reference lab; flow cytometry)
– RR: 6%-35%
– Ideal: > 15%
• NK cell activity (measures ability of NK cells to lyse malignant
cells in-vitro)
– Low < 50 activity units [use RR of reference lab]
• Note: NK cell activity varies daily and is affected by diet,
exercise and stress therefore repeat the test in order to
ascertain a pattern.
24
Telomere testing
• There is a direct correlation between shortened telomeres
and both an increased risk of developing cancer and increased
risk of dying from cancer—especially cancer of the lung,
breast, prostate, and colon.
– Specifically, short telomere length at baseline is associated with a 3fold increase in risk of cancer and a 2-fold increased risk of cancer
mortality.
• Testing uses Real-time polymerase chain reaction (PCR)-based
method. The results are reported as a relative ratio of
telomere quantity divided by a reference gene quantity (T/S
ratio).
• Typically telomere length is measured in leukocytes, as these
cells offer the advantage of accessibility.
Willeit P et al. JAMA. 2010;304(1):69-75.
25
Breast Cancer Natural Strategies
•
•
•
•
Diet
Exercise
Stress management
Dietary Supplements
–
–
–
–
–
–
–
Green tea
Flavonoids
Mushrooms, PSK
Intravenous ascorbic acid
Melatonin
Fermented Wheat Germ Extract
Black cohosh
26
Diet: WHEL study
• The Women’s Healthy Eating and Living (WHEL) Randomized Trial:
Multi-institutional randomized controlled trial of dietary change in
3088 women previously treated for early stage breast cancer who
were 18 to 70 years old at diagnosis.
• The intervention group (n=1537) was randomly assigned to receive
a telephone counseling program supplemented with cooking
classes and newsletters that promoted daily targets of:
–
–
–
–
5 vegetable servings plus 16 oz of vegetable juice
3 fruit servings
30 g of fiber
Limit energy intake from fat to 15% to 20%
• The comparison group (n=1551) was provided with print materials
describing the “5-A-Day” dietary guidelines.
Pierce, et al. JAMA. 2007;298(3):289-298
27
Secondary analysis of WHEL study
• Self-report of hot flashes (HFs) after treatment for
early-stage breast cancer has been associated with
an approximately 25% to 30% decreased risk for
additional breast cancer events, independent of the
type of antiestrogen therapy.
– The HF are due, in part, to lowered levels of circulating
estrogen.
• Hypothesis: the protective dietary effect might be
limited to the subgroup of patients with potentially
higher circulating estradiol levels and worse
prognosis (ie, women without HFs at baseline).
Gold, et al. J. Clin Oncol, 28: 2008.
28
Dietary influences on estrogen levels
• Changes in dietary patterns to either
decrease energy from fat or increase
fiber intake can alter the enterohepatic
recirculation of estrogens, leading to
lower circulating estrogen concentrations.
• Reduction in fat consumption has been shown to result in 18% 27% reductions in circulating estrogen levels.
• Binding of fiber to unconjugated estrogens in the gut impedes
reabsorption of estrogen, resulting in up to 20% difference in
circulating estrogen levels in high fiber diets vs. low fiber diets.
29
Conclusions
• This dietary intervention was associated with reduced risk of
second breast cancer events among women who reported no
HFs at baseline.
– These women had a 31% lower event rate than HF-negative
women in the comparison group over 7.3 years of follow-up
– Among HF-negative postmenopausal women, the intervention
effect was even stronger, with a 47% reduction in risk compared
with HF- women assigned to the comparison group.
30
Prudent diet and breast cancer risk
• Meta-analysis:
– Case-control and cohort studies that identified:
• prudent/healthy diet (n= 18)
• Western/unhealthy diet (n = 17) and
• drinker (n = 4) dietary patterns.
– In total, 18 studies met the inclusion criteria and were included in the
analysis.
• Evidence of a 11% decrease in the risk of breast cancer in the
highest compared to the lowest categories of prudent/healthy
dietary patterns (OR = 0.89; 95% CI: 0.82, 0.99; P= 0.02) in all
studies and in pooled cohort studies alone.
– Prudent/healthy diets tended to have high quantities of fruit,
vegetables, poultry, fish, low-fat dairy and whole grains.
Brennan SF, et al. Am J Clin Nutr. 2010 May;91(5):1294-302
31
Weight
• Being overweight or obese is responsible for one in six cancer
deaths in the United States
• Weight, weight gain, and obesity account for approximately
20% of all cancer cases.
• Being overweight more than doubles the risk of dying of
breast cancer.
• However, recent research indicates that underweight women
(BMI <18.5 kg/m2) are at increased risk of breast cancer
recurrence (HR: 1.59)
Wolin et al. The Oncologist. 2010;15:556–565
Magheli et al. Urology. 2008;72(6):1246-51.
Poole EM , et al. Breast Cancer Res. 2013:139(2):529-37
32
Obesity, Insulin and Estrogen
33
Soy
• Soy consumption can reduce the risk of breast cancer.
• Women with a history of ER+ breast cancer have a decreased risk of
recurrence and decreased risk of dying from breast cancer if they
regularly consume soy foods:
– >23mg soy (equivalent to 1 glass soy milk or ½ cup tofu) decreases risk of
dying from any cause by 9% and reduces risk for breast cancer recurrence
by 15% compared to women who do not eat soy.
• Prospective cohort study of women receiving adjuvant endocrine
therapy.
– median follow-up period for the 524 patients in this study was 5.1 years.
• Among premenopausal patients, the overall death rate (30.6%) was
not related to intake of soy isoflavones
• The risk of recurrence for postmenopausal women in the highest
quartile of soy intake was 33% lower (HR = 0.67, 95% CI 0.54–0.85, p for
trend = 0.02) than in the lowest quartile of soy isoflavone intake.
Shu XO, et al. JAMA, 2009
Kang X, et al. CMAJ, 2010
34
Soy and BrCA recurrence
• Pooled analysis of three studies: Shanghai Breast Cancer Survival Study
(SBCSS), the Life After Cancer Epidemiology (LACE) Study, and the
Women’s Healthy Eating & Living (WHEL) Study
• 9514 breast cancer survivors, dx’ed btw 1991-2006
• Mean follow-up 7.4 years
• Consumption of > 10 mg isoflavones/d associated with:
– statistically sig reduced risk recurrence HR: 0.75
– non-stat. sig reduced risk all cause mortality HR: 0.0.87
– non-stat sig reduced risk breast-cancer specific mortality HR: 0.83
• Inverse association in Tamoxifen users
– HR: 0.63 for > 10 mg vs < 4 mg/d isoflavones
• Inverse association with ER neg. survivors slightly stronger than ER+
– HR: 0.64 for >10 mg vs. < 4 mg/d isoflavones
Nechuta SJ, et al. American Journal of Clinical Nutrition. 2012 Jul 1;96(1):123-132
35
Alcohol and breast cancer risk
• Women who drink between one and two alcoholic drinks per day
increase their relative risk of breast cancer by 10% compared with
light drinkers who drink less than one drink a day
• 1 drink/d raises a 50y woman’s 5 yr absolute BrCA risk from
3% to 3.45%
• Between 3 – 5 drinks/week is associated with reduced allcause mortality in women
• The risk of breast cancer increases by 30% in women who drink
more than three drinks a day.
▫ 30% increased risk is the same risk from HRT
▫ 30% increased risk is the same risk from smoking 1 pack cigarettes daily
• Red wine = white wine = beer = liquor therefore the risk is
attributable to ethyl alcohol
• No differences across ethnicities
Klatsky, et al., ECCO – The European Cancer Conference 2007, Barcelona, Spain
(http://www.fecs.be)
Newcomb P. et al. J Clin Oncol. 2013; 31(16):1939-46
36
Alcohol intake and BrCA recurrence risk
• Associated risk of recurrence with alcohol intake
is
only relevant for women who are postmenopausal at the time
of initial diagnosis.
– Postmenopausal women who regularly consumed alcohol (≥6.0 g/day)
had an almost 20% increased risk of recurrence. There was no
association with overall mortality in any groups. This level of
consumption, which is essentially equivalent to 4 drinks daily.
• There is no statistical significance in premenopausal women.
– According to the authors of ABCPP: “Overall, compared with
nondrinking, regular alcohol intake (≥6.0 g/day) was not associated
with risk of recurrence.”
Poole EM et al. Breast Cancer Res Treat. 2013;139(2):529-37
37
Is folate protective?
• Participants were 35,023 postmenopausal women aged 50-76y in the
Vitamins And Lifestyle (VITAL) cohort study; breast cancer was
diagnosed in 743 of these women between baseline (2000-2002) and
2006
• Women consuming >1272 dietary folate equivalents (DFE)/d of total
folate (10-y average) had a 22% decrease in breast cancer risk
compared with women consuming <345 DFE/d (RR: 0.78; 95% CI:
0.61, 0.99; P for trend = 0.05).
• A greater benefit was observed for estrogen-receptor (ER) negative
than for ER+ breast cancers (RR: 0.38; 95% CI: 0.18, 0.80; P for trend =
0.02; P = 0.02 for the difference between ER- and ER+)
• Multivitamin use attenuated the increased risk of breast cancer
associated with alcohol drinking (P for interaction = 0.02)
Maruti S. et al., Am J Clin Nutr. 2009 Feb;89(2):624-33
38
Exercise
 Exercise is preventive
o
Meta-analysis (27 observational studies
published between 1950 and 2011): Consistent
evidence that physical activity is associated with
reduced risk (41% - 61%) of all-cause, breast and
colon cancer specific mortality.
o Physical activity improves quality of
life of people diagnosed with cancer.

Exercise reduces obesity, now
characterized as an independent risk
factor for cancer
Ballard-Barbash R, et al. J Natl Cancer Inst 2012;104:815-840
39
Exercise and Mortality risk
• Data over a median of 23 months post-diagnosis (interquartile
range 18–32 months) were pooled in the After Breast Cancer
Pooling Project (n = 13,302).
• 2.5 h (10 MET-hours/week) of moderate intensity physical
activity per week was associated with:
– 27% reduction in all cause mortality (n = 1,468 events, Hazard
Ratio (HR) = 0.73, 95% CI, 0.66–0.82)
– 25% reduction in breast cancer mortality (n = 971 events, HR =
0.75, 95% CI 0.65–0.85)
• compared with women who did not meet the physical activity
Guidelines (<10 MET-hours/week).
Beasley JM, et al. Breast Cancer Res Treat. 2012 Jan;131(2):637-43
40
Exercise and Breast CA
• The prevalence of inactivity in the general population is estimated to be 38.8%
• 10% of all incident breast cancers are attributed to inactivity
• Meta-analysis of prospective studies examining the relationship between
exercise and breast cancer risk.
– Overall, 31 studies with 63,786 cases were included
• The overall association between physical activity and breast cancer risk was
RR= 0.88 (CI=0.85–0.91).
• Stronger inverse associations were found for subjects with BMI<25 kg/m2
[0.72 (0.65–0.81)], premenopausal women [0.77 (0.72–0.84)], and estrogen
and progesterone receptor-negative breast cancer [0.80 (0.73–0.87)].
• Vigorous exercise reduced BrCA risk more than moderate activity [RR = 0.86
(0.82-0.89) vs. RR = 0.97 (0.94-0.99)]
• The risk of breast cancer decreased by:
– 2% (P < 0.00) for every increment of 10h light household activity (= 25 metabolic
equivalent (MET)-h) per week in non-occupational physical activity
– 3% (P < 0.00) for every 4 h/week of walking at 2 miles/h or 1 h/week of running at
6 miles/h (= 10 MET-h/week) increment in recreational activity
– 5% (P < 0.00) for every 2 h/week increment in vigorous recreational activity
Wu Y. et al. Breast Cancer Res Treat. 2013 Feb;137(3):869-82.
41
Exercise and Breast cancer
• Women who engaged in the equivalent of at least two to
three hours of brisk walking each week in the year before they
were diagnosed with breast cancer were 31% less likely to die
of the disease than women who were sedentary before their
diagnosis. [multivariable hazard ratios (HR) = 0.69 (95% CI,
0.45 to 1.06; P = .045)]
• Women who increased physical activity after diagnosis had a
45% lower risk of death (HR = 0.55; 95% CI, 0.22 to 1.38) when
compared with women who were inactive both before and
after diagnosis
• Women who decreased physical activity after diagnosis had a
four-fold greater risk of death (HR = 3.95; 95% CI, 1.45 to
10.50).
Irwin et al. J Clin Oncol. 2008 Aug 20;26(24):3958-64.
42
The combination counts
• A combination of 5-6 servings of vegetables/d and exercise
equivalent to walking 30m 6 days/week (540 MET) reduced
the risk of death from breast cancer by 44% among early
stage breast cancer patients (hazard ratio, 0.56; 95% CI,
0.31 to 0.98).
• Prospective study of 1,490 women diagnosed and
treated for early-stage breast cancer between 1991 and
2000. Enrollment was an average of 2 years post
diagnosis. Only seven women were lost to follow-up
through December 2005.
• Randomly assigned to the comparison group
of the ongoing Women’s Healthy Eating
and Living Study.
Pierce, et al. Journal of Clinical Oncology. 2007;25 (17):2345-41
43
Diet, Exercise and Survival
Kaplan-Meier survival after Women’s Healthy Eating and Living (WHEL) Study enrollment by four
diet and physical activity categories. Low vegetables-fruits (VF), less than 5 servings/d; high VF, ≥
5 servings/d; low physical activity (PA), less than 540 metabolic equivalent task (MET) -min/wk;
high PA, ≥ 540 MET-min/wk. Survival is plotted as a function of number of years enrolled in WHEL
Study.
44
Sleep and Breast cancer
• In a prospective study of 23,995 Japanese women, short sleep
duration was associated with higher risk of breast cancer (143
cases).
• Women who slept </= 6 hr per day had a 62% increased risk
of developing breast cancer compared to women who slept 7
h per day (multivariate hazard ratio 1.62 (95% confidence
interval: 1.05-2.50; P for trend=0.03)
• A duration of 30+ years of working the night shift is
associated with a 2-fold increased risk of breast cancer.
Kakizaki M. et al. Br J Cancer. 2008 Sep 23.
Grundy A. et al. Occ. Environ. Med., 2013 Jul 1.
45
Stress and Breast Cancer
•
•
•
•
A twofold increase in breast cancer risk is evident after
disruption of marriage owing to divorce, separation or death
of a spouse.
Cancer risk has been shown to be increased after chronic
depression that has lasted for at least 6 years.
The combination of extreme stress and low social support
was related to a 9-fold increase in breast cancer incidence.
However, findings have been inconsistent. In general,
stronger relationships have been observed between psychosocial factors and cancer progression than between
psychosocial factors and cancer incidence.
Lillberg K et al. Am J Epidemiol. 2003;157(5):415-23.
Penninx B, et al. J Natl Cancer Inst. 1998; 90(24):1888-93.
Price MA, et al. Cancer. 2001;91(4):679-85.
46
Social isolation, stressed
fat and breast cancer
• Based on rodent models of TN
breast cancer, social isolation
causes a heightened stress
response which, in turn,
increases expression of genes
in adipocytes that increase
glucose metabolism, lipid
synthesis and leptin secretion.
• These metabolic changes
increased the conversion of
mammary carcinoma in situ
to invasive carcinoma.
– Mammary fat has heightened
sensitivity to stress hormones
over visceral fat, making breast
tissue esp. vulnerable to stress
Volden P. et al. Cancer Prev Res;2013 Jun;1-12.
47
Mindfulness based stress reduction
• A meta-analysis of 10 studies showed a significant
improvement in psychological and physical quality of life.
• MBSR has been shown to reduce depression and fear of
recurrence in women diagnosed with breast cancer.
• MBSR lowers cortisol, reduces IL-6, lowers systolic blood
pressure and improves NK cell activity.
Ledesma D and Kumano H. Psychooncology 2009;18:571.
Lengacher CA, et al. Psychooncology 2009;18:1261.
Witek-Janusek L, et al. Brain Behav Immun. 2008;22:969.
48
Dietary Supplements
•
•
•
•
•
•
•
•
•
Multivitamins
Green tea
Flavonoids
Mushrooms, PSK
Taurox
Intravenous ascorbic acid
Melatonin
Fermented Wheat Germ Extract
Black cohosh
49
Multivitamins after BrCA
• Based upon data from The After Breast Cancer Pooling Project
(ABCPP) which uses 4 ongoing prospective studies and combines
the results in a systematic way to preserve the integrity of the data
• The use of antioxidant supplements (multivitamins, vitamin C, or E)
was associated with a 16% decreased risk of death from any cause
(95% CI: 0.72–0.99).
• Vitamin C alone was associated with decreased risk of death from
any cause (RR: 0.81; 95% CI: 0.72–0.92).
• Vitamin E was associated with a decreased risk of recurrence (RR:
0.88; 95% CI: 0.79–0.99).
• Vitamin D was associated with decreased risk of recurrence among
ER positive, but not ER negative tumors (P-interaction=0.01).
• None of the supplements, alone or in combination, was associated
with increased risk of recurrence or death. There were no
statistically significant associations with breast cancer mortality
specifically.
Poole EM et al. Breast Cancer Res Treat. 2013;139(2):529-37.
50
Conjugate
Carcinogen
Induction of phase II
conjugation  detoxification
of carcinogens
Reduction of hydroxyl radicals
and modulation of DNA repair
Oncogene formation
and tumor initiation
Induces apoptosis
of initiated cells
Tumor
promotion
Inhibition of growth signals
Tumor inhibition by
Green tea
polyphenols
Tumor
progression
Inhibition of matrix enzymes
Tumor invasion
and metastasis
50
51
Green tea and BrCA prevention
•
Pre-surgical trial of postmenopausal women (all non-tea drinkers)
–
–
•
•
•
•
The green tea intervention group (N=13) featured 12 patients with primary invasive stage I or II
breast cancer and 1 with ductal carcinoma in situ (DCIS) of mixed hormonal status.
The control group (N=21) featured six patients who declined to be in the intervention group, five
patients with DCIS, and 10 invasive cancers.
The daily dose was three standardized extract capsules so each participant received 940
mg of EGCG daily, which is the equivalent to about 8 to 10 cups of green tea.
The intervention took place between breast cancer diagnosis and initial surgery date
with an average green tea duration of 35 days. The women in the control group did not
take any capsules so this was not a placebo-controlled trial.
In the green tea group, patients experienced a decrease in Ki-67 activity (-3.14%) in
benign cells (P = 0.007), as well as in malignant cells (-4.29%) (P = 0.10) compared to
patients in the control group who experienced a statistically insignificant changes in Ki67 in the benign cell components of -0.75% (p=0.22) and an increase in malignant cells
of +0.68% (P=0.91).
High Ki-67 in residual disease after neoadjuvant therapy for breast cancer is associated
with higher recurrence rates and worse disease-free survival. The findings of this clinical
study indicate that green tea can reduce cell proliferation in breast tissue.
Yu SS, et al. Frontiers in Oncology. 2013;3(298)
de Azambuia E et al. Br J Cancer. 2007;96(10):1504-13
52
Green Tea and Breast Cancer: clinical data
Histologically confirmed invasive breast carcinoma
n = 472
Japanese premenopausal women
Stages I – III
Followed for 7 years post surgery
P < 0.05
Nakachi et al, Jpn J Cancer Res, 1998 Mar;89(3):254-61.
53
Green tea and Breast cancer: clinical
data
54
Green tea and breast cancer
• A prospective cohort study conducted over a 9-year period from 1990 to
1999.
• In 1990, 1160 new surgical cases of invasive breast cancer in female
patients at a Japanese cancer center were enrolled in the study.
• During 5264 person-years of follow-up (average 4.5 years per subject),
133 subjects (12%) experienced recurrence.
Risk of Recurrence with consumption of
> 3 cups Green Tea/day
Patients
HR
95% Confidence Interval
All stages
0.69
0.47-1.00
Stage I
0.43
0.22 -0.84
Stage III and IV
No change
---
Inoue, et al, Cancer Lett, 2001 Jun 26;167(2):175-82.
55
Synergy
• Evidence suggests that the simultaneous administration of
multiple phytochemicals is more effective than each one
alone.
• Curcumin, Genistein, Indol-3-Carbinol, Spirulina platensis
combined with Selenium, Resveratrol and Quercetin
• The combination, in physiologically relevant levels, resulted in
a significant decrease in cellular proliferation, an increase in
apoptosis, decreased migratory and invasive capacity of MCF7
ER+ breast cancer cells.
– The proliferation decreased 8-fold by day 6; an effect not observed
with any of the compounds used singly.
– Also the expression of mutated p53 decreased in metastatic breast
cancer cell lines
Ouhtit A. et al. J Cancer. 2013;4(9):703-15
56
Flavonoids and IL-6 (mBrCA)
• Tissue-specific fibroblasts and the factors they produce can
promote breast cancer disease progression.
• There is a direct correlation between the ability of breast, lung,
and bone fibroblasts to enhance ERalpha-positive breast cancer
cell growth by increasing their production of soluble interleukin-6
(IL-6).
• Epigallocatechin-3-gallate (EGCG), luteolin, apigenin inhibit IL-6
production in fibroblasts.
– Good dietary sources of luteolin and apigenin include: celery hearts,
hot peppers, rutabagas, spinach, fennel, parsley, chives, peppermint,
thyme
Studebaker AW, et al. Cancer Res. 2008 Nov;68(2):9087-95.
Ahmed S, et al. Proc Natl Acad Sci U S A. 2008 Sep;105(38):14693-7.
Hou RR, et al. Cell Biol Int. 2008 Jan;32(1):22-30.
Choi EM, Pharmazie. 2007 Mar;62(3):216-20.
57
Studebaker, et al. Cancer Res 2008; 68: (21). November 1, 2008
58
Lowering IL-6: Immune shift
• IL 6, also known as B cell stimulatory factor-2 (BSF-2), is a
terminal differentiation factor for B cells that is produced by
peripheral blood mononuclear cells (PBMC) - monocytes and
lymphocytes - as part of Th2 immune activation.
• Shifting immune activity away from Th2 and towards Th1 will
decrease PBMC production of IL-6.
• Increase Th1 with:
–
–
–
–
Coriolus (Trametes) versicolor
Ganoderma lucidum (maitake)
Agaricus blazeii
Thymic extracts
59
Melatonin
• Endogenous hormone
• Also present in fruits, vegetables
and botanical extracts
• Melatonin is an indoleamine (N-acetyl-5methoxytryptamine)
▫ Derived from tryptophan  serotonin  melatonin
• Bioavailability varies from 10%- 56% (variation due to
hepatic first pass)
• Normal peak nocturnal concentrations in humans are
60-80 pg/mL; average nocturnal concentration = 1840pg/mL; ½ life is 30-47 minutes
• This same concentration can be achieved with the
ingestion of 300 mcg of exogenous melatonin
Di WL, et al. NEJM, 1997 Apr;336(14):1028-9
Dollins AB, et al. Proc Natl Acad Sci, USA, 1994 Mar;91(5):1824-8
60
61
Melatonin: physiological functions
• Circadian rhythm monitor
• Free radical scavenger and antioxidant
• Cytoprotective (via free radical scavenging and regulation
of GABA  decreased neuroexcitation
• Immunomodulator (increases Tcell activity and interferon
gamma, IL- 1, 2, 6, 12 production
• Decreases estrogen production
• Oncostatic (decreases linoleic acid uptake, inhibits
telomerase, decreases angiogenic endothelin-1, increases
p53 expression)
• Thermoregulator
Ravindra T, et al. Ind J Med Sci, 2006 Dec;60(12):523-35.
62
Melatonin
• At nocturnal levels, melatonin inhibits cell
proliferation by delaying cells in G1 phase of
cell division
• At pharmacological levels, melatonin:
▫ Exerts cytotoxic effects on cancer cells by stimulating
apoptosis
▫ Alters adhesion molecule expression thus reducing
invasiveness
▫ Regulates ER expression
▫ Influences kinase pathways
Blask, et al. Endocrine. 2005 Jul;27(2):179-88.
63
Melatonin
•
•
•
•
Over 1534 scientific publications on melatonin and cancer
Over 88 human clinical trials on melatonin in cancer
41 Randomized Clinical Trials
In a meta analysis of 8 RCT’s in solid tumor cancers (n=761), 20mg of
melatonin po nightly in conjunction with chemo or radiation.
• Melatonin significantly improved the complete and partial remission (16.5%
vs. 32.6%; RR = 1.95, 95% CI, 1.49-2.54; P < 0.00001)
• Melatonin improved 1-year survival rate over control (52.2% vs. 28.4%; RR =
1.90; 95% CI, 1.28-2.83; P = 0.001)
• Melatonin significantly decreased radiochemotherapy-related side effects
including:
o
o
o
thrombocytopenia (19.7 vs. 2.2%; RR = 0.13; 95% CI, 0.06-0.28; P < 0.00001)
neurotoxicity (15.2 vs. 2.5%; RR = 0.19; 95% CI, 0.09-0.40; P < 0.0001)
fatigue (49.1 vs. 17.2%; RR = 0.37; 95% CI, 0.28-0.48; P < 0.00001).
• Effects were consistent across different types of cancer. No severe adverse
events were reported.
Wang et al. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20.
64
Melatonin levels in Women with ER+
Breast Cancer
• Plasma melatonin concentrations were determined over a period of
24 hours in 20 women with clinical stage I or II breast cancer.
• In 50% (ten) of the patients, whose tumors were estrogen receptor
positive, the nocturnal increase in plasma melatonin was much
lower than that observed in eight control subjects.
• Women with the lowest peak concentration of melatonin had
tumors with the highest concentrations of estrogen receptors.
• This data suggests that low nocturnal melatonin concentrations
may indicate the presence of estrogen receptor positive breast
cancer and could conceivably have etiologic significance.
Tamarkin, Science, 1982. May 28;216(4549):1003-5.
65
Melatonin and Breast Cancer
14 patients with metastatic breast cancer:
3 were non-responders to TMX
11 progressed after initial disease stabilization with TMX
Patients received TMX 20mg/d +
MLT 20mg QHS [mean duration of treatment = 8 mo.]
Partial response in 4/14 patients (28.5%)
IGF-1 decreased in
responders
Lissoni P, et al. Br J Cancer, 1995 Apr;71(4):854-6.
66
Melatonin and ER+ tumors
• Melatonin inhibits cyp19 Aromatase and NADPH-cyp
reductase which catalyze androgens to estrogens
• Aromatase activity is higher in breast tumor tissue than in
healthy breast tissue
• Melatonin demonstrates significant aromatase inhibition in
MCF-7 human breast cancer cells
▫ Melatonin inhibits aromatase mRNA expression
• Inhibition was observed using 1nM of melatonin – equivalent
to nocturnal levels of melatonin
Cos S, et al. J Pineal Res, 2005 Mar;38(2):136-42.
Melatonin and ER+ cancers
67
1. Dowregulates gonadal
Estrogen synthesis
2. Decreases ERα expression
And inhibits E2-ER complex
Binding to ERE in DNA = SERM
3. SEEM (selective estrogen
Enzyme modulator): decreases
Aromatase activity
Sanchez-Barcelo EJ, et al. J Pineal Res, 2005 May;38(4):217-22.
68
Melatonin (MLT) and cytokines
CD4
exogenous
MLT
IL-2
IL-12
People with cancer
Have  Th2:Th1 ratio
Th1
MLT
Th2
+
MLT
IFNγ
NK cell
Tumor
destruction
Tcell
MLT
TNFα
X
MLT
Cachexia
IL-2
Carrillo-Vico A, et al, FASEB J, 2004 Mar;18(3):537-9
Giannoulia-Karantana A, et al, NeuroImmunoModulation, 2006;13(3):133-44
69
Mushrooms as immunomodulators: Trametes
versicolor or Coriolus versicolor
Background
Polysaccharide peptides extracted from the medicinal
mushroom Trametes versicolor (PSK Krestin ) have
been shown to improve disease free survival in31
randomized clinical trials conducted in Japan,
Korea and China.
TM
PSK (KrestinT M) was approved in 1977 as a cancer therapy
by the Japanese National Health Registry and represents25% of the
total national costs of cancer care in Japan.
Hobbs, International Journal of Medicinal Mushrooms, 2004 as cited in
Standish et al, Botanicals Integrative Oncology, 2008
70
Trametes versicolor
71
PSK and Breast Cancer: clinical data
• RCT of 914 women with breast cancer receiving Tamoxifen
as an addition to the then-conventional chemotherapy.
• Randomized subgroups received PSK immune therapy
(3000 mg/day for 24 months) in addition to
chemotherapy.
• PSK significantly extended survival in ER-negative, stage
IIA patients without lymph node involvement.
• A five-year, post-operative, RCT comparing chemotherapy to
PSK immune therapy in 376 women with stage II ER negative
breast cancer.
• The 5-year overall and relapse-free survival rate for ER
negative receptor patients was the same regardless of
whether they had received chemotherapy alone (a prodrug of 5-fluorouracil) or PSK (3000 mg/day) alone.
Toi M, et al. Cancer, 1992 Nov;70(10):2475-83
Morimoto T, et al. Eur J Cancer,1996 Feb;32A(2):235-42
72
PSK and breast cancer: clinical data
• RCT conducted in Japan evaluated the efficacy of PSK as an
adjunctive immune therapy to combination chemotherapy in
227 operable breast cancer patients with vascular invasion in
the tumor and/or metastatic lymph node involvement.
• Patients were randomized to receive chemotherapy of 5fluoruracil, cyclophosphamide, mitomycin C and prednisolone
(FEMP) alone, FEMP + levasimole, or FEMP + PSK.
• PSK was orally administered at 3000 mg/day for 28 days.
• The five and ten-year survival curves for the FEMP + PSK group
was superior to either FEMP alone or FEMP + levamisole.
Iino Y, et al. AntiCancer Res, 1995 Nov-Dec;15(6B):2907-11
73
Fermented Wheat Germ Extract (2,6-DMBQ)
74
EFFECT OF AVEMAR ON ESTROGEN RECEPTOR POSITIVE AND NEGATIVE TUMOR
IN XENOGRAFT MODEL
MDA-MB-231 (ER-)
T-47/D (ER+)
4,5
p<0,01
4
Tumor volume (cm3)
3,5
3
2,5
p<0,005
2
1,5
1
0,5
0
kontroll
Control
Avemar 3 g/kg
Kontroll
Control
Értékelés
tumorafter
transzplantálás
utáni 48 napon
Evaluation
48adays
tumor transplantation
Avemar 3 g/kg
3. ábra
75
Influence of FWGE on the tumor
inhibitory effect of Tamoxifen and Aromatase inhibitor
compounds
tumor volume
(cm )3
7
Evaluation : 25 th days after tumor transplantation
6
5
4
3
2
1
100%
50%
66%
59,2%
70,7%
Avemar
Anastrozol
60,5%
53,5%
39,6%
0
Control
Avemar
Tamoxifen
+
Tamoxifen
Avemar Exemestane
+
Anastrozol
Avemar
+
Exemestane
Marcsek Z, et al. Cancer Biother Radiopharm. 2004 Dec;19(6):746-53
76
FWGE: Quality of Life
• Endpoints: chemotherapy side effects + body mass
• 39 patients; average length of AVEMAR therapy:
19.3 months
• Results
– Side effects of chemotherapy:
• 38.5% no changes;
• 25.6% improved;
• 35.9% completely disappeared
– Body mass:
• average increase = 7.4% (p < 0.001)
Unpublished study by Szeged, et al. 2008
77
QOL2: Breast Cancer
• Endpoint: quality of life (EORTC QLQ-C30 questionnaire)
• 55 patients; average length of AVEMAR therapy:
32.2 mos.
• Results:
– Improvement in functional scales:
• physical functions (p < 0.05)
• emotional functions (p < 0.001)
• global state of health (p < 0.01)
– Improvement of symptomatic scales:
•
•
•
•
fatigue (p < 0.01)
nausea and vomiting (p < 0.01)
insomnia (p < 0.01)
constipation (p < 0.01)
78
Actea racemosa (Black cohosh)
formerly Cimicifuga racemosa
• Blk cohosh extracts induce cell cycle
arrest at G1.
• Cyclin D1 promotes transition from G1
to S and is overexpressed in 50%-60%
of primary human breast carcinomas.
• Blk. cohosh, actein in particular,
decreases cyclin D1.
• This growth inhibition was
demonstrated with alcoholic extract of
Blk. cohosh for both ER+ and ER- cells.
• Effect in humans and required dose is
unknown.
LN Alschuler, 2009
Einbond LS, et al.Breast Cancer Res Treat, 2004Feb;83(3):221-31
80
Black cohosh: safety in breast cancer patients
• Meta-analysis
• Ability of black cohosh to relieve menopausal symptoms is
inconclusive
• Antiproliferative action demonstrated, particularly in breast and
prostate cancers.
– This is not, however, due to a phytoestrogenic effect as black
cohosh lacks estrogenic activity
– Due, instead to pro-apoptotic mechanisms
• Safety profile is good
– Isolated reports of liver toxicity are likely due to Chinese sourced
Actea products; products also potentially contaminated with trace
pharmaceuticals or pesticides
• Conclusion: black cohosh is safe in women with breast cancer and, in
fact, exerts protective and anti-proliferative effects through nonhormonal mechanisms.
Walji R, et al. Support Cancer Care, 2007 Aug;15(8):913-21
81
Black cohosh: clinical data
• Population based control study with 949 breast
cancer patients and 1524 controls from Philadelphia
metropolitan area
• Assessed use of Hormone Related supplements and
association with breast cancer
• Use of black cohosh has a significant cancer
protective effect (adjusted odds ratio 0.39, 95% CI
0.22-0.70).
Rebbeck TR, et al. Int J Cancer, 2007 Apr;120(7):1523-8.
82
Black cohosh: clinical data
• Investigation of the effect of isopropanolic extract on disease
free survival (including ER+) after a diagnosis of breast
cancer
• Observational retrospective cohort study
• 18,861 subjects observed for an average of 3.6 years
• After two years from diagnosis, 14% of control group
developed recurrence
• The black cohosh group took 6.5 years to reach 14%
recurrence
• After controlling for age, tamoxifen use and other
confounders, black cohosh use demonstrated a protective
effect on the rate of recurrence (hazard ratio 0.83, 95% CI
0.69-.099)
Henneicke-von Zepelin HH, et al. Int J Clin Pharmacol Ther. 2007 Mar;45(3):143-54.
83
Black cohosh: clinical data
Zepelin, et al. Int J Clin Pharm Therapeut, 2007
84
Black cohosh: clinical data
Zepelin, et al. Int J Clin Pharm Therapeut, 2007
85
Black cohosh dosing
• Isopropanolic standardized extract: standardized to 1
mg triterpene glycosides
• 20mg – 40mg+ (?) daily
86
Wellness in Breast Cancer
Stage
5-year Relative
Survival Rate
0
100%
I
100%
IIA
92%
IIB
81%
IIIA
67%
IIIB
54%
IV
20%
Source: American Cancer Society
• Breast cancer can be
a door to greater
health, and lifeaffirming well-being.
87
To me, survivorship is very much an
attitude; it’s a state of mind. How we
interpret the experience of cancer and
integrate it into our lives is fundamental to
how we coexist with it. I have learned that
hope is forever changing, and healing can
come without curing.
~ Selma Schimmel, breast cancer
survivor
[Julie Silver, What Helped Get Me Through: Cancer Survivors Share
Wisdom and Hope]
Tests referenced
•
•
•
•
•
•
•
CV Health/ Cardiovascular Health Profile
MetSyn Guide
Adrenocortex Stress Profile
EstroGenomic Profile
Vitamin D
Comprehensive Thyroid Assessment
Toxic Effects CORE
Q & A Session
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Integrative Strategies for Supporting
Patients Diagnosed with Breast Cancer:
Part 1
Lise Alschuler, ND, FABNO
Genova Diagnostics LiveGDX
May 28, 2014