|
Issues
in Prevention and Risk Reduction
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Hormone Replacement
Therapy/Hormone Therapy:
Risk factors for breast cancer such as age at menarche,
first birth, and menopause strongly suggest hormonal
influences for the development of breast cancer, and
it is known that both estrogen and progestin can induce
growth and proliferation of breast cells (women with
breast cancer tend to have higher endogenous circulating
levels of estrogen and androgens).
Combination hormone replacement therapy, (hereafter,
HRT, estrogen-progestin, and hormone therapy (HT)
will be used interchangeably unless finer distinction
is called for) has been shown to be associated with
an increased risk of breast cancer development. Numerous
studies have found higher levels of endogenous estrogen
and androgen levels in women who develop breast cancer
than in those who do not (see the Endogenous Hormones
and Breast Cancer Collaborative Group in J Natl Cancer
Inst: Endogenous
Sex Hormones and Breast Cancer in Postmenopausal Women:
Reanalysis of Nine Prospective Studies.
The WHI (Women’s Health Initiative), an randomized
controlled trial (RCT) which examined the impact of
HRT and dietary interventions on women’s health, terminated
early one arm of the study, that investigating the
effect of combination estrogen/progestin therapy on
health risks (Writing Group for the Women's Health
Initiative Investigators in JAMA: Risks
and Benefits of Estrogen Plus Progestin in Healthy
Postmenopausal Women),
due to the fact that the trial showed an excess risk
of invasive breast cancer, but not in situ breast
cancer, associated with combination therapy compared
with placebo, and within 1 year on the trial, women
on HRT evidenced a higher percentage of abnormal mammograms,
persisting throughout the trial. In addition, later
applications, with which Evidencewatch concurs, have
weighed all findings and in the light of potential
benefits and countervailing adverse effects, concluded
that "the risk of breast cancer outweighs the
benefits of osteoporosis prevention from HRT"
(Deady in J Manag Care Pharm (2004): Clinical
Monograph: Hormone Replacement Therapy
[pdf]).
The trial, and subsequent confirming studies, demonstrated
in addition the adverse effects of hormone therapy
on atherosclerotic and thrombotic cerebrovascular
effects. Later studies have further shown, settling
uncertainty, an adverse effect on cognition in women
65 and older using HRT (Espeland et al. in JAMA: Conjugated
Equine Estrogens and Global Cognitive Function in
Postmenopausal Women
and Shumaker et al. in JAMA: Conjugated
Equine Estrogens and Incidence of Probable Dementia
and Mild Cognitive Impairment in Postmenopausal Women),
in contrast to a number of earlier observational studies
which suggested a putatively protective role for exogenous
estrogen in cognitive function in postmenopausal women.
Note, however, that the evidence of an association
between estrogen-only therapy and incidence of breast
cancer is not determinative: some observational data
suggest a small increase of risk, but the only completed
RCT (randomized controlled trial) to date actually
(and surprisingly) suggests a decreased risk of breast
cancer.
In conclusion, it is important to articulate and exploit
methods known to decrease endogenous estrogen:
(1) maintenance of ideal body weight (see section
on obesity, below),
(2) adoption of a low-fat diet in postmenopausal women
(see Prentice et al. in J Natl Cancer Inst:
Dietary fat reduction and plasma estradiol concentration
in healthy postmenopausal women. The Women's Health
Trial Study Group)
, and
(3) moderate exercise in adolescent girls (see Morimoto
et al. in Cancer Causes Control: Obesity,
body size, and risk of postmenopausal breast cancer:
the Women's Health Initiative)).
It is to be hoped that such interventions will decrease
breast cancer risk, although further study is required
to conclude this definitively.
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Oral
Contraceptives:
Some studies suggest that oral contraceptives
are associated with a small increased risk of breast
cancer, although some controversy and uncertainty
continued in this arena. First, in 1996 the Collaborative
Group on Hormonal Factors in Breast Cancer reviewed
and reanalyzed the worldwide epidemiological evidence
(pooled analysis of more than 50 studies with more
than 150,000 patients) on the relation between breast
cancer risk and use of hormonal contraceptives (Collaborative
Group on Hormonal Factors in Breast Cancer, Lancet
(1996):
Breast cancer and hormonal
contraceptives: Collaborative reanalysis of individual
data on 53297 women with breast cancer and 100239
women without breast cancer from 54 epidemiological
studies), finding a slight increase
in the risk of breast cancer with previous oral contraceptive
use, with no evidence of an increase in the risk of
having breast cancer diagnosed 10 or more years after
cessation of use; we note that the included studies
were of variable methodological quality.
Against this, a later high-quality case-control study
and failed to find such an association between breast
cancer risk and oral contraceptive use (Marchbanks
et al. in N Engl J Med: Oral
Contraceptives and the Risk of Breast Cancer;
see also Farquhar's commentary on this study in CMAJ:
Oral
Contraceptives and the Risk of Breast Cancer),
even when taken for in excess of 25 years. Furthermore,
the estrogen-only WHI study found an almost statistically
significant reduction in breast cancer incidence in
the estrogen-only arm (compared with placebo), although
such an effect is possible to have come about by chance.
However, recently Milne et al. (Cancer Epidemiol Biomarkers
Prev (2005): Oral
Contraceptive Use and Risk of Early-Onset Breast Cancer
in Carriers and Noncarriers of BRCA1 and BRCA2 Mutations)
examined the narrow question of whether oral contraceptive
use is associated with increased risk for women with
germ line mutations in BRCA1 or BRCA2, finding no
evidence that use of current low-dose oral contraceptive
formulations increases risk of early-onset breast
cancer for either type of mutation carrier, and that
furthermore there may actually be a reduced
risk for BRCA1 mutation carriers (in the case of OC
use for at least 12 months) was associated with decreased
breast cancer risk for BRCA1 mutation carriers ).
They conclude from this that given that current OC
formulations may reduce, or at least not exacerbate,
ovarian cancer risk for mutation carriers, OCs should
not be contraindicated for women with a germ line
mutation in BRCA1 or BRCA2.
Finally, Dumeaux et al. (Cancer Epidemiol Biomarkers
Prev (2004): Use
of Oral Contraceptives, Alcohol, and Risk for Invasive
Breast Cancer) have recently helped
to untangle a complex interaction, namely that between
breast cancer risk on the one hand and OC use and
alcohol consumption, either jointly or singly. They
found (1) that long-term users of OCs (10 years)
who consumed 10.0 g/daily or more of alcohol had almost
a two-fold increase in breast cancer risk compared
with nonconsumers of alcohol who never used OCs; (2)
the increased risk was roughly the same when nondrinkers
used OCs during a long time or when nonusers of OCs
drank 10.0 g/daily or more of alcohol; (3) among women
consuming less than 5.0 g/daily of alcohol, the risk
of breast cancer increased significantly with the
total duration of OC use or with the estrogen dose
from OCs; (4) in contrast, among women consuming 5.0
g/daily or more of alcohol, duration of OC use and
estrogen dose from OCs did not add any excess risk
of breast cancer compared with women consuming the
same amount of alcohol and who never used OCs; (5)
a negative interaction between alcohol and duration
of OC use (or estrogen dose from OCs) was observed;
and (6) the association between high alcohol intake
and breast cancer was more prominent among postmenopausal
women than among premenopausal women, with no significant
interaction between alcohol and duration of OC use
was observed after stratification on menopausal status.
This suggest strongly that alcohol and OCs have antagonistic
effects on breast cancer risk through a common pathway.
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A
Critique of the Kahlenborn / Mayo OC Study
Recently there appeared a widely-cited study of Kahlenborn
et al. (Kahlenborn et al., Mayo Clin Proc (2006):
Oral
Contraceptive Use as a Risk Factor for Premenopausal
Breast Cancer: A Meta-analysis [pdf])
on OC (oral contraceptive) use and breast cancer risk.
The principle author is Chris Kahlenborn, who is
a former US Congressman and physician, the author
of Breast cancer: its link to abortion and the
birth control pill (2000) in which the author
acknowledges that he is an opponent of all forms of
artificial contraception (on the author's political
and ideological stance in this arena, see Patricia
Jasen's
Breast Cancer and the Politics of Abortion in the
United States; in addition, C Kahlenborn
is on the advisory board of the national (self-acknowledged)
right-wing Christian organization Concerned Women
for America which defines itself as anti-gay, anti-choice,
anti-feminism and anti-sex education, and actively
lobbies for legislation recognizing the abortion-breast
cancer link. Despite the clear potential for significant
bias consequent to all this, no conflict of interest
in declared either in the article itself, nor on the
associated Mayo site.
Some Confounding Factors:
-
Changing
patterns of contraceptive use in the population
(larger numbers of younger women are OC users,
with usage of increasing duration),
-
the newly
introduced use of low-dose and ultra-low-dose
formulations delivering dramatically lower estrogen
dose levels,
-
along
with new progestin agents such desogestrel (Marvelon
/ Mercilon / Mircette / Apri / Desogen / Ortho-Cept
/ Cyclessa) and norgestimate (Ortho-Prefest, often
along with shorter hormone-free intervals,
-
the epidemiology
of breast cancer, with associated steady increase
in the incidence of breast cancer,
-
the studies
meta-analysis of 39 independent case-control studies
failed to even attempt to explain for the significant
heterogeneity across the individual studies;
All of which
may entail divergent results in future cohort studies
(thus, AA Kubba's comprehensive review (J R Soc Med
(2003):
Breast cancer and the pill), among
many others, and which includes the results of the
Oxford Collaborative Group Study, concluded that although
OCs may have some small potential to promote the growth
of preexisting tumors in some women (and note that
the cancers diagnosed in women who had used combined
oral contraceptives were less advanced clinically
than those diagnosed in women who had never used these
contraceptives for ever-users compared with never-users),
"It does not increase the lifetime risk of breast
cancer. Women over 35, whether current or past users,
do not show an increased incidence. In women in their
20s the absolute risk of breast cancer is very low,
and any excess attributable to the pill is small (around
1 in 10 000)".
Absolute Risk
-
Although
OCs may be carcinogenic, the relative risk is small,
and the absolute risk, meaning the excess breast
cancers due to OC exposure, is barely perceptible:
the most comprehensive relevant data from the pooled
analysis (from the Oxford Collaborative Group) estimates
that the excess number of cases of breast cancer
expected up to 10 years after discontinuation of
OC use among a population of 10,000 is:
-
a half a
case (0.5 cases) for OC use from age 16 to 19 years,
-
1.5 cases
for OC use from age 20 to 24 years, and
-
4.7 cases
for OC use from 25 to 29 years, and
-
with increasing
duration, risk becomes insignificant (there was
no significant excess risk of having breast cancer
diagnosed 10 or more years after stopping use -
there was no excess risk in women aged over 45
as found by
the Collaborative Group on Hormonal Factors in Breast
Cancer (Oxford Collaborative Study Group), Lancet (1997):
Breast cancer and hormone replacement therapy: collaborative
reanalysis of data from 51 epidemiological studies of
52,705 women with breast cancer and 108,411 women without
breast cancer. Collaborative Group on Hormonal Factors
in Breast Cancer); such risk is dwarfed,
for instance, by the much larger risks associated with
even modest social alcohol consumption.
Risk-Benefit
Ratio
-
Furthermore,
a risk-benefit analysis must be weighed in any such
considerations: so for instance, the IARC (IARC
Monographs on the Evaluation of Carcinogenic Risks
to Humans. Vol 72 (1999):
Hormonal Contraception and Post-menopausal Hormonal
Therapy [pdf]) concluded that there
is convincing evidence that OCs decrease the risk
of both ovarian and endometrial cancer (see also
the confirming findings of Medard Lech and Lucyna
Ostrowska's recent review (Lech & Ostrowska, Eur
J Contracept Reprod Health Care (2006):
Risk of cancer development in relation to oral contraception),
where it was concluded that "The risk of developing
ovarian cancer in women using COCs is at least 40%
smaller than in other women; the degree of protection
given by COCs is directly proportional to the duration
of use of this form of contraception. Reliable scientific
data prove convincingly that the risk of endometrial
cancer is smaller in women who used COCs than in
women who never took them".
-
there is
accumulating evidence that they may lower the risk
of colorectal cancer.
-
Noncontraceptive
health benefits associated with OCs:
(see IARC review, cited above), including:
-
relief
from menstrual disorders;
-
reduced
risk of:
-
pelvic
inflammatory disease,
-
benign
breast disease,
-
uterine
leiomyomas, and
-
ovarian
cysts; and
-
improved
bone mineral density/BMD (see the recent systematic
review of Lee & Lebrun, Br J Sports Med (2006):
Effect of oral contraceptives and hormone replacement
therapy on bone mineral density in premenopausal
and perimenopausal women: a systematic review).
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Progesterone
Cream:
As progesterone can be absorbed through the skin,
progesterone creams have common into increasing use,
especially in the OTC (over-the-counter) marketplace,
primarily for treatment of menopausal vasomotor symptoms,
osteoporosis and for skin antiaging and skin-firming
treatment. [Note: a widely promoted OTC product, Mexican
yam, although claimed to either contain progesterone,
or to be convertible into progesterone via one of
its constituents, diosgenin, actually contains no
progesterone whatever, and diosgenin conversion into
progesterone can only be effected industrially, but
by any body-intrinsic mechanisms.] Its efficacy in
these conditions has to date not been convincingly
well established by consistent and methodologically
sound evidence, but the primary issue under focus
here is its safety in oncologic settings, especially
problematic given its well-known highly unpredictable
dermal absorption.
In this context, Hermann et al. (J Clin Pharmacol
(2005): Over-the-Counter
Progesterone Cream Produces Significant Drug Exposure
Compared to a Food and Drug Administration–Approved
Oral Progesterone Product) compared
200-mg oral progesterone (once daily) with a 40 mg
OTC progesterone cream (twice daily), both given for
12 days, finding that the progesterone cream delivered
a measured dose-normalized 24-hour progesterone exposure
equivalent to the powerful oral preparation (a finding
prompting the authors to question whether topical
progesterone products should be available OTC). At
these levels, therefore, it is not impossible that
even if it promoted an anti-proliferative on uterine/
endometrial tissue, it could like progesterone deployed
in HRT regimens exert a proliferative effect on breast
tissue.
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Alcohol:
Alcohol, currently listed as a known human carcinogen
by several agencies - IARC (International Agency for
Research on Cancer) and the US National Toxicology
Program, among others - is a known risk factor for
several cancers, including those of the mouth, larynx,
esophagus and liver; it has been conjectured that
the mechanism for causing cancer may be through alcohol's
alteration of estrogen levels (themselves known to
be associated with breast cancer risk), and/or its
interference with DNA repair, and as B Macmahon has
observed (Int J Cancer (2005): Epidemiology
and the causes of breast cancer), the
three known causes of human breast cancer
are (1) ionizing radiation, (2) exogenous ovarian
hormones, and (3) beverage alcohol consumption. And
Kroman et al. (Ugeskr Laeger (2005): Is
the rising incidence of breast cancer a consequence
of lifestyle? [in Danish])
that the observed increase in the incidence of breast
cancer is attributable in terms of modifiable lifestyle
factors primarily to obesity and alcohol use.
Many epidemiological studies have shown an increased
risk of breast cancer associated with alcohol consumption.
Individual data from 53 case-control and cohort studies
were included in a British meta-analysis (Hamajima
et al. in Br J Cancer: Alcohol,
tobacco and breast cancer — collaborative reanalysis
of individual data from 53 epidemiological studies,
including 58,515 women with breast cancer and 95,067
women without the disease. Collaborative Group on
Hormonal Factors in Breast Cancer)
which found alcohol to be an independent risk factor
for breast cancer. There was a 7% increase in risk
with each 10 g (about 1 drink) of alcohol per day
and this finding argues against the previous conception
of a threshold effect for alcohol. This translates
to the outcome that consumption of 15 g/day of alcohol
raised breast cancer risk by 2.5-fold so that women
who average 1.5 drinks per day have a 30% increase
in risk. Given that alcohol consumption is one of
rare known risk factors for breast cancer that is
a potentially modifiable behavior, it would be prudent
for women in general, and certainly for any woman
at especial risk, to refrain from regular alcohol
consumption (in agreement, see the conclusions of
Kristan Aronson at Queens University, Ontario in her
thoughtful commentary (CMAJ: Alcohol:
a recently identified risk factor for breast cancer)).
These findings are further validated by the NIAAA
State of the Science Report (National Institute on
Alcohol Abuse and Alcoholism (12/19/2003): State
Of The Science Report On The Effects Of Moderate Drinking)
which found that women with
a family history of breast cancer are as a group at
substantially increased risk even at low doses of
alcohol consumption which found that, compared
with nondrinkers, women who
consume an average of 1 drink per day appear to have
a 10% increase in breast cancer risk. See
the confirmative findings on this by Vachon et al.
(Cancer (2001): Investigation
of an interaction of alcohol intake and family history
on breast cancer risk in the Minnesota Breast Cancer
Family Study)
who found a risk ratio of 2.45 in daily drinkers who
were first-degree relatives of breast cancer probands,
as compared with never-drinkers (risk for second degree
relatives was not significant, and there was no association
for women who were not biologically related); see
also Go et al. (J Nutr (2004): Diet
and cancer prevention: evidence-based medicine to
genomic medicine).
Suzuki et al. (J Natl Cancer Inst (2005): Alcohol
and Postmenopausal Breast Cancer Risk Defined by Estrogen
and Progesterone Receptor Status: A Prospective Cohort
Study) have valuably clarified the
association of alcohol with the estrogen receptor
(ER) and progesterone receptor (PR) status of the
breast tumors, finding that alcohol consumption was
associated with an increased risk for the development
of ER-positive tumors, irrespective of PR status,
a serious negative impact given that because the majority
of breast tumors among postmenopausal women overexpress
ER. Even more importantly perhaps is their secondary
finding of a statistically significant interaction
between alcohol intake and the use of postmenopausal
hormones on the risk for ER+PR+ tumors.
And although
some evidence exists for a potential cardiovascular
benefit for modest alcohol consumption (as wine),
note that (1) for most women it would prove easier
and probably more desirable to achieve a comparable
cardiovascular benefit through other techniques (for
example, diet, supplements, exercise) than to attempt
to gain a proportionate reduction in risk of breast
cancer, (2) most women probably find the prospect
of breast cancer more viscerally intimidating than
that of cardiovascular disease, regardless of mortality
statistics, and (3) it is not at all clear whether
drinking's potential cardiovascular benefit is due
to resveratrol and polyphenol components, independent
of the alcohol content itself, in which case separate
supplementation minus the alcoholic content may again
be more prudent. (See the recent study of Irene Mattison
and her colleagues at Lund University, Sweden (Int
J Cancer: High
fat and alcohol intakes are risk factors of postmenopausal
breast cancer: a prospective study from the Malmo
diet and cancer cohort)
which concluded that "high wine intake was associated
with a significantly elevated breast cancer risk".
Finally, on a positive note, there is some evidence
that alcohol and folate consumption interact to affect
risk, with differences in associations for those with
or without p53 mutations, and that causal pathways
may vary for pre- and postmenopausal women (Freudenheim,
Carcinogenesis: Diet
and alcohol consumption in relation to p53 mutations
in breast tumors).
And adequate folate supplementation may protect against
alcohol related increased risk of breast cancer, as
found in the prospective cohort study (population
of 17,000 Australian women over 10 years) of Baglietto
and colleagues ((BMJ (2005): Does
dietary folate intake modify effect of alcohol consumption
on breast cancer risk? Prospective cohort study).
They found that women who regularly consumed more
than 40 g (5 units) a day of alcohol had a 40% greater
risk of invasive breast cancer than lifetime abstainers,
but that a daily folate intake of 400 µg (micrograms)
in this drinking group was however associated with
a significant reduction in risk, when compared with
a lower daily intake of 200 µg. This is an important
preventive message, as it demonstrates that the known
adverse effect of alcohol consumption may be reduced
by sufficient dietary intake of folate.
Furthermore, the findings of Tjonneland et al. (Eur
J Clin Nutr (2005): Folate
intake, alcohol and risk of breast cancer among postmenopausal
women in Denmark) also support the
evidence that adequate folate intake may attenuate
the risk of breast cancer associated with high alcohol
intake, and confirming the conclusion from other studies
that alcohol intake and risk of breast cancer are
associated mainly among women with low folate intake;
they note that among women with a folate intake higher
than 350 micrograms, there was no association between
the alcohol intake and the breast cancer incidence.
Some genotype influence does appear to play a role:
individuals differ in their ability to metabolize
alcohol, through genetic differences in the enzyme,
alcohol dehydrogenase (ADH), that catalyzes the oxidation
of about 80% of ethanol to acetaldehyde, which is
a known carcinogen; there is individual variation
in the ADH genotype, with one locus, ADH3, being polymorphic
in Caucasians The question whether fast metabolizers
of alcohol, as measured by the a refined measure of
the ADH3 genotype, have a higher risk of breast cancer
from alcohol intake compared to those individuals
who are slow metabolizers, but consume comparable
amounts of alcohol, and Terry et al. (Carcinogenesis
(2005): ADH3
genotype, alcohol intake, and breast cancer risk)
evaluated just this scenario, finding that fast metabolizers
of alcohol have a higher risk of breast cancer risk,
especially premenopausally, from alcohol intake than
slow metabolizers.
[new] Alcohol,
Breast Cancer and Hormone-Responsiveness
It appears on the balance of the evidence that the
association of alcohol consumption and breast cancer
risk is primarily if not exclusively in hormone-responsive
populations: Huiyan Ma at the USC/Norris Comprehensive
Cancer Center and coresearchers (Breast Cancer Res
(2006): Hormone-Related
Risk Factors for Breast Cancer in Women Under Age
50 Years by Estrogen and Progesterone Receptor Status:
Results From a Case-Control and a Case-Case Comparison)
found that the average number of alcoholic drinks
per week in the recent 5 years was positively associated
with ER+/PR+ breast cancer and weakly associated with
all types of cancer together but not associated with
ER-/PR- breast cancer.
[updated:
1/19/07] Update on the Status of Resveratrol
and Wine
Resveratrol, a non-flavonoid polyphenol, and a natural
constituent of both grapes and therefore wine, has
been studied as a potential anticancer agent in vitro
and in vivo. Yun Wang and coresearchers (Toxicol Sci
(2006): The
Red Wine Polyphenol Resveratrol Displays Bilevel Inhibition
on Aromatase in Breast Cancer Cells)
reasoned that given that the rate-limiting reaction
of estrogen biosynthesis is catalyzed by cytochrome
P450 CYP19 enzyme or aromatase, the polyphenolic compound
resveratrol, derived from grape peel, with known structural
resemblance to estrogen and demonstrated agonistic
and antagonistic properties on the estrogen receptor,
may exert aromatase-inhibitory effect on the expression
and enzyme activity of the aromatase enzyme, finding
that testosterone-induced cell proliferation of MCF-7
breast cancer cells was significantly reduced by a
pharmacological dose (10µM) of resveratrol,
while a higher 50µM dose significantly reduced
CYP19-encoding mRNA; thus pharmacological dose levels
of resveratrol can inhibit aromatase at both the enzyme
and mRNA levels.
Breast Cancer Prevention Watch
notes that other anticancer benefits of resveratrol
may be via indirect enhancement activity on other
agents. Thus J Wietzke and colleagues at the University
of Notre Dame (J. Steroid Biochem. Mol. Biol (2003):
Phytoestrogen
regulation of a vitamin D3 receptor promoter and 1.25-dihydroxyvitamin
D3 actions in human breast cancer cells)
have shown that resveratrol increases the effects
of vitamin D in breast tumor cells, and it also blocks
the growth-promoting effects of linoleic acid in the
Western diet, which converts to arachidonic acid (and
ultimately to proliferative factors such as prostaglandin
E2 and leukotriene B4) that promote inflammatory processes
stimulative of cancer cell growth (see Nakagawa et
al., J Cancer Res Clin Oncol (2001): Resveratrol
inhibits human breast cancer cell growth and may mitigate
the effect of linoleic acid, a potent breast cancer
cell stimulator
who demonstrated that resveratrol inhibited the breast
cancer cell growth and blocked linoleic acid's growth-promoting
activity).
In addition, Austrian researchers have shown that
resveratrol blocks the ability of cancer cells to
metastasize to bone, especially for breast, renal,
and pancreatic cancer (Ulsperber et al. Int J Oncol
(1999): Resveratrol
pretreatment desensitizes AHTO-7 human osteoblasts
to growth stimulation in response to carcinoma cell
supernatants)
Recently Swiss researchers Levi et al. (Eur J Cancer
Prev (2005): Resveratrol
and breast cancer risk) have examined
epidemiological data, analyzing the relation between
dietary resveratrol intake and breast cancer risk
using data from a case-control study (conducted between
1993 - 2003), finding a significant inverse association
for resveratrol from grapes, but not for wine. Given
what is already known about the hazards of alcohol
intake on breast cancer risk, this study suggests
that an overall positive benefit of resveratrol on
breast cancer risk reduction can be still be made
when that component is consumed through grapes directly,
and research is underway to examine whether a comparable
scenario exist vis a vis the cardiac benefits of resveratrol.
In addition, Masala et al. (Int J Cancer (2005): Dietary
and lifestyle determinants of mammographic breast
density. A longitudinal study in a Mediterranean population)
found a positive association between increasing consumption
of wine and high mammographic breast density, which
is known to be associated with increased breast cancer
risk, even after adjustment for established BC risk
factors. This has been cross-confirmed by Maskarinec
et al. (Int Journal Cancer (2005): Alcohol
consumption and mammographic density in a multiethnic
population) who found that alcohol
consumers had higher percent breast densities than
did abstainers.
[new:
1/19/07] Why
Wine is Irrelevant as a Source of Resveratrol
Finally, Breast Cancer Prevention
Watch noted that although it is often cited
that organic red wines from certain areas of Europe
contain the highest level of resveratrol, nonetheless
given standard pesticidal treatment of grapes and
other factors, most wines contain either no resveratrol
whsoever, or non-therapeutic trace amounts (usually
a few micrograms per glass). Thus, contrary to popular
opinion, although wine is a dietary source, the amounts
of resveratrol are both widely variant, and therapeutically
negligible (Pennington Biomedical Research Center,
Pennington Nutrition Series:
Resveratrol [pdf]), with an average
of 1.5 micrograms of resveratrol/ml, so that for a
full glass of wine - which is about 5 fluid ounces
(= 150 ml.), total resveratrol content would be 225
micrograms, or just above 2 tenths of one milligram,
and similarly for grapes and grape juice. But it appears
that pharmacological dose ranges between a minimum
of 10 mg. to about 32 mg. to 40 mg. at typical optimal
level, so to ingest just the lower range amount of
10 mg. would require approximately 50 glasses of wine
or an indigestible amount of grapes. Hence the only
feasible source for pharmaceutical / therapeutic levels
of resveratrol therefore is by standardized supplementation.
Breast Cancer
Watch Commentary:
The Facts on Alcohol and Breast Cancer Risk
(1)
Alcohol is incontrovertibly both a known
and recognized human carcinogen and a significant
breast cancer risk factor, with each 10 grams
= 1 drink consumption being associated with at least
7% - 10% increase in risk.
(2) There is no safe minimum consumption,
with each drink adding an additional 7% to 10%
risk increase linearly, and statements made
to the effect that increased risk begins only at 2
or more drinks daily are in error and wholly without
evidentiary support.
(3) A family history of breast cancer influences
further increases the risk factor above these levels:
in first-degree relatives of breast cancer
probands, there is a risk ratio of 2.45 in daily drinkers
as
compared with never-drinkers.
(4) Alcohol consumption is associated with an
increased risk for the development of ER-positive
tumors, irrespective of PR status, and there
is a statistically significant interaction between
alcohol intake and the use of postmenopausal hormones
on the risk for ER+ PR+ tumors.
(5) Resveratrol, a non-flavonoid polyphenol, and a
natural constituent of both grapes and therefore wine,
appears to be a potential anticancer agent. In terms
of dietary resveratrol intake and breast cancer risk,
there is a significant inverse association for resveratrol
from grapes, but not for wine.
(6) There is a positive association between
increasing consumption of wine and high mammographic
breast density, which is known to be associated
with increased breast cancer risk.
(7) A high daily folate intake may attenuate
the risk of breast cancer associated with high alcohol
intake, to the extent that folate intake
higher than 350 - 400 µg (micrograms),
but not lower, showed no association between
the alcohol intake and the breast cancer incidence.
Warning: However, at least one recent study
failed to support the hypothesis that high folate
intake reduces breast cancer risk; Stolzenberg-Solomon
et al. (Am J Clin Nutr (2006): Folate
intake, alcohol use, and postmenopausal breast cancer
risk in the Prostate, Lung, Colorectal, and Ovarian
Cancer Screening Trial)
instead found that a high intake may actually increase
the risk in postmenopausal women.
-
Pesticides
/ Environmental Toxins:
The role of pesticides and other environmental toxins
in the promotion of human breast carcinoma has not
been fully settled, however there is reasonable evidence
of probable role that dioxin, polycyclic
aromatic hydrocarbons (PAHs), the organochlorine pesticide
DDT, PCBs (polychlorinated biphenyls), and ethylene
oxide in the development of breast cancer (see the
latest Breast Cancer Fund report: State
of the Evidence 2006: What Is the Connection Between
the Environment and Breast Cancer?
[pdf].).
PCBs
With respect to PCBs. note that although the majority
of early reports did not find sufficient evidence
of a role of PCB exposure in breast cancer, these
studies failed to consider and control for individual
genetic susceptibility to PCB effects determined partially
by polymorphisms in the gene encoding the biotransformation
enzyme cytochrome CYP1A1: the seminal study of Francine
Laden at the Brigham and Women’s Hospital and
Harvard Medical School and her colleagues demonstrated
that PCBs and other xenobiotics can be metabolized
to carcinogenic intermediates in the presence of the
variant genotype, and although among postmenopausal
case-control pairs, there was no evidence of an association
of either the variant CYP1A1 genotype or exposure
to PCBs with breast cancer risk, nonetheless the risk
for women with high plasma PCB levels and at least
one variant (of the CYP1A1-exon 7 allele) was elevated,
and there is furthermore some suggestion that PCBs
may enhance the metabolism of PAHs, and finally high
levels of PCBs may yet be associated with breast cancer
risk in the subgroup of women who have the variant
CYP1A1-exon7 polymorphism (Laden et al., Cancer Epidemiol
Biomarkers Prev (2002): Polychlorinated
Biphenyls, Cytochrome P450 1A1, and Breast Cancer
Risk in the Nurses’ Health Study).
Furthermore, adipose PCB concentrations were significantly
associated with breast tumor recurrence, also affected
by smoking (as demonstrated by Joshua Muscat at the
Institute for Cancer Prevention and coresearchers,
Cancer Epidemiol Biomarkers Prev (2003): Adipose
Concentrations of Organochlorine Compounds and Breast
Cancer Recurrence in Long Island, New York).
However, in contrast to the Muscat data for New York,
Ole Raaschou-Nielsen with the Danish Cancer Society
/ Institute of Cancer Epidemiology failed to find
that higher organochlorine body levels increase the
risk of breast cancer in postmenopausal women (Cancer
Epidemiol Biomarkers Prfev (2005): Adipose
Organochlorine Concentrations and Risk of Breast Cancer
Among Postmenopausal Danish Women),
but we note that this study found an inverse association
between concentrations of some organochlorines and
the risk of breast cancer, most evident for estrogen
receptor-negative breast cancer, and the authors prudently
note that the interpretation of these results is currently
unclear and will require confirmation in further trials
(and Lindsey Mason and colleagues at the University
of Aberdeen found no consistent associations between
breast cancer and CYP1A1 polymorphisms (Am J Epidemiol
(2005): Cytochrome
P-450 1A1 Gene Polymorphisms and Risk of Breast Cancer:
A HuGE Review); see also the thoughtful
commentary of Peter Shield of the Lombardi Comprehensive
Cancer Center, Cancer Epidemiol Biomarkers prev (2006):
Understanding
Population and Individual Risk Assessment: The Case
of Polychlorinated Biphenyls).
PBDEs
Polybrominated diphenyl ethers (PBDEs) are a class
of brominated flame retardants (BFRs) with some structural
similarities to PCBs, and despite legislative curtailment
both here and in Europe, are environmental contaminants
still detected in soil, sediment, sludge, air, and
in fish, wildlife and other biota, including in human
tissues and fluids such as blood, breast milk, and
adipose tissue, with evidence of accumulation of specific
PBDEs in humans (as shown by Andreas Sjödin and
colleagues at the CDC in Environ Health Perspec (2004):
Retrospective Time-Trend
Study of Polybrominated Diphenyl Ether and Polybrominated
and Polychlorinated Biphenyl Levels in Human Serum
from the United States).
In the issue of the role of PBDEs in breast cancer
is a complicated one. Early studies suggested that
PCDEs were inductors of the p450 cytochrome CYP1A1
enzyme which, along with CYP1A2 and CYP2B2, is a carcinogen-activating
enzyme (metabolizing many of these chemicals into
mutagenic and toxic intermediates), with the induction
it was thought via the aryl hydrocarbon receptor (AhR),
which is a ligand-activated transcription factor,
regulating the transcription of diverse genes through
binding to the xenobiotic-responsive element (XRE).
AhR may be activated by a variety of environmental
contaminants including polycyclic aromatic hydrocarbons
(PAH), planar chlorinated biphenyls (PCB), and halogenated
aromatic hydrocarbons (HAH) such as TCDD (2, 3, 7,
8, -tetrachlorodibenzo-p-dioxin), dibenzofurans (PCDFs)
and dibenzo-p-dioxins (PCDDs), among other dioxin-like
contaminants, although it is now known that AhR plays
important roles in normal development and physiology,
including that of reproduction and growth, and cell
cycle, cell growth, cell differentiation, and apoptosis,
not just in toxicity, or the defense from toxicity,
of xenobiotic / environmental chemicals (see Nathalie
Tijet at the University of Toronto and her coresearchers,
Mol Pharmacol (2006): Aryl
Hydrocarbon Receptor Regulates Distinct Dioxin-Dependent
and Dioxin-Independent Gene Batteries,
and also the review of Paola Pocar of the Martin Luther
University Halle-Wittenberg and coresearchers, Reproduction
(2005):
Molecular interactions of
the aryl hydrocarbon receptor and its biological and
toxicological relevance for reproduction
of the molecular cross-talk of AhR across multiple
signal transduction pathways affecting female reproduction).
If correct, that these contaminant are CYP1A1-inductors
via AhR-mediated activity, these studies would have
direct relevance to breast cancer given the stipulated
role of AhR in mammary gland tumorigenesis (Jennifer
Schlezinger and colleagues at Boston University School
of Public Health, Biol Chem (2006): A
role for the aryl hydrocarbon receptor in mammary
gland tumorigenesis).
However, these earlier studies suggesting CYP1A1-induction
by PBDEs via AhR competitive binding appear now to
have been largely if not wholly an artifact of an
impurity effect of low-level contamination of these
tested compounds by PCDFs and PBDDs and possibly other
AhR-active CYP1A1 inducers, as first shown by Annelieke
Peters with the Institute for Risk Assessment Sciences
(IRAS) at Utrecht University and coresearchers (Toxicol
Sci (2004): Effects
of Polybrominated Diphenyl Ethers on Basal and TCDD-Induced
Ethoxyresorufin Activity and Cytochrome P450-1A1 Expression
in MCF-7, HepG2, and H4IIE Cells),
and more recently and decisively by Annelieke Peters
again in her doctoral study (AK Peters, University
of Utrecht (2006): Polybrominated
Diphenyl Ethers, Aspects of the mechanism of action
[pdf]) where no CYP1A1 induction was observed in the
AhR responsive MCF-7 (human breast carcinoma), HepG2
(human hepatoma) and H4IIE (rat hepatoma) cell lines,
nor in cynomolgas monkey hepatocytes. Thus it must
now be concluded that PBDE-mediated toxicity is consequent
to AhR-independent mechanisms given that when tested
PBDE congeners are subjected to rigorous purification
techniques removing possible contamination with dioxin-like
compounds such as PBDFs and other AhR-active compounds,
AhR-mediated activation of CYP1A1 induction is not
evidenced (see also the same author's study in Toxicol
Sci (2006): Interactions
of Polybrominated Diphenyl Ethers with the Aryl Hydrocarbon
Receptor Pathway).
The question then shifts to what mechanisms and pathways
underlie PBDE toxicity and to what extent if any are
these connected to breast cancer promotion (or its
opposite). Part of the puzzle's solution is provided
by recent research examining the potential alteration
of expression of several CYP P450 enzymes, including
CYP2B and CYP3A, and especially in particular CYP3A4,
involved as it is in the metabolism of a large number
(over 50%) of clinically deployed drugs including
oncotherapeutic agents (both endocrine, and chemotherapeutic),
given that dioxin-like chemicals are able to induce
CYP3A4 gene expression, indicating that there exists
some essential interaction between the AhR and the
human pregnane X receptor (hPXR), as discussed by
Peters (AK Peters, University of Utrecht (2006): Polybrominated
Diphenyl Ethers, Aspects of the mechanism of action
[pdf]). Such interference of xenobiotics with CYP3A4
if confirmed would have broad implications for drug-drug
and drug-CAM (complimentary and alternative medicine)
agent interactions, since CYP3A4 is the predominant
drug metabolizing enzyme in the human liver. What
Peters found was that the observed in vitro effects
by PBDEs occurred at medium concentrations that usually
exceed the average European human blood levels, so
that it would not be expected that human concentrations
would be sufficiently high enough to initiate a possible
PBDE-induced CYP3A4 interaction, although given that
levels in North America are typically higher than
European levels by some order of magnitude, the potential
for significant interaction in these latter populations
cannot be excluded, in concurrence also with the findings
of Johnny Sanders at North Carolina State University
in his doctoral study (JM Sanders, North Carolina
State University (2006): Mechanisms
of Toxicity of Polybrominated Diphenyl Ethers
[pdf]) who concluded that PBDEs appear to pose little
carcinogenic risk to humans through phenobarbital-like
(that is, via CYP2B and CYP3A gene induction) epigenetic
mechanisms at current exposure levels, although here
too we note again as with Peters that this conclusion
may be geographically constrained (see also his earlier
study in Toxicol Sci (2005): Differential
Expression of CYP1A, 2B, and 3A Genes in the F344
Rat following Exposure to a Polybrominated Diphenyl
Ether Mixture or Individual Components).
In this connection, Rocío F. Cantón
at the Institute for Risk Assessment Sciences, IRAS
Utrecht University and colleagues (Toxicol ASci (2005):
Inhibition and Induction of Aromatase (CYP19) Activity
by Brominated Flame Retardants in H295R Human Adrenocortical
Carcinoma Cells) explored the endocrine-disruptive
potential of several brominated flame retardants (BFRs)
in a human adrenocortical carcinoma cell line (H295R),
an effect apparently regulated by aromatase (CYP19),
which in addition to mediating the conversion of androgens
to estrogens through the bioconversion process of
aromatization, is of course intimately involved in
estrogen-dependent carcinogenesis. They found that
PBDEs or their structural analogs exerted an inhibiting
or inducing effect on aromatase activity, with the
brominated triphenol TBP (brominated phenols/anisols
2,4,6-tribromophenol) capable of strongly inducing
aromatase in vitro, and this is consonant with other
studies showing that TBP can bind to the estrogen
receptor as well as to the thyroid hormone transport
protein transthyretin (Cristel Olsen and colleagues
at the National Institute of Public Health, Norway,
in Toxicol. Lett (2002): Brominated
phenols: Characterization of estrogen-like activity
in the human breast cancer cell-line MCF-7),
although for other than TBP, most BFRs studied demonstrated
an antiestrogenic effect via aromatase inhibition.
Thus, at least in vitro TBP can interfere in steroidogenesis
by aromatase induction, suggesting that this PBDE
is an in vivo endocrine disruptor requiring further
investigation. given that such induction enables hormone-dependent
carcinogenesis, although the authors speculate that
in vivo aromatase interaction by these PBDE metabolites
would not easily be achieved for required concentration
levels.
Building on this and pushing further, and closer to
the breast carcinoma arena, Jonathan Barber and colleagues
at Lancaster University examined the activities of
low-dose PBDEs in MCF-7 cells, finding elevations
in micronucleus formation and also significant elevations
in growth kinetics even at levels of reported concentrations
measured in UK serum samples (J Barber et al., Mutagenesis
(2006): Low-dose
treatment with polybrominated diphenyl ethers (PBDEs)
induce altered characteristics in MCF-7 cells).
And notice that this is singly, yet we know that endocrine-disruptors
can act and react together, allowing small, apparently
non-significant quantities of individual agents to
exert major cumulative effect (as noted by Julia Brody
and Ruthann Rudel (Environ Health Perspect (2003):
Environmental
Pollutants and Breast Cancer); see
also the report from the UK Working Group on the Primary
Prevention of Breast Cancer (2005): Breast
Cancer: an environmental disease).
Again in this connection, of interest is the recent
finding from Yasmeen Barnes-Nkrumah and colleagues
at Florida A&M University (Proc Amer Assoc Cancer
Res, Volume 47, 2006: Diallyl
sulfide inhibits 2,2'4,4'-tetra brominated biphenyl
ether (BDE-47) induced DNA strand breaks and cell
proliferation in MCF10A breast epithelial cells)
that the most abundant PBDE congener in human, animal
and environmental samples, BDE-47, induces cell proliferation
via genotoxicity (DNA strand breakage), but that DAS
(diallyl sulfide, an organosulfur compound found in
garlic), both inhibits such DNA damage and promotes
apoptosis in affected cells. The authors speculate
that DAS action contrary to that of BDE-47 can thus
prevent cancer formation. However, Breast
Cancer Prevention Watch in these pages has
put forth evidence that suggests the potential of
garlic and other Allium components to exert adverse interaction with
the efficacy of certain oncotherapeutic agents via
activity over the CYP3A4 and CYP2D6 metabolic pathways;
see our own Issues
in Drug Interactions in Oncology coverage
for fuller discussion and supporting research.
Breast Cancer Prevention Watch
Summary
On the balance of the evidence we find that it is
plausible given in particular the recent cell studies
of Barber and those of Barnes-Nkrumah, cited above,
with the further evidence concerning cytochrome p450
system interaction, especially in respect to CYP3A4,
that at least certain PBDE congeners, especially BDE-47
and TBD, may exert a cell proliferative effect on
human breast carcinoma cells, either singly or in
combination with other xenobiotics, but further studies
of high methodological quality are needed to determine
both whether this activity is at levels that are clinically
significant in human trials, and whether the aggregate
effect is either enhanced by other xenobiotics, or
in the contrary, muted by dietary or other coadministered
non-pharmaceutical interventions in the natural human
setting, and it is imperative as we have seen above
that laboratory testing be conducted under rigorous
standards for sample purification to assure no significant
contamination by other xeniobiotics.
-
Smoking:
The Collaborative
Group on Hormonal Factors in Breast Cancer
(see above, Alcohol) found that among women who reported
drinking no alcohol there was little or no effect
on breast cancer risk of having ever smoked tobacco,
compared with having never smoked.
However, a recent assessment of 10 studies with breast
cancer incidence as the outcome concluded that there
may indeed be an association between passive smoking
and breast cancer (see Morabia in Environ Mol Mutagen:
Smoking
(active and passive) and breast cancer: epidemiologic
evidence up to June 2001;
see also Terry et al. in Int J Cancer: Cigarette
smoking and breast cancer risk: a long latency period?
and Kropp et al. in Am J Epidemiol: Active
and passive smoking and risk of breast cancer by age
50 years among German women).
In addition, several studies have begun to assess
gene–environment interactions re smoking (Zheng
et al. in Cancer Causes Control: Cigarette
smoking, glutathione-s-transferase M1 and t1 genetic
polymorphisms, and breast cancer risk
(United
States),
and Chang-Claude et al. in Cancer Epidemiol Biomarkers:
Differential
effect of NAT2 on the association between active and
passive smoke exposure and breast cancer risk).
Furthermore, Reynolds et al. (J Natl Cancer Inst (2004):
Active Smoking, Household
Passive Smoking, and Breast Cancer: Evidence From
the California Teachers Study), reporting
on the California Teachers Study (CTS) found (1) that
irrespective of inclusion of passive smokers in the
reference category, the incidence of breast cancer
among current smokers was higher than that among never
smokers, (2) among active smokers, breast cancer risks
were statistically significantly increased, compared
with all never smokers, among women (a) who started
smoking at a younger age, (b) who began smoking at
least 5 years before their first full-term pregnancy,
or (c) who had longer duration or greater intensity
of smoking, (3) current smoking was associated with
increased breast cancer risk relative to all nonsmokers
in women without a family history of breast cancer
but not among women with such a family history, and
(4) breast cancer risks among never smokers reporting
household passive smoking exposure were not greater
than those among never smokers reporting no such exposure.
In sum, therefore, this large prospective analysis
found an elevated risk of breast cancer associated
with active smoking that increased with smoking intensity
and, to a lesser extent, duration.
Evidencewatch Commentary:
Passive Smoking and Breast Cancer Risk
However, the CTS trial would appear to suggest little
or no risk from exposure to passive smoking, a conclusion
critically questioned by KC. Johnson in his commentary
(J Natl Cancer Inst (2004): Re: Active
Smoking, Household Passive Smoking, and Breast Cancer:
Evidence From the California Teachers Study)
on the original paper, who notes correctly the CTS
trial does not include degree of exposure or occupational
exposure, being based only on a binary evaluation
of household passive smoking exposure (yes/no) and
the timing of that exposure (childhood, adult, or
both), especially problematic given that, as Reynolds
et al. themselves concede in their response (J Natl
Cancer Inst (2004): RESPONSE:
Re: Active Smoking, Household Passive Smoking, and
Breast Cancer: Evidence From the California Teachers
Study), during the 1980s, the workplace
replaced the home as the primary source of passive
smoking exposures in this cohort, and in any case,
such a conclusion is against the balance of the evidence
of high-quality studies (Morabia et al., Am J Epidemiol
(1996): Relation
of breast cancer with passive and active exposure
to tobacco smoke; Johnson et al., Cancer
Causes Control (2000): Passive
and active smoking and breast cancer risk in Canada,
1994–97); Terry & Rohan, Cancer
Epidemiol Biomarkers Prev (2002): Cigarette smoking
and the risk of breast cancer in women: a review of
the literature; kropp & Chang-Claude, Am. J. Epidemiol
(2002): Active
and Passive Smoking and Risk of Breast Cancer by Age
50 Years among German Women.
-
Radiation:
The relationship between exposure to ionizing radiation
and the risk of developing breast cancer is by now
well-established: increased breast cancer risk is
consistently associated with a variety of exposures
such as tuberculosis fluoroscopy, dermatologic radiation
treatments for acne and tinea, or radiation treatment
for Hodgkin’s lymphoma (NCI: Breast
Cancer (PDQ): Prevention).
The risk of breast cancer associated with medical
radiology is estimated to be less than 1% of the total,
although it may be that certain populations, such
as AT (ataxia telangiectasia) heterozygotes (AT is
a rare, progressive, neurodegenerative childhood disease),
may be at increased risk from typical radiation exposures.
A natural concern is whether treatment-radiation exposure
(radiotherapy), such as that involved when breast
cancer patients are treated with lumpectomy and radiation
therapy (so-called L-RT, or LRT), may itself place
a patient at increased risk for either second breast
or other malignancies, as opposed to patients treated
by mastectomy alone with radiation. This question
was taken up at Yale (Obedian et al, J Clin Oncol:
Second
malignancies after treatment of early-stage breast
cancer: lumpectomy and radiation therapy versus mastectomy),
however, and with a median follow-up of 15 years,
no increased risk of second malignancies was found
in patients undergoing L-RT, a finding confirmed in
several other RCTs (Fisher et al, N Engl J Med: Twenty-year
follow-up of a randomized trial comparing total mastectomy,
lumpectomy, and lumpectomy plus irradiation for the
treatment of invasive breast cancer;
Veronesi et al., N Engl J Med: Twenty-year
follow-up of a randomized study comparing breast-conserving
surgery with radical mastectomy for early breast cancer;
Fisher et al.: N Engl J Med: Twenty-five-year
follow-up of a randomized trial comparing radical
mastectomy, total mastectomy, and total mastectomy
followed by irradiation).
-
Abortion:
Another issue is whether there is any association
between induced abortion and subsequent breast cancer.
Recently the Collaborative Group on Hormonal Factors
in Breast Cancer (Beral et al., Lancet:
Breast
cancer and abortion: collaborative reanalysis of data
from 53 epidemiological studies, including 83,000
women with breast cancer from 16 countries)
has taken up this issue, finding that the risk of
breast cancer did not differ significantly according
to the number or timing of aborted pregnancies. However,
researchers at the Breast Cancer Prevention Institute
(BCPI: Abortion
and Breast Cancer: re: "collaborative reanalysis
of data" published in Lancet 3/25/04)
have raised some issues of serious methodological
flaws in the Beral study suggesting that the study
is insufficiently powered to found their conclusions.
Nonetheless, an Evidencewatch systematic review (summer,
2005) has discovered two methodologically sound studies
that convincingly challenge the abortion / breast
cancer association: (1) the prospective study of Palmer
et al. (Cancer Causes Control (2004): A
prospective study of induced abortion and breast cancer
in African-American women)
determined that induced abortion does not increase
breast cancer risk in African-American women; and
(2) the study of Brewster et al. (J Epidemiol Community
Health (2005): Risk
of breast cancer after miscarriage or induced abortion:
a Scottish record linkage case-control study)
has concluded that the data do not support the hypothesis
that either miscarriage or induced abortion represents
a substantive risk factor for the future development
of breast cancer.
The Issue of Breast Implants
:
A common concern expressed by many women is whether
there is any association between breast implants and
cancer risk, whether breast or otherwise. This
issue was address directly by the National Cancer
Institute Breast Implant Study (NCI Factsheet: National
Cancer Institute Breast Implant Study)
initiated in 1992 to explore the on the long-term
health effects associated with silicone breast implants,
with findings first reported in 2000 in a series of
reports. It was determined by Brinton et al. (Cancer
Causes & Control (2000):
Breast cancer following
augmentation mammoplasty (United States))
that there was no association between breast implants
and the subsequent risk of breast cancer, nor with
any particular type of implant, and no
significant difference in breast cancer mortality
between the implant and comparison patients. In addition,
neither was there any increased risk for cancers of
the stomach, large intestine, cervix, uterus, ovary,
bladder or thyroid, connective tissue nor immune system
cancers (such as soft tissue sarcomas, lymphoma, and
multiple myeloma).
However, the same researchers in another report (Brinton
et al., Ann Epidemiol (2000): Cancer
Risk at Sites Other than the Breast Following Augmentation
Mammoplasty) from the same initiative
did find that cancer rates for brain and respiratory
cancers were higher in the implant patients compared
to other plastic surgery patients, although only the
rates of respiratory cancers were statistically significant.
And a later report (Brinton et al., Epidemiol (2001):
Mortality
among Augmentation Mammoplasty Patients)
explored the broader issue of mortality in general
in breast implant populations, finding a higher overall
mortality among the implant patients which reflected
increases for respiratory tract and brain cancers,
and for suicide. Nonetheless, it is not clear if this
is truly causal: the researchers themselves cautiously
note that "It is possible that the higher
risks observed for respiratory and brain cancers are
not related to exposure to silicone, but are due to
either chance findings or to factors common to women
who choose to have implants" and in addition
many of the cancers showing excesses in the study
were defined on the basis of death certificates, a
foundation that always requires some caution in interpretation.
But more recent research has shown that the putative
association with brain cancer however is neither confirmable
nor supportable under later more methodologically
sound scrutiny: McLaughlin (Ann Plast Surg (2004):
Brain
cancer and cosmetic breast implants: a review of the
epidemiologic evidence) reviewed the
epidemiologic evidence, concluding that the epidemiologic
evidence overall failed to support an association
between breast implants and brain cancer incidence.
Similarly, on the balance of the evidence, there is
no excess of connective tissue disease (rheumatoid
arthritis, systemic sclerosis, systemic lupus erythematosus
and Sjogren's syndrome) among women with cosmetic
silicone breast implants (Lipworth et al, Ann Plast
Surg (2004): Silicone
Breast Implants and Connective Tissue Disease: An
Updated Review of the Epidemiologic Evidence),
nor any association with subsequent fibromyalgia (Lipworth
et al., Ann Plast Surg (2004): Breast
Implants and Fibromyalgia: A Review of the Epidemiologic
Evidence).
-
Environmental
Factors :
Evidence of the effect of occupational, environmental,
or chemical exposures on breast cancer risk is not
to date wholly conclusive. Laden et al. (Int J Cancer:
Plasma
organochlorine levels and the risk of breast cancer:
An extended follow-up in the Nurses' Health Study)
found no support for the hypothesis that exposure
to DDT and PCBs increases the breast cancer risk,
and the latest NCI: Breast
Cancer (PDQ) concludes
that "the possibility that such substances, some
of which are known to have weak estrogenic effects,
influence breast cancer risk remains unproven".
Evidencewatch
Commentary:
However, Evidencewatch
disagrees with such a clear repudiation as that of
the NCI. The recent comprehensive review of Mitra
et al. (J Environ Health: Breast
cancer and environmental risks: where is the link?)
has concluded that many environmental factors are
significantly associated with breast cancer:
(1) the evidence is mixed re organochlorine exposure
and breast cancer risk;
(2) dieldrin and lindane are associated with breast
cancer risk, atrazine is not; (3) evidence of a link
between benzene and breast cancer is inconclusive;
(4) risk of breast cancer with smoking is strong in
families with a history of breast cancer, ovarian
cancer, or both;
(5) there is a positive association of breast cancer
with heterocyclic amines in women who eat well-done
meat (see our Evidencewatch
section on Heterocyclic
Amines (HCAs) and Cooked Meats).
In addition Coyle (Breast Cancer Res Treat: The
effect of environment on breast cancer risk)
concluded that "Although, most of the environmental
factors discussed in this review have not been convincingly
found to influence breast cancer risk, research suggests
that environmental exposure in combination with genetic
predisposition, age at exposure, and hormonal milieu
have a cumulative effect on breast cancer risk",
finding, among other things, that (1) passive smoke
exposure is associated with increased breast cancer
risk, (2) solar radiation is associated with reduced
breast cancer risk, supporting the hypothesis that
vitamin D is a protective agent in breast cancer reduction.
Other studies are also in substantial agreement (see
Mitra & Faruque, South Med J: Breast
cancer incidence and exposure to environmental chemicals
in 82 counties in Mississippi;
O'Leary et al., Environ Res: Pesticide
exposure and risk of breast cancer: a nested case-control
study of residentially stable women living on Long
Island;
Note also the work of Schernhammer and Schulmeister
(Photochem Photobiol: Light
at night and cancer risk)
on environmental lighting and breast cancer risk,
who concluded that "environmental lighting powerfully
suppresses the physiologic release of melatonin, which
typically peaks in the middle of the night. This decreased
melatonin production has been hypothesized to increase
the risk of cancer. Evidence from experimental studies
supports a link between melatonin and tumor growth.
There is also fairly consistent indirect evidence
from observational studies for an association between
melatonin suppression, using night work as a surrogate,
and breast cancer risk". (On environmental lighting,
see also our Evidencewatch
discussion of melatonin under the section Radioprotection).
-
SERMS
(Selective
Estrogen Receptor Modulators):
The role of SERMs in breast cancer prevention and
treatment is examined critically in the separate Evidencewatch
Evidence Report Breast Cancer:
Treatment.
-
Genetics:
There is known to be some underlying genetic susceptibility
of individuals influencing the carcinogenic process,
but this account for only a small proportion of breast
cancers (approx. 5%), although research in this arena
may help identify high-risk populations who are more
likely to need and benefit from preventive intervention.
The BRCA gene is a tumor suppressor gene, with two
types well studied in this connection: BRCA1 and the
less common BRCA2, and it is well established that
women who inherit a deleterious BRCA1 or BRCA2 mutation
have an increased lifetime risk of breast and ovarian
cancer (possibly also colon cancer), with several
mutations in BRCA1 and BRCA2 observed to occur more
frequently among those of Ashkenazi Jewish descent.
BRCA2 deleterious mutations are associated with an
increased risk of breast cancer in men and possibly
prostate cancer, as well as other cancers (for example,
pancreatic cancer and lymphoma). Among women with
BRCA1 or BRCA2, estimates of lifetime risk of breast
cancer vary from 56% to as high as 80% to 85%, with
BRCA2 carriers typically exhibiting lower risk than
BRCA1, although there are some considerations suggesting
that these figures may be overestimates, and present
knowledge of other factors influencing when and if
a deleterious-mutation carrier develops cancer is
still relatively primitive.
Other genes may also be implicated in inherited breast
cancers, among which are:
(1) the ATM (ataxia-telangiectasia mutation) gene,
responsible for repairing damaged DNA; some families
with a high rate of breast cancer appear to have an
ATM gene mutation;
(2) the CHEK-2 gene also appears to increase breast
cancer risk under mutation;
(3) the p53 tumor suppressor gene; inherited mutations
of this gene can also increase risk of breast cancer
development, as well as leukemia, brain cancer, and/or
sarcomas (bone or connective tissue cancer);
(4) the HER2 (human epidermal growth factor receptor
2) oncogene: HER2, a key component in regulating cell
growth, represents a protein found on the surface
of cells; altered HER2 protein leads to the production
of extra HER2 protein receptors (HER2 over-expression),
causing increased cell growth and reproduction, which
frequently results in more aggressive breast cancer
cells (women with HER2 over-expression may not be
as responsive to certain standard breast cancer treatments
including certain chemotherapy regimens).
Although the goal is to use such genetic information
to identify and target women who may especially benefit
from enhanced early detection or from preventive intervention,
nonetheless the latest NCI: Breast
Cancer (PDQ): Prevention
guidelines conclude that "at this time, there
is little scientific evidence to support or quantify
this potential beneficial effect". See also Pichert
et al. (Ann Oncol: Evidence-based
management options for women at increased breast/ovarian
cancer risk).
-
Breast Size:
Kusano et al. (Epidemiol (2005): A
prospective study of breast size and premenopausal
breast cancer incidence) found that
larger bra cup size at a young age is associated with
a higher incidence of premenopausal breast cancer,
though this association is limited to leaner women.
-
Prophylactic
Mastectomy and Breast Reduction:
The role of prophylactic mastectomy in breast cancer
prevention has been recently and comprehensively examined
by Hartman et al (J Clin Oncol: Prophylactic
mastectomy for BRCA1/2 carriers: progress and more
questions)
where it is argued that the procedure results in a
marked decrease in the risk of breast cancer, although
they sensibly conclude that there are many substantive
questions remaining. The latest NCI (NCI: Breast
Cancer (PDQ))
concludes that "although this study provides
the best evidence available to date that prophylactic
surgery offers benefits despite the fact that some
breast tissue remains following surgery, some factors
may bias the estimate of benefit", also the conclusion
of Klaren et al. (J Natl Cancer Inst: Potential
for bias in studies on efficacy of prophylactic surgery
for BRCA1 and BRCA2 mutation), who
argue that several potential biases may result in
an overestimation of the benefit from such prophylactic
surgery. (See also Pichert et al. (Ann Oncol: Evidence-based
management options for women at increased breast/ovarian
cancer risk)).
Clearly, therefore, the option of prophylactic mastectomy
must be done in association with mature cancer risk
assessment and individual counseling regarding all
available preventive options, including tamoxifen
and possibly also various aromatase inhibitors (AIs)
as a emergent preventive agents.
An interesting question arises
here as to whether a far less radical option than
prophylactic mastectomy,
breast reduction surgery,
would also appreciably reduce risk of breast cancer.
This question was taken up by Tarone et al. (Plast
Reconstr Surg: Breast
reduction surgery and breast cancer risk: does reduction
mammaplasty have a role in primary prevention strategies
for women at high risk of breast cancer?)
who review the literature and conclude that "evidence
from these studies is sufficiently strong to warrant
the evaluation of breast reduction surgery as an option
for primary prevention in clinical studies of women
at increased risk of breast cancer".
-
Prophylactic
Oophorectomy:
The studies of Rebbeck et al. (N Engl J Med: Prophylactic
oophorectomy in carriers of BRCA1 or BRCA2 mutations
and Kauff et al. (N Engl J Med: Risk-Reducing
Salpingo-oophorectomy in Women with a BRCA1 or BRCA2
Mutation)
found that oophorectomy (Salpingo or bilateral) in
carriers of BRCA mutations can decrease the risk of
breast cancer and BRCA-related gynecologic cancer
(coelomic epithelial cancer). However, The latest
NCI (NCI: Breast
Cancer (PDQ))
soberly observes that "these observational studies,
however, are confounded by selection bias, family
relationships between patients and controls, indications
for oophorectomy, and inadequate information about
hormone use" (see also the discussion of Garber
and Hartman, J Clin Oncol: Prophylactic
Oophorectomy and Hormone Replacement Therapy: Protection
at What Price?),
Pichert et al. (Ann Oncol: Evidence-based
management options for women at increased breast/ovarian
cancer risk),
and McKelvey &
Evans, J. Nutr: Cancer
Genetics in Primary Care).
-
Antibiotic
Use:
The study of Dr. Christine Velicer (Department of
Epidemiology, University of Washington, Seattle) et
al. (JAMA (2004): Antibiotic
Use in Relation to the Risk of Breast Cancer)
suggests that long-term use of antibiotics may increase
the risk of breast cancer, although the study was
not sufficiently powered to determine whether such
antibiotic use is causally
related to breast cancer, rather than
more narrowly associated
with breast cancer; the study found an increase in
the incidence of breast cancer associated with cumulative
increase in the number of days of antibiotic use,
and number of antibiotic prescriptions. Soberly the
authors note that the association may be due to whatever
might be the indication for antibiotic use, or possibly
overall weakened immune function, or still other factors,
but legitimately conclude nonetheless that "these
findings reinforce the need for prudent long-term
use of antibiotics". (See also NCI:
Questions and Answers: Study Shows Link Between Antibiotic
Use and Increased Risk of Breast Cancer,
and NeLH, Hitting the Headlines: Antibiotics
linked to risk of breast cancer).
In the aftermath of the Velcier study (cited above),
Kay & Jick (Epidemiol (2005): Antibiotics
and the Risk of Breast Cancer) reviewed
the UK General Practice Research Database, and concluded
that the data do not support the hypothesis that antibiotic
use is associated with an increased risk of breast
cancer. Rodríguez & González-Pérez
(Am J Epidemiol (2005): Use
of Antibiotics and Risk of Breast Cancer)
then attempted to replicate the Velcier findings,
again using General Practice Research Database in
the United Kingdom, failing to find a clear association
between breast cancer and antibiotic use.
Breast Cancer Prevention Watch concludes on the basis
of systematic review of the literature to date (August
2006) that there is on the balance of the evidence
no compelling data to suggest a causal link between
antibiotic use and increased breast cancer risk. However
we note that it is still possible that there may be
be an association that is receptor status dependent:
Rossini et al. (Cancer Res (2006): Influence
of Antibiotic Treatment on Breast Carcinoma Development
in Proto-neu Transgenic Mice) examined
the effect of prolonged antibiotic treatments on tumor
development in a model of HER-2-neu transgenic mice,
finding such prolonged exposure affects the mammary
glands in terms of increased tumor growth rate and
increased lobulization, but these preclinical findings
await further exploration and confirmation.
-
Aspirin,
NSAIDs, and Acetaminophen/Paracetamol:
Aspirin
Aspirin and other NSAIDs may be effective chemoprotective
agents for breast cancer, it is speculated due aspirin's
inhibition of either prostaglandin synthesis or inhibition
of cyclooxygenase or both, which could result in lower
concentrations of estrogen and the inhibition of estrogen
production in the breast. The most recent study, that
of Rodríguez & González-Pérez
(Br J Cancer: Risk
of breast cancer among users of aspirin and other
anti-inflammatory drugs)
suggests that aspirin at cardioprophylactic doses
(75mg) used for one year or longer is associated with
a reduced risk of breast cancer, while NSAID use showed
no such association, confirming similar findings of
several previous studies; however, the effect may
be limited only to receptor-positive tumors (see the
study led by Mary Beth Terry, Columbia University,
NY - Terry et al., JAMA: Association
of Frequency and Duration of Aspirin Use and Hormone
Receptor Status With Breast Cancer Risk).
More recently, the study of Cook et al. (JAMA (2005):
Low-Dose Aspirin in the Primary Prevention of Cancer
- The Women’s Health Study: A Randomized Controlled
Trial)
suggested that low-dose aspirin for an average 10
years of treatment does not lower risk of breast cancers
(nor colorectal or other site-specific cancers). However,
Breast Cancer Prevention Watch believes that
the studies implications are clouded by the uncommon
regimen deployed, that of alternate day 100mg aspirin;
it would have been interesting to have seen the results
of the more typical low-dose daily aspirin regimen,
especially as the study of Swede et al. (Oncology
(2005): Association
of Regular Aspirin Use and Breast Cancer Risk)
corroborated the growing body of observational evidence
that regular aspirin use may be associated with reduced
risk of breast cancer, in finding that both regular
(1 tablet per week for 1 year) and occasional use
were inversely associated with breast cancer, and
that among regular users, an inverse trend was found
for number of tablets consumed per week (1, 2-6, or
7) with corresponding better overall survival; finally,
daily use spanning 10 or more years was associated
with a more pronounced reduction in risk.
Less noticed and reported, was the finding that acetaminophen
/ paracetamol at analgesic doses (up to 2000mg) was
also associated with significant breast cancer risk
reduction. This appears to be in conflict with earlier
studies that find no effect for NSAIDs and acetaminophen
/ paracetamol, so additional studies are needed to
clarify their role. Again, only an association, not
a causal relationship, has been demonstrated for aspirin
consumption (the greatest risk reduction was for a
regimen of once-daily use or greater per week) and
risk reduction of breast cancer, although the findings
of aspirin's benefit in in other cancers like colorectal
cancer is strongly suggestive, in the cumulative,
of a chemopreventive activity.
Coxibs (COX-2 Inhibitors)
Coxibs (COX-2
Inhibitors), such as rofecoxib (Vioxx), celecoxib
(Celebrex), and valdecoxib (Bextra), selectively inhibit
pro-inflammatory cyclooxygenase (COX)-2, and unlike
traditional NSAIDs (non-steroidal anti-inflammatory
drugs), most coxibs do not significantly inhibit COX-1,
suggesting a potential less toxicity to the gastrointestinal
tract, but due to several postulated mechanisms, in
many, but not all, clinical studies, the coxibs became
associated with higher risks of myocardial infarction
(MI) and stroke (E. Fosslein, Ann Clin Lab Sci (2005):
Cardiovascular
complications of non-steroidal anti-inflammatory drugs),
leading to the removal of two of the three coxibs,
rofecoxib (Vioxx) and valdecoxib (Bextra) from US
and European markets; note, however, as we observe
below, there are clinically significant intra-class
differences among the coxibs.
An earlier insight connecting the Coxibs with oncotherapy
and potential chemoprevention was that cyclooxygenase-2
(COX-2) is overexpressed in several epithelial tumors,
including breast cancer, and COX-2-positive tumors
tend to be larger, higher grade, node-positive and
HER-2/neu-positive, yielding the association of high
COX-2 expression with poor prognosis and directly
suggesting COX-2 inhibition as a pathway to tumor
reduction, probably consequent to increased apoptosis,
reduced angiogenesis and/or proliferation (Bundred
& Barnes, Br J Cancer (2005): Potential
use of COX-2-aromatase inhibitor combinations in breast
cancer). This study found evidence
to suggest that combining Coxibs with AIs (aromatase
inhibitors), growth factor receptor blockers, or chemo-
or radiotherapy may be particularly effective. They
cite preliminary results from combination therapy
with celecoxib (Celebrex) and exemestane (Aromasin)
in postmenopausal women with advanced breast cancer
yielding increased the time to recurrence. Given,
as they note, that up to 80% of DCISs (ductal carcinomas
in situ) express COX-2, COX-2 inhibition may be of
particular use in the DCIS setting, and that furthermore,
as COX-2 expression correlates strongly with expression
of HER-2/neu, the combination of aromatase inhibitors
and coxibs may be particularly useful in both DCIS
and invasive cancer, especially in patients with HER-2/neu-positive
tumors (see also Chow et al., Biomed Pharmacother
(2005): Current
directions for COX-2 inhibition in breast cancer).
This was further confirmed by Chow et al. (med Pharmacother
(2005): Study
of COX-2, Ki67, and p53 expression to predict effectiveness
of 5-flurouracil, epirubicin and cyclophosphamide
with celecoxib treatment in breast cancer patients)
who demonstrated the efficacy of a preoperative FECC
regimen (5-fluorouracil, epirubicin, and cyclophosphamide,
with celecoxib in breast invasive ductal carcinomas.
The same authors (Chow et al., Biomed Pharmacother
(2005): Serum
lipid profiles in patients receiving endocrine treatment
for breast cancer—the results from the Celecoxib
Anti-Aromatase Neoadjuvant (CAAN) Trial)
in the CAAN trial performed a proof of principle study
to investigate the efficacy and side effects including
changes in lipid profiles of an Coxib+AI
regimen combining anti-aromatase therapy and
COX-2 inhibitor (exemestane (Aromasin) 25 mg daily
and celecoxib (Celebrex) 400 mg twice-daily) preoperatively
in hormone sensitive postmenopausal breast cancers,
finding that after 18 weeks of treatment cholesterol
levels for patients on Coxib+AI dropped progressively,
with significantly lowered cholesterol and LDL levels
compared to patients on exemestane or letrozole (Femara)
alone, suggesting that combination of AIs with celecoxib
may have a beneficial effects on the serum lipid profiles.
And the Ohio State University Comprehensive Cancer
Center is also conducting a clinical trial of this
Coxib+AI combination (Clinical Trials: Exemestane
With Celecoxib as Neoadjuvant Treatment in Postmenopausal
Women With Stage II, III, and IV Breast Cancer),
and the same combination is also being investigated
in an NCI-sponsored trial (Clinical Trials: Exemestane
and Celecoxib in Postmenopausal Women at High Risk
for Breast Cancer), while another open-label,
multicenter study is examining the benefit of celecoxib
(Celebrex) in ER-negative populations (Clinical Trials:
Phase
II Chemoprevention Study of Celecoxib in Premenopausal
Women at High Risk For Estrogen Receptor-Negative
Breast Cancer).
The first results from these Coxib+AI studies was
recently (June 20 2006) reported by the French researchers
G. Freyer et al. from the Oncology Service of Cedntre
Hospitalier Lyon Sud, at the Annual ASCO meeting (ASCO
Annual Meeting Proceedings (Post-Meeting Edition)
Abstract 565), J Clin Oncol (2006): Celecoxib
(Ce) + exemestane (Ex) versus placebo + Ex in post-menopausal
(PM) metastatic breast cancer (MBC) patients (pts):
A double-blind phase III GINECO study)
who noted from their RCT that previous in vitro and
in vivo studies suggest that COX-2 inhibitors not
only demonstrate antitumor activity but may enhance
the activity of aromatase inhibitors (AIs), and on
this foundation examined celecoxib (400 mg bid) +
exemestane (Aromasin) (25mg/d) compared to exemestane
alone, finding that overall response rate was significantly
higher (35% versus 20%) with the Ce (celecoxib ) +
Ex (exemestane) regimen, with PFS significantly longer
PFS (progression free survival) in the subgroup of
patients who developed MBC (metastatic breast cancer)
under tamoxifen or within 12 months after its termination;
in terms of adverse events, the CE + Ex patients was
better tolerated, and experienced less pain, arthralgias,
asthenia, and grade 1–3 insomnia, but more hypersensitivity
reactions and edema, although promisingly no increase
in gastrointestinal toxicity was experienced. The
66 subjects were all menopausal hormone-responsive
(ER+ and/or PR+) patients with metastatic breast cancer
(MBC) and measurable lesions. The trial was prematurely
stopped in December 2004 in the wake of of other trials
reporting celecoxib cardiovascular toxicity; however,
no cardiac toxicity was observed in this trial (except
a single case of arrhythmia in a patient with arrhythmia
history).
This benefit appears to be consequent to the fact
that COX-2 overexpression in breast cancer activates
prostaglandin E2 (PGE2) activity, which then induces
a cascade of processes: the aromatase gene promoter,
immunosuppression, EGFR activation, inhibition of
apoptosis, and secretion of angiogenic factor, processes
all known to be involved in breast tumor development,
and we may conclude that both the aromatase inhibitors,
including exemestane, and celecoxib (Celebrex), share
a common target, the aromatase enzyme.
Coxibs and Cardiovascular
Risk
Although the cardiovascular risk associated with rofecoxib
(Vioxx) and valdecoxib (Bextra) are by now well established,
some studies, notably the APC (Adenoma Prevention
with Celecoxib) study (Solomon et al., N Engl J Med
(2005): Cardiovascular
Risk Associated with Celecoxib in a Clinical Trial
for Colorectal Adenoma Prevention)
have suggested that this may also be true for celecoxib
(Celebrex). However this has been challenged (in the
same issue, JM Brophy, N Eng J Med (2003): Cardiovascular
Risk Associated with Celecoxib) and
appears on the balance of the evidence to be in error
(but see also the editorials of Juni et al., BMJ (2005):
COX 2 inhibitors, traditional
NSAIDs, and the heart; Dieppe et al.,
BMJ (2005): Lessons
from the withdrawal of rofecoxib, and
the observational study of Hippisley-Cox & Coupland
(2005): Risk
of myocardial infarction in patients taking cyclo-oxygenase-2
inhibitors or conventional non-steroidal anti-inflammatory
drugs: population based nested case-control analysis).
JM Brophy systematically reviewed (Expert Opin Drug
Saf (2005): Celecoxib
and cardiovascular risks) the evidence
surrounding COX-2 inhibitors and cardiovascular risk,
finding that although the evidence suggests a fairly
consistent cardiovascular risk with rofecoxib (Vioxx),
the evidence for cardiovascular risk with celecoxib
(Celebrex) is more equivocal, and although isolated
studies have suggested some cardiovascular risk for
celecoxib, the totality of the evidence suggests that
any risk is likely to be small and comparable to traditional
NSAIDs. Indeed, the cardiovascular risk of celecoxib
may actually be less than NSAIDs: in a retrospective
cohort study, Hudson et al. (BMJ (2005): Differences
in outcomes of patients with congestive heart failure
prescribed celecoxib, rofecoxib, or non-steroidal
anti-inflammatory drugs: population based study)
found that the combined risk of death and recurrent
congestive heart failure was higher in patients prescribed
NSAIDs or rofexocib (Vioxx) than in those prescribed
celecoxib (Celebrex), so that celecoxib currently
seems to be the safest choice for treating elderly
patients with congestive heart failure. See also the
review on coxibs and cardiovascular risk by Antman
et al. (Circulation (2005): Cyclooxygenase
Inhibition and Cardiovascular Risk).
The risk of cardiovascular complications during long-term
coxib therapy can be reduced with concurrent low-dose
aspirin supplementation (E. Fosslein, Ann Clin Lab
Sci (2005): Cardiovascular
complications of non-steroidal anti-inflammatory drugs).
[new]
Breast Cancer Prevention Watch:
COX-2 Inhitory Breast Cancer Chemoprevention
In sum, the positive findings cited above, coupled
with the fact as concluded in their recent review
by Randall Harris and colleagues (BMC Cancer (2006):
Reduction in the risk of
human breast cancer by selective cyclooxygenase-2
(COX-2) inhibitors) from the Ohio State
University College of Medicine and Public Health that
even in the short window of exposure to these compounds,
the selective COX-2 inhibitors produced a significant
(71%) reduction in the risk of breast cancer suggests
a high potential for their deployment in the chemoprevention
of breast cancer when any potential cardiovascular
concerns are recognized, monitored and addressed.
NSAIDs
NSAIDs (nonsteroidal anti-inflammatory drugs) such
as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn),
and indomethacin (Indocin), among many others, also
appear to have some beneficial activity in breast
cancer: Rahme et al. (BMC Cancer (2005): Association
between frequent use of nonsteroidal anti-inflammatory
drugs and breast cancer) found that
women who use NSAIDs, or doses of aspirin > 100
mg, frequently may have a lower risk of breast cancer;
it is important to note they a corollary of these
findings is that use of aspirin at doses <= 100
mg/day did not have any association with breast cancer.
Also Zhang et al. (Am J Epidemiol (2005): Use
of nonsteroidal antiinflammatory drugs and risk of
breast cancer: the Case-Control Surveillance Study
revisited) found that long-term regular
use of NSAIDs was associated with decreased risk of
breast cancer, and this was independent of the type
of NSAID used or the hormone receptor status of the
tumor.
Antiperspirant/Deodorant
Use
On the one hand, McGrath
(Eur J Cancer Prev (2003):
An earlier age of breast
cancer diagnosis related to more frequent use of antiperspirants/deodorants
and underarm shaving [pdf]) found the
age of breast cancer diagnosis was significantly lower
in women who used these products and shaved their
underarms more frequently, and that in addition, women
who began both of these underarm hygiene habits before
16, were diagnosed with breast cancer at an earlier
age than those who began these habits later. Although
raising suspicion, a small retrospective study such
as this, the researchers admit, cannot conclusively
link a woman’s underarm habits to breast cancer.
On the other hand, Mirick (J Natl Cancer Inst (2002):
Antiperspirant Use and the
Risk of Breast Cancer) found on the
basis of epidemiologic evidence that the risk for
breast cancer did not increase with any of the following
activities: 1) antiperspirant or deodorant use; 2)
product use among subjects who shaved with a blade
razor; or 3) application of products (antiperspirant
or deodorant) within 1 hour of shaving. See also the
NCI Factsheet (updated: 10/04/2004): Antiperspirants/Deodorants
and Breast Cancer: Questions and Answers
commentary on the issue and these two contradictory
studies. The suspicion of an association in part hinges
on the fact that aluminum, a component common in antiperspirants
and deodorants, is known to have a genotoxic profile,
capable of causing both DNA alterations and epigenetic
effects, consistent with a potential role in breast
cancer if such effects occurred in breast cells (Dabre,
J Inorg Biochem (2005): Aluminium,
antiperspirants and breast cancer);
this study of Dabre's demonstrated that aluminum in
the form of aluminum chloride or aluminum chlorhydrate
is a metalloestrogen,
that is, can interfere with the function of oestrogen
receptors of MCF7 human breast cancer cells, leaving
open the question of degree of dermal absorption in
the local area of the breast and whether long term
low level absorption could play a significant role
in breast cancer.
In conclusion, our systematic review of the literature
has failed to uncover any conclusive evidence linking
the use of underarm antiperspirants or deodorants
and the development of breast cancer, but further
research is nonetheless required to be dispositive
of the issue given contradictory findings.
-
Melatonin
Melatonin Radio/Chemo-Protection
Melatonin (at levels of 20mg/daily) may be a radioprotector
agent, protecting against the harm of radiation and
radiotherpy (see Weiss and Landauer, Toxicology (2003):
Protection
against ionizing radiation by antioxidant nutrients
and phytochemicals;
also Blask et al., Curr Top Med Chem (2002): Melatonin
as a chronobiotic/anticancer agent: cellular, biochemical,
and molecular mechanisms of action and their implications
for circadian-based cancer therapy);
see also Karslioglu et al. (J Radiat Res (Tokyo) (2005):
Radioprotective
effects of melatonin on radiation-induced cataract)
who conclude that "supplementing cancer patients
with adjuvant therapy of melatonin may reduce patients
suffering from toxic therapeutic regimens such as
chemotherapy and/or radiotherapy and may provide an
alleviation of the symptoms due to radiation-induced
organ injuries").
Note that other natural agents appear to have a similar
chemoprotective activity: a recent study by Branda
et al. (Cancer (2005): Effect
of vitamin B12, folate, and dietary supplements on
breast carcinoma chemotherapy-induced mucositis and
neutropenia)
determined that the neutrophil count decrease consequent
to chemotherapy was ameliorated by dietary supplementation
with a multivitamin or vitamin E (but this neutrophil
decrease was actually exacerbated by high serum folate
levels).
These findings are cross-validated in the review of
Vijayalaxmi et al. (Int J Radiat Oncol Biol Phys (2004):
Melatonin as a radioprotective
agent: a review) where it was found
that melatonin administration, either alone or in
combination with traditional radiotherapy, results
in a favorable efficacy:toxicity ratio during the
treatment of human cancers.
Melatonin Antitumor Activity
Taking the protective role for melatonin further,
Kim et al. (J Cardiovasc Pharmacol (2005): Modulation
by Melatonin of the Cardiotoxic and Antitumor Activities
of Adriamycin)
have shown that given melatonin's oncolytic activity,
the combination of adriamycin and melatonin improved
the antitumor activity of adriamycin, as indicated
by an increase in the number of long-term survivors
as well as decreases in body-weight losses resulting
from adriamycin treatment, suggesting that melatonin
not only protects against adriamycin-induced cardiotoxicity
but also enhances its antitumor activity and further
suggesting that a melatonin and adriamycin combination
represents a potentially useful regimen for the treatment
of human neoplasms, by virtue of the fact that it
allows the use of lower doses of adriamycin, thereby
avoiding the toxic side effects associated with this
drug.
Furthermore, the research findings of Cos et al. J
Pineal Res (2005): Melatonin
modulates aromatase activity in MCF-7 human breast
cancer cells)
have demonstrated that melatonin, at physiological
concentrations, decreases aromatase activity and expression
in MCF-7 cells, and that this aromatase inhibitory
effect of melatonin, together with its already known
antiestrogenic properties interacting with the estrogen-receptor,strongly
suggests a role in the prevention and treatment of
hormone-dependent mammary neoplasias; see also the
study of COs et al. (Int J Cancer (2005): Melatonin
inhibits the growth of DMBA-induced mammary tumors
by decreasing the local biosynthesis of estrogens
through the modulation of aromatase activity),
which investigated the in vivo aromatase-inhibitory
properties of melatonin, noting that melatonin inhibits
the growth of breast cancer cells by interacting with
estrogen-responsive pathways, thus behaving as an
antiestrogenic hormone, and concluding from their
in vivo study that melatonin could exert its antitumoral
effects on hormone-dependent mammary tumors by inhibiting
the aromatase activity of the tumoral tissue, and
phase II studies report an increase of objective responses
in cancer patients using melatonin. Partially on the
basis of this and related findings, Abrial et al.
(Pathol Biol (Paris) (2005): Potentiel
thérapeutique de la mélatonine dans
la prise en charge de la pathologie cancéreuse
[Therapeutic potential of melatonin in cancer treatment])
initiated a phase II randomised study of melatonin
versus placebo in metastatic breast cancer patients
after two lines of treatment. And Y. Touitou (Bull
Acad Natl Med (2005): Melatonin:
what for?)
concluded that melatonin has both strong antioxidant
properties - stronger than those of vitamin E - and
oncostatic action. Furthermore, according to the research
of Martinez-Campa et al. (Breast Cancer Res Treat
(2005): Melatonin
enhances the inhibitory effect of aminoglutethimide
on aromatase activity in MCF-7 human breast cancer
cells),
melatonin may be a novel means to increase the efficacy
of competitive aromatase inhibitors used in treating
breast cancer.
Melatonin as a SERM, Aromatase
Inhibitor, and Anti-Estrogen
Melatonin demonstrates an an oncostatic role on hormone-dependent
mammary tumors, interacting with estrogen-signaling
pathways via three antiestrogenic mechanisms:
(1) acting through the estrogen receptor to interfere
with the effects of endogenous estrogens (in keeping
with selective estrogen receptor modulator (SERM)
activity); and
(2) interfering with estrogen synthesis by inhibiting
the enzymes that control the interconversion from
their androgenic precursors (in keeping with anti-aromatase
/ inhibitory activity);. and
(3) decreasing circulating levels of estradiol (anti-estrogen
activity)
(on these melatonin mechanism, see the review of Sánchez-Barceló
and colleagues (J Pineal Res (2005): Melatonin–estrogen
interactions in breast cancer) who
conclude that melatonin fulfills all the requirements
to be considered as a true antiestrogenic agent. This
is reinforced by the findings of Cos et al. (Cancer
Detect Prev (2006): Estrogen-signaling
pathway: A link between breast cancer and melatonin
oncostatic actions) who conclude that
"melatonin's direct effect on mammary tumor
cells is that it interferes with the activation of
the estrogen receptor, thus behaving as a selective
estrogen receptor modulator", and citing
the multiple activities on distinct endocrine pathways,
adds "It is these action mechanisms that collectively
make melatonin an interesting anticancer drug in the
prevention and treatment of estrogen-dependent tumors,
since it has the advantage of acting at different
levels of the estrogen-signaling pathways".
The antiestrogen activity of melatonin is further
documented in the discussion of "Melatonin as
an oncostatic substance" in Pandi-Perumal et
al.'s review (FEBS (2006): Melatonin:
Nature's most versatile biological signal?)
who observe that (1) melatonin exhibits a growth inhibitory
effect in estrogen-positive, MCF human breast cancer
cell lines, (2) melatonin inhibits the growth of estrogen-responsive
breast cancer by modulating the cell's estrogen signaling
pathway, and (3) can exert its action on cell growth
by modulation of estradiol receptor transcriptional
activity in breast cancer cells.
For further clarification of the complex and multiple
pathways melatonin exerts activity over, see Bartsch
& Bartsch, Pineal
Gland and Cancer–An Epigenetic Approach to the
Control of Malignancy: Evaluation of the Role of Melatonin
(Chapter 7 in Pandi-Perumal & Cardinali (Ed.),
Melatonin: Biological Basis
of its Function in Health and Disease (Landes
Bioscience (2005)) who observe that fresh tumors are“sensed”
by the pineal gland via neuroimmunoendocrine changes,
leading to a stimulation of melatonin secretion which
in turn activates endogenous defense processes, and
they further document the mobilization of endogenous
defense mechanisms against malignant processes by
melatonin, thus improving survival, suggesting that
melatonin via indirect systemic mechanisms is able
to favorable affect even advanced forms of malignancy,
although a caution is that melatonin also exerts stimulatory
effects on the hematopoietic system, thus potential
aggravating a bone marrow cancer like leukemia.
Circadian Disruption and Breast
Cancer
A new hypothesis has been postulated about the relation
of melatonin, light at night, and breast cancer, known
as circadian disruption.
Thus there appears to be an inverse association between
sleep duration and breast cancer risk, possibly due
to greater overall melatonin production in longer
sleepers, according to a recent population-based study
(Verkasalo et al., Cancer Res (2005): Sleep
Duration and Breast Cancer: A Prospective Cohort Study),
and this is consonant with the recent findings of
Blask et al. (Endocrine (2005): Putting
cancer to sleep at night: the neuroendocrine/circadian
melatonin signal) who found in their
animal study that nocturnal dietary supplementation
with melatonin, at levels contained in a melatonin-rich
diet inhibits tumorogenesis, possibly by multiple
activities: via inhibition of cell proliferation,
a stimulation of differentiation and apoptosis, and
melatonin-induced suppression of tumor linoleic acid
(LA) uptake (note that light during darkness suppresses
nocturnal melatonin production and stimulates the
LA metabolism and growth of human breast cancer).
These findings are the first demonstrating that tumor
growth response to exposure to light-during-darkness
is (1) intensity dependent and (2) that the human
nocturnal circadian melatonin signal both inhibits
human breast cancer growth, but also is an effect
nullified by short-term ocular exposure to bright
white light at night.
And cross-confirmation exists from the animal research
of Saez et al. (Mol Cell Biochem (2005): Melatonin
increases the survival time of animals with untreated
mammary tumours: neuroendocrine stabilization)
who found that strongly suggest that melatonin per
se is beneficial during advanced breast cancer, by
increasing survival time, perhaps by improving the
homeostatic and neuroendocrine equilibrium which is
imbalanced during advanced breast cancer. And light
and lighting during typical periods of darkness, as
at night, of sufficient intensity can disrupt circadian
rhythms, including reduction of circulating melatonin
levels and resetting of the circadian pacemaker, and
this reduced melatonin may increase breast cancer
risk through several mechanisms, including increased
estrogen production and altered estrogen receptor
function (RG Stevens, Epidemiology (2005): Circadian
Disruption and Breast Cancer: From Melatonin to Clock
Genes). See also Mahmoud et al. (Am
J Hosp Palliat Care (2005): The
therapeutic application of melatonin in supportive
care and palliative medicine) who concluded
that circadian disruption is linked to increased cancer
risk, and that the chronobiotic capacity of melatonin
to reset circadian clocks may provide a verifiable
strategy to reduce cancer risk and enhance quality
of life by diminishing cancer-induced circadian disruption.
And related to this, it appears that although shorter
sleep duration (< 7 hours nightly) is not associated
with breast cancer risk reduction, it was the case
that increasing sleep duration (9 or more hours nightly)
is modestly associated with an increased breast cancer
risk (McElroy et al., J Sleep Res (2006): Duration
of sleep and breast cancer risk in a large population-based
case–control study), a finding
the may hinge on melatonin and cortisol activity.
And in addition, melatonin has the potential therapeutic
value to enhance immune function in aged individuals
and in patients in an immunocompromised state such
as cancer disease and the immunocompromised state
induced by various oncotherapies (including chemotherapy,
endocrine/hormonal therapy, biological therapy and
radiotherapy (Srinivasan et al., Immune Ageing (2005):
Melatonin,
immune function and aging).
And the recent systematic review of randomized controlled
trials and meta analysis reported the efficacy of
melatonin in solid tumor cancer patient (Mills et
al., J Pineal Res (21005): Melatonin
in the treatment of cancer: a systematic review of
randomized controlled trials and meta-analysis),
with the presence of melatonin prolonging both disease
progression-free and overall 1-year survival in many
randomized controlled trials (Indian J Med Sci (2006):
Melatonin
in pathogenesis and therapy of cancer).
See also Paula Witt-Enderby and her colleagues at
Duquesne University (J Pineal Res (2006): Therapeutic
treatments potentially mediated by melatonin receptors:
potential clinical uses in the prevention of osteoporosis,
cancer and as an adjuvant therapy).
Night-shift Breast Cancer
These findings are in keeping with what is known about
so-called night-shift breast cancer phenomenon: an
increased risk of breast cancer is seen among subjects
not sleeping during the period of the night when nocturnal
melatonin levels are typically at their highest, and
hence with graveyard shiftwork, with even some indication
of an increased risk among subjects with the brightest
bedrooms (Davis et al, J Natl Cancer Inst: Night
Shift Work, Light at Night, and Risk of Breast Cancer,
where it was concluded that "to the extent that
graveyard shiftwork and nonpeak sleep reflect exposure
to light at night, the results of this study add to
a growing body of evidence that such exposure, for
whatever reason, may be linked to breast cancer risk",
speculated to be due to the fact that light at night
exposure reduces nocturnal melatonin levels, which
can result in increased circulating estradiol concentrations
in the blood). (See also Schernhammer et al, J Natl
Cancer Inst: Rotating
Night Shifts and Risk of Breast Cancer in Women Participating
in the Nurses' Health Study
and Schernhammer et al, Cancer Epidemiol Biomarkers
Prev: Epidemiology
of urinary melatonin in women and its relation to
other hormones and night work).
Evidencewatch Commentary
Although a recent study (Travis et al, J Natl Cancer
Inst: Melatonin
and Breast Cancer: A Prospective Study)
found no evidence that the level of melatonin is strongly
associated with the risk for breast cancer, this study
measured the level of 24-hour melatonin excretion
despite the fact, as pointed out by Hrushesky &
Black (J Natl Cancer Inst (2004): Re:
Melatonin and Breast Cancer: A Prospective Study)
in their commentary that differences in the nocturnal
duration of melatonin secretion and thus its distribution
across the night cannot be accounted for by measuring
24-hour excretion levels, and it may be necessary
to examine whether instead cancer risk is conferred
not by average 24-hour melatonin exposure, but by
the circadian temporal organization of melatonin availability.
Hrushesky & Black also correctly point out that
in those studies which have evidenced a relationship
between cancer risk and melatonin excretion, have
discovered the relationship based on circadian amplitude
or phase (time of melatonin upswing), not on the 24-hour
average amount of melatonin metabolite excreted.
Nor did the Travis study (above) control for the potentially
confounding factor of the relative nighttime light
exposure of case patients and control subjects, given
the well-established fact light exposure and especially
nocturnal light exposure may confer cancer risk through
modulation of the melatonin circadian pattern: see
Schernhammer & Hankinson (J Natl Cancer Inst (2005):
Urinary
Melatonin Levels and Breast Cancer Risk)
who used a prospective case–control study nested
within the Nurses' Health Study II cohort, finding
the prospective data supporting the hypothesis that
higher melatonin levels are associated with a lower
risk of breast cancer; also Schernhammer et al. (Cancer
Epidemiol Biomarkers Prev (2004): Epidemiology
of Urinary Melatonin in Women and Its Relation to
Other Hormones and Night Work)
who also concluded that women working on rotating
night shifts appear to experience changes in hormone
levels, as measured by urinary melatonin, that may
be associated with the increased cancer risk observed
among night-shift workers; and similar findings have
emerged with respect to colorectal cancer (see Schernhammer
et al., J Natl Cancer Inst (2003): Night-Shift
Work and Risk of Colorectal Cancer in the Nurses’
Health Study
who found that working a rotating night shift at least
three nights per month for 15 or more years may increase
the risk of colorectal cancer in women. (Although
the exact mechanisms involved in noctural light, decreased
melatonin levels, and increased cancer risk are still
being study, the molecular mechanisms are beginning
to be defined: the recent animal research of Flipski
et al. (J Natl Cancer Inst (2005): Effects
of Light and Food Schedules on Liver and Tumor Molecular
Clocks in Mice)
has found that altered light-dark modifies the expression
of molecular clock genes and genes involved in carcinogenesis
and tumor progression).
In addition, Megdal et al. (Eur J Cancer (205): Night
work and breast cancer risk: A systematic review and
meta-analysis)
conducted a systematic review and meta-analysis of
13 qualifying observational studies between January
1960 to January 2005 in order to assess the effects
of night work on breast cancer risk, concluding that
the studies to date collectively show an increased
breast cancer risk among women, with publication bias
unlikely to have influenced the results.
In conclusion, therefore, Evidencewatch finds that
numerous systematic reviews and meta-analyses, and
their underlying research, provide in the balance
compelling evidence of an
increased risk of breast cancer consequent to night
shift work and its known adverse impact on melatonin
production.
Radiation-induced
Dermatitis: Calendula:
Numerous agents have been proposed and tested for
both symptomatic care of radiation-induced dermatitis
and for potential protective activity against induced
skin toxicities. The efficacy of aloe
vera gel, a therapy commonly used to prevent
radiation-induced dermatitis and related skin toxicity,
has been rigorously evaluated in RCTs. Williams et
al (Int J Radiat Oncol Biol Phys (1996):
Phase III double-blind evaluation
of an aloe vera gel as a prophylactic agent for radiation-induced
skin toxicity) compared skin toxicity
between those receiving aloe vera gel and a control
group, finding that aloe vera exhibited no protective
effect for those receiving breast irradiation.
The FDA-approved preparation Biafine
(Medix Pharmaceuticals) is a wound-healing product
from France and has been marketed with claims to reduce
radiation-related skin toxicity, via its capacity
to recruit macrophages to epidermal wounds and promote
granulation tissue formation. However, Fisher et al.
(Int J Radiat Oncol Biol Phys (2000): Randomized
phase III study comparing best supportive care to
biafine as a prophylactic agent for radiation-induced
skin toxicity for women undergoing breast irradiation:
Radiation therapy oncology group (RTOG) 97-13)
compared Biafine with best supportive care, which
consisted of Aquaphor and aloe vera, in an RCT of
women receiving breast irradiation, finding no statistical
difference in skin toxicity between those receiving
Biafine and those treated with best supportive care.
Topical steroids are commonly used to treat radiation-induced
skin inflammation and dermatitis, having been shown
to inhibit the upregulation of the proinflammatory
cytokine IL-6 in response to ionizing radiation. One
RCT tested the efficacy of the corticosteroid cream
mometasone furoate (MMF) as a prophylactic and therapeutic
intervention, finding that prophylactic application
of MMF combined with an emollient cream significantly
decreased acute radiation dermatitis compared with
emollient cream alone (as reported in NBCC (National
Breast Cancer Centre) (2004): Skin
Care during Radiotherapy for Breast Cancer: A summary
of Key Research Findings [pdf]).
Thus, the effectiveness of many nonsteroid topical
agents for the prevention of acute dermatitis during
adjuvant radiotherapy for breast carcinoma has not
been demonstrated. An exception is the natural agent,
calendula cream: Pommier
et al. (J Clin Oncol: Phase
III Randomized Trial of Calendula Officinalis Compared
With Trolamine for the Prevention of Acute Dermatitis
During Irradiation for Breast Cancer)
compared the effectiveness of calendula with that
of trolamine, which is considered in many institutions
to be the reference topical agent. Calendula was found
to be highly effective for the prevention of acute
dermatitis of grade 2 or higher and may be proposed
for patients undergoing postoperative irradiation
for breast cancer.
Finally the NBCC review cited above found that moisturizers
containing sucralfate
or hyaluronic acid were
superior to those not containing one of those active
ingredients, in reducing the severity of skin lesions
and promoting healing of dry desquamation.
-
Endocrine
Therapy: Tamoxifen, Raloxifene, and AIs
Chemoprevention of breast
cancer essentially refers to interventions for breast
cancer risk reduction especially in individuals at
high risk, not to true prevention. Until recently,
the most widely studied chemopreventive class has
been SERMs (selective estrogen
receptor modulators) which includes tamoxifen
(Nolvaldex) and raloxifene
(Evista).
RCTs comparing the SERMs, either tamoxifen or raloxifene,
with placebo for reducing the risk of breast cancer:
Fisher et al. (J Natl Cancer Inst (1998): Tamoxifen
for Prevention of Breast Cancer: Report of the National
Surgical Adjuvant Breast and Bowel Project P-1 Study);
.
When considered together, the tamoxifen prevention
trials showed a 38% (95% CI 28-46; p<0.0001) reduction
in breast-cancer incidence. There was no effect for
breast cancers negative for estrogen receptor (ER;
hazard ratio 1.22 [0.89-1.67]; p=0.21), but ER-positive
cancers were decreased by 48% (36-58; p<0.0001)
in the tamoxifen prevention trials. Age had no apparent
effect. Rates of endometrial cancer were increased
in all tamoxifen prevention trials (consensus relative
risk 2.4 [1.5-4.0]; p=0.0005) and the adjuvant trials
(relative risk 3.4 [1.8-6.4]; p=0.0002). Venous thromboembolic
events were increased in all tamoxifen studies (relative
risk 1.9 [1.4-2.6] in the prevention trials; p<0.0001).
The evidence shows, therefore, that tamoxifen can
reduce the risk of ER-positive breast cancer. It is
clear from the completed trials that identification
of a subgroup of high-risk, healthy women for whom
the risk-benefit ratio is sufficiently positive is
possible.
|
|
Prevention:
Lifestyle and CAM Interventions
-
Exercise:
Active exercise may reduce breast cancer risk particularly
in young parous women. There are numerous observational
studies that have examined the relationship between
physical activity and breast cancer risk. Most of
these studies have shown an inverse relationship between
level of physical activity and breast cancer incidence.
The average relative risk reduction is reportedly
30% to 40% (Thune et al., N Engl J Med: Physical
activity and the risk of breast cancer;
see also McTiernan et al., JAMA: Recreational
physical activity and the risk of breast cancer in
postmenopausal women. The women's health initiative
cohort study),
and Bernstein et al. (J Natl Cancer Inst (2005):
Lifetime Recreational Exercise Activity and Breast
Cancer Risk Among Black Women and White Women)
who found an inverse association between physical
activity and breast cancer among black women and among
white women,
Note that the McTiernan study provides the additional
evidence:
(1) that both current exercise and exercise engaged
in after menopause are associated with a decreased
risk of breast cancer,
(2) that the effects appear to be induced even with
a relatively small amounts of exercise (1.25–2.5
hours per week of brisk walking),
(3) that the reduction in risk associated with exercise
was seen among both women on HRT and those not on
HRT. (See also the synopsis of Pritchard, in CMAJ:
Is
exercise effective in reducing the risk of breast
cancer in postmenopausal women?).
And a recent prospective observational study (Holmes
et al., JAMA (2005):
Physical Activity and Survival
After Breast Cancer Diagnosis) concluded
that physical activity after a breast cancer diagnosis
may improve survival, with the greatest benefit in
women who performed the equivalent of walking 3 to
5 hours per week at an average pace (absolute unadjusted
mortality risk reduction was 6% at 10 years). See
also Knols et al. (J Clin Oncol (2005): Physical
Exercise in Cancer Patients During and After Medical
Treatment: A Systematic Review of Randomized and Controlled
Clinical Trials).
However, it is not known if or to what degree the
observed association is due to confounding variables,
such as diet or a genetic predisposition to breast
cancer, although the weight of the evidence appears
to suggests that greater physical activity is associated
with lower serum concentrations of estradiol, estrone,
and androgens in postmenopausal women (see the review
of this and other breast cancer protective factors
by McTiernan, Oncologist: Behavioral
Risk Factors in Breast Cancer: Can Risk Be Modified?).
In this connection, Malin et al. (Cancer Epidemiol
Biomarkers Prev (2005): Energy
Balance and Breast Cancer Risk) found
that that promotion of behavior patterns that optimize
energy balance (weight control and increasing physical
activity) may be a viable option for breast cancer
prevention. See also the recent comprehensive review
of Lawrence Kushi and colleagues (Kishi et al., J
Nutr (2007): Lifestyle
Factors and Survival in Women with Breast Cancer).
[new] Independent
of this however, it would appear that a combination
of physical activity (as endurance training) couple
with low intake of both low calorie and low protein
dietary intake is associated with low plasma growth
factors and hormones linked to increased risk of cancer,
and low protein intake in particular may have the
additional protective effect as it is associated with
a decrease in the adverse factor of circulating IGF-I
(and of the concentration ratio of IGF-I to IGF binding
protein 3), independent of body fat mass (Am J Clin
Nutr (2006): Long-term
low-protein, low-calorie diet and endurance exercise
modulate metabolic factors associated with cancer
risk).
-
Obesity/Weight:
Over a hundred studies have examined the associations
between weight or BMI and incidence of breast cancer.
Obesity is associated with increased breast cancer
risk, especially among postmenopausal women who do
not use HRT/hormone therapy. The Women’s Health
Initiative Observational Study found that among women
who never used hormone replacement therapy or hormone
therapy, increased breast cancer risk was associated
with weight as the strongest predictor, with a relative
risk (RR) of 2.85 for women weighing more than 82.2
kg (180.8 lbs), compared with those weighing less
than 58.7 kg (129.1 lbs). (See Morimoto et al. in
Cancer Causes Control: Obesity,
body size, and risk of postmenopausal breast cancer:
the Women's Health Initiative).
See also Dignam et al. (J Nat Cancer Inst (2003):
Obesity,
Tamoxifen Use, and Outcomes in Women With Estrogen
Receptor–Positive Early-Stage Breast Cancer)
and Berclaz et al. (Ann Oncol (2004): Body
mass index as a prognostic feature in operable breast
cancer: the International Breast Cancer Study Group
experience), where jointly it was found
that although obesity had no significant effect on
recurrence risk or on tamoxifen efficacy, overall
mortality was significantly greater for obese breast
cancer patients compared with those of normal weight
(Jain et al., J Natl Cancer Inst (1994): Premorbid
diet and the prognosis of women with breast cancer;
McTiernan et al., JAMA (2003): Recreational
Physical Activity and the Risk of Breast Cancer in
Postmenopausal Women: The Women's Health Initiative
Cohort Study; also Enger et al. (Arch
Sug (2004): Body
Weight Correlates With Mortality in Early-Stage Breast
Cancer) who found that body weight
at diagnosis and ER status are important predictors
of breast cancer death in early-stage disease. This
is in essential agreement with Borugian et al. ( Am
J Epidemiol (2003): Waist-to-Hip
Ratio and Breast Cancer Mortality)
who found that waist-to-hip ratio was directly related
to breast cancer mortality in postmenopausal women
but not in premenopausal women; waist-to-hip ratio
(WHR) is a marker for insulin resistance and hyperinsulinemia,
and high insulin levels have been associated with
increased risk of breast cancer and poorer survival
after a breast cancer diagnosis.
Additional research has tended to be highly confirming
of the associated between obesity and increased risk
of breast cancer, especially as it is mediated through
dietary habits: see Goodwin et al. (J Clin Oncol (2003):
Diet
and Breast Cancer: Evidence That Extremes in Diet
Are Associated With Poor Survival)
who suggest that the association of key dietary variables
with breast cancer survival may be U-shaped rather
than linear: midrange intake of most major energy
sources is associated with the most favorable outcomes,
and extremes are associated with less favorable outcomes.
This nonlinear U-shaped association is in keeping
also with the association of body size (BMI) and breast
cancer risk, as overweight but also underweight status
is predictive of an unfavorable prognosis of breast
cancer (Suissa et al., Cancer Res (1989): Body
size and breast cancer prognosis: a statistical explanation
of the discrepancies, who offers this
as a possible explanation for the discrepancies among
previous studies on the topic).
See also Rock & Demark-Wahnefried (J Clin Oncol
(2002):
Nutrition and Survival After
the Diagnosis of Breast Cancer: A Review of the Evidence);
Rock & Demark-Wahnefried (J Nutr (2002: Can
Lifestyle Modification Increase Survival in Women
Diagnosed with Breast Cancer?); Brown
et al. (CA Cancer J Clin (2003): Nutrition
and Physical Activity During and After Cancer Treatment:
An American Cancer Society Guide for Informed Choices);
Selvan et al., (J Health Manag (2004): Social
and Dietary Changes Associated with Obesity and Breast
Cancer Risk [pdf]); Dignam & Mamounas
(Ann Oncol (2004): Obesity
and breast cancer prognosis: an expanding body of
evidence); Mai et al. (Int J Epidemiol
(2005): Diet
quality and subsequent cancer incidence and mortality
in a prospective cohort of women);
Whiteman et al. (Cancer Epidemiol Biomarkers Prev
(2005): Body
Mass and Mortality After Breast Cancer Diagnosis);
Loi et al. (Cancer Epidemiol Biomarkers Prev (2005):
Obesity and Outcomes in
Premenopausal and Postmenopausal Breast Cancer;
and Lukanova (Epidemiol (2005): Body
mass index and cancer: Results from the Northern Sweden
Health and Disease Cohort) found that
not only was BMI (body mass index) is positively associated
with cancer risk, but that up to 7% of all cancers
were attributable to overweight and obesity and could
be avoided by keeping BMI within the recommended range.
Also in essential agreement, are the three papers
on the CMAJ 2005 Clinical Practice Guidelines on the
Care and Treatment of Breast Cancer: Grunfeld et al.
(CMAJ (2005): Clinical
practice guidelines for the care and treatment of
breast cancer: follow-up after treatment for breast
cancer (summary of the 2005 update));
Grunfeld et al. (CMAJ (2005): Clinical
practice guidelines for the care and treatment of
breast cancer: 9. Follow-up after treatment for breast
cancer (2005 update)), and Grunfeld
et al. (CMAJ (2005): Questions
and answers on follow-up care after breast cancer
treatment: A guide for women and their physicians);
and Kroenke et al. (J Clin Oncol (2005): Weight,
Weight Gain, and Survival After Breast Cancer Diagnosis)
found that weight and weight gain were related to
higher rates of both recurrence of and mortality from
breast cancer,with the associations most apparent
in never-smoking women.
Furthermore, obese women are more likely to have higher
caloric and fat intakes, and at the same time lower
physical activity when compared with nonobese women,
with all three factors being associated with increased
breast cancer recurrence risk.
In conclusion, the evidence from this study and dozens
of others taken together, establishes:
(1) that overweight or obese women had a 30%-50% greater
risk for postmenopausal breast cancer development
than leaner women. In addition, and by contrast, excess
weight is associated with a somewhat lower risk of
breast cancer development during premenopausal years;
however, note that the study of Weiderpass et al.
(Cancer Epidemiol. Biomarkers Prev: A
Prospective Study of Body Size in Different Periods
of Life and Risk of Premenopausal Breast Cancer)
has clarified that the decreased risk of premenopausal
breast cancer was observed only in overweight and
obese women without a family history of breast cancer,
no in those with breast cancer family history;
(2) that adult weight gain is consistently associated
with a greater risk for postmenopausal breast cancer;
(3) that greater central adiposity is associated with
an approximate doubling of breast cancer risk among
postmenopausal women. (See McTiernan, Oncologist:
Behavioral
Risk Factors in Breast Cancer: Can Risk Be Modified?);
see also Chlebowski (J Clin Oncol (2005): Obesity
and Early-Stage Breast Cancer).
Seen from a risk reduction/prevention perspective,
Michels & Ekbom (JAMA: Caloric
Restriction
and Incidence of Breast Cancer),
observing that in experimental animals restricting
caloric intake is a highly effective way of extending
lifespan and reducing spontaneous tumor occurrence,
take up the question of whether similar associations
hold in humans, concluding that severe caloric restriction
in humans may confer protection from invasive breast
cancer. Indeed, although energy restriction remains
one of the most effective ways known to prevent breast
cancer in animal models, until recently energy intake
has not been consistently associated with risk of
breast cancer in humans, but energy intake, in addition
to BMI and physical activity may be independently
associated with breast cancer risk, and in addition,
these three aspects of energy balance may act jointly
in determining breast cancer risk, according to the
findings of the prospective trial of Change et al.
(Cancer Epidemiol Biomarkers Prev (2006): Association
of energy intake and energy balance with postmenopausal
breast cancer in the prostate, lung, colorectal, and
ovarian cancer screening trial).
A final unexpected risk for overweight / obese women
with breast cancer is the outgrowth of the fact that
these patients often receive intentionally reduced
doses of adjuvant chemotherapy, not the optimal initial
and overall full weight-based doses (Griggs et al.,
JAMA (2005): Undertreatment
of Obese Women Receiving Breast Cancer Chemotherapy),
thus compromising outcome.
-
Folate:
Although one study by Branda et al. (Cancer (2005):
Effect
of vitamin B12, folate, and dietary supplements on
breast carcinoma chemotherapy-induced mucositis and
neutropenia)
determined that the neutrophil count decrease consequent
to chemotherapy was ameliorated by dietary supplementation
with a multivitamin or vitamin E, but this neutrophil
decrease was actually exacerbated by high serum folate
levels, Zhang et al. (J Natl Cancer Inst (2005): Plasma
Folate, Vitamin B6, Vitamin B12, Homocysteine, and
Risk of Breast Cancer)
recently found that higher plasma levels of folate
(with intake at least 600 µg/day) - and possibly
vitamin B6 - may reduce the risk of breast cancer
development. They concluded that "achieving adequate
circulating levels of folate may be particularly important
for women at higher risk of developing breast cancer
because of higher alcohol consumption". Similarly,
Lajous et al. (Cancer Epidemiol Biomarkers Prev (2006):
Folate, Vitamin B6, and
Vitamin B12 Intake and the Risk of Breast Cancer Among
Mexican Women) that among postmenopausal
women, intakes of folate and vitamin B12 were associated
with a lower risk of breast cancer and those associations
were stronger than among premenopausal women, with
the inverse association of folate and breast cancer
being stronger among women who consumed a high level
of vitamin B12 as compared with women consuming diets
low in vitamin B12. No association was observed for
vitamin B6 intake
And there is some evidence that alcohol and folate
consumption interact to affect risk, with differences
in associations for those with or without p53 mutations,
and that causal pathways may vary for pre- and postmenopausal
women (Freudenheim, Carcinogenesis: Diet
and alcohol consumption in relation to p53 mutations
in breast tumors).
And adequate folate supplementation may protect against
alcohol related increased risk of breast cancer, as
found in the prospective cohort study (population
of 17,000 Australian women over 10 years) of Baglietto
and colleagues (BMJ (2005): Does
dietary folate intake modify effect of alcohol consumption
on breast cancer risk? Prospective cohort study).
They found that women who regularly consumed more
than 40 g (5 units) a day of alcohol had a 40% greater
risk of invasive breast cancer than lifetime abstainers,
but that a daily folate intake of 400 µg (micrograms)
in this drinking group was however associated with
a significant reduction in risk, when compared with
a lower daily intake of 200 µg. This is an important
preventive message, as it demonstrates that the known
adverse effect of alcohol consumption may be reduced
by sufficient dietary intake of folate.
Furthermore, the findings of Tjonneland et al. (Eur
J Clin Nutr (2005): Folate
intake, alcohol and risk of breast cancer among postmenopausal
women in Denmark) also support the
evidence that adequate folate intake may attenuate
the risk of breast cancer associated with high alcohol
intake, and confirming the conclusion from other studies
that alcohol intake and risk of breast cancer are
associated mainly among women with low folate intake;
they note that among women with a folate intake higher
than 350 micrograms, there was no association between
the alcohol intake and the breast cancer incidence.
Warning:
However, at least one recent study failed to support
the hypothesis that high folate intake reduces breast
cancer risk; Stolzenberg-Solomon et al. (Am J Clin
Nutr (2006): Folate
intake, alcohol use, and postmenopausal breast cancer
risk in the Prostate, Lung, Colorectal, and Ovarian
Cancer Screening Trial)
instead found that a high intake may actually increase
the risk in postmenopausal women.
[new]
Breast Cancer Prevention
Watch: Folate and Breast Cancer
A recent meta-analysis from Sarah Lewis and her colleagues
(J Natl Cancer Inst (2006): Meta-analyses
of Observational and Genetic Association Studies of
Folate Intakes or Levels and Breast Cancer Risk)
at the University of Bristol concludes that alack
of dietary folate intake is not associated with the
risk of breast cancer, while another meta-analysis
from Susanna Larsson and coresearchers (J Natl Cancer
Inst (2006): Folate
and Risk of Breast Cancer: A Meta-analysis),
although finding no clear support for an overall relationship
between folate intake or blood folate levels and breast
cancer risk, did conclude that adequate folate intake
may reduce the increased risk of breast cancer that
has been associated with moderate or high alcohol
consumption. But there are inherent problems with
the sampled case–control studies and the subgroup
analyses, where the heterogeneity across studies with
respect to lifestyle, genetic makeup, and instruments
used for dietary assessment are left unexamined (as
noted in the ditorial of Han-Yao Huang, J Natl Inst
Cancer (2006): Customized
Diets for Cancer Prevention According to Genetic Polymorphisms:
Are We Ready Yet?), and in addition
since nutrient intake is often associated with other
lifestyle factors - and still other nutrients (methionine,
betaine, choline, B vitamins) can influence the breast
cancer / folate association - the variability in the
extent of adjustment for lifestyle factors among the
studies renders the validity of conclusions from their
meta-analyses uncertain, especially given that Larsson
admits that dietary folate intake was indeed statistically
significantly inversely associated with risk of breast
cancer in case–control studies, but not so in
prospective studies, and it is well known that prospective
and retrospective studies can give different estimates
for associations between dietary exposures and cancer
risk, and case-control studies may be affected by
inaccurate recall of dietary intake. Finally the amount
of folate supplementation is generally not held consistent
across various sampled studies, and co-factors such
as homocysteine and others cited above may influence
the association critically, and are not explicitly
measured or held constant in cross-study comparisons.
However, weighing all this potential confounding factors
and methodological issues together, our conclusions
are that the overall association between folate intake
or folate blood levels and breast cancer risk is not
at present strongly evidenced from the available data
base, and we still require additional methodoligically
high-quality studies to draw more definitive conclusions
in this arena.
-
I3C
/ Cruficerous Vegetables:
Epidemiological studies provide evidence that the
consumption of cruciferous vegetables protects against
cancer more effectively than the total intake of fruits
and vegetables. The indole-3-carbinol (I3C) component
in brassica and cruciferous vegetables may may also
be protective in cervical and possibly prostate cancers,
probably by enhancing 2-hydroxyestrone (an estrogen
receptor antagonist - non-stimulative of breast tumors
- produced in estrogen breakdown) at the expense of
16-hydroxylation (an estrogen receptor agonist - promoting
breast tumors - also produced in estrogen breakdown),
thus shifting the ratio to the favorable estrogen
breakdown product (see Keck and Fenley, Integr Cancer
Ther: Cruciferous
vegetables: cancer protective mechanisms of glucosinolate
hydrolysis products and selenium).
Epidemiological, laboratory, animal and translational
studies increasingly indicate that dietary indole-3-carbinol
(I3C) prevents the development of estrogen-enhanced
cancers including breast, endometrial and cervical
cancers (Auborn et al., J Nutr: Indole-3-carbinol
is a negative regulator of estrogen)
(see also von Poppel, Exp. Med. Biol: Brassica
vegetables and cancer prevention. Epidemiology and
mechanisms;
Terry et al., JAMA: Brassica
vegetables and breast cancer risk,
where it was found that consumption of brassica vegetables
was inversely associated with breast cancer risk,
especially 1 to 2 servings per day, lowers the risk
of breast cancer by as much as 20% to 40%, possibly
by shifting the pathway of estrogen metabolism) (Ambrosone
et al., J Nutr: Breast
Cancer Risk in Premenopausal Women Is Inversely Associated
with Consumption of Broccoli, a Source of Isothiocyanates,
but Is Not Modified by GST Genotype,
which found that vegetables may play an important
role in decreasing the risk of premenopausal, but
not postmenopausal, breast cancer) (Fowke et al.,
Cancer Res: Urinary
isothiocyanate levels, brassica, and human breast
cancer,
which found that "greater Brassica vegetable
consumption, as measured by the urinary ITC biomarker,
was associated with significantly reduced breast cancer
risk among Chinese women"; also Fowke et al.,
Cancer Epidemiol. Biomarkers Prev: Urinary
Isothiocyanate Excretion, Brassica Consumption, and
Gene Polymorphisms among Women Living in Shanghai,
China)
(Bell et al, Gynecol. Oncol: Placebo-controlled
trial of indole-3-carbinol in the treatment of CIN)
(Shukla et al., Teratog Carcinog Mutagen: Antigenotoxic
potential of certain dietary constituents).
One specific dietary regimen that has been reported
to be effective is a high fiber diet including the
consumption of 50 g of cabbage or 100 g of broccoli
twice weekly; see Lord et al., Altern Med Rev: Estrogen
metabolism and the diet-cancer connection: rationale
for assessing the ratio of urinary hydroxylated estrogen
metabolites
[pdf]) (Brignall, Altern Med Rev: Prevention
and treatment of cancer with indole-3-carbinol
[pdf]) (Kelloff et al., J Nutr: Progress
in cancer chemoprevention: development of diet-derived
chemopreventive agents,
where it is suggested that the anti-breast cancer
activity of I3C may be exerted through modulation
of cytochrome P450-dependent estradiol metabolism,
by enhancing 2-hydroxyestrone (estrogen receptor antagonist)
at the expense of 16-hydroxylation (estrogen receptor
agonist. And Reed et al. (Cancer Epidemiol Biomarkers
Prev (2005): A
Phase I Study of Indole-3-Carbinol in Women: Tolerability
and Effects)
have recently determined with respect to I3C supplementation
that no more than 400 mg I3C daily would elicit maximal
protective effect.
Issue: The Safety of I3C
Recently, several studies have raised safety concerns
for I3C consumption. One concern centers around aflatoxin-induced
tumors, expressed as hepatocarcinogenesis. RH Dashwood
and colleagues at the Department of Environmental
Biochemistry, University of Hawaii (Dashwood et al.,
Cancer Res (1991): Promotion
of aflatoxin B1 carcinogenesis by the natural tumor
modulator indole-3-carbinol: influence of dose, duration,
and intermittent exposure on indole-3-carbinol promotional
potency) found that such tumors in
fish (trout) are inhibited by I3C when it is given
prior to aflatoxin exposure, but aflatoxin-induced
tumor activity was promoted by I3C when given after
aflatoxin initiation, also confirmed independently
by Aram Oganesian and colleagues at Oregon State University
(Organesian et al., Carcinogenesis (1991): Potency
of dietary indole-3-carbinol as a promoter of aflatoxin
B1-initiated hepatocarcinogenesis: results from a
9000 animal tumor study), and more
recently by another team of researchers at Oregon
State University headed by Susan Tilton and colleagues
(Toxicol Sci (2006): Toxicogenomic
Profiling of the Hepatic Tumor Promoters Indole-3-Carbinol,
17ß-Estradiol and ß-Naphthoflavone in
Rainbow Trout) who also found that
another compound DIM (3,3'-diindolylmethane), a major
in vivo component of I3C, might be an even more potent
hepatic tumor promoter than I3C itself.
However, against this, in a somewhat more plausible
rat study, MM Manson and colleagues (Manson et al.,
Carcinogenesis (1999): Chemoprevention
of aflatoxin B1-induced carcinogenesis by indole-3-
carbinol in rat liver--predicting the outcome using
early biomarkers [pdf]) at the University
of Leicester found that I3C inhibited the progression
of aflatoxin-induced hepatocarcinogenesis at both
the initiation and promotion stages, in direct contradiction
of the Dashwood and Oganesian in rainbow trout, and
this positive finding has been more recently confirmed
by Matthew Wallig and colleagues at the University
of Illinois (Wallig et al., J Nutr (2005): Synergy
among Phytochemicals within Crucifers: Does It Translate
into Chemoprotection). And also contradicting
the studies cited above that purport to find a potential
for I3C to promote hepatocarcinogenesis in certain
but not all species, the animal study (on Wistar rats)
of Yogeshwer Shukla and colleagues (Skukla et al.,
Nutr Cancer (2004): Chemopreventive
Effect of Indole-3-Carbinol on Induction of Preneoplastic
Altered Hepatic Foci)
confirmed a chemopreventive effect of I3C in rat hepatocarcinogenesis
through the suppression by I3C of diethylnitrosamine
(DEN)- and acetylaminofluorene (AAF)-induced altered
hepatic foci (AHF) development, an action opposite
to hepatocarcinogenesis. And still another contradicting
study is that of Aram Oganesian and coresearchers
(Oganesian et al. Cancer Lett (1997): Long
term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated
hepatocarcinogenesis in the infant mouse model)
who, citing concerns raised regarding the potential
tumor-promotional potency of I3C in other target organs
such as liver, examined directly the hepatic tumor-modulatory
properties of I3C when fed to mice (C57BL/6J) initiated
with diethylnitrosamine (DEN), finding that there
was actually a statistically significant inhibition
of hepatocarcinogenesis observed for I3C-fed animals
initiated with high dose of DEN, concluding that that
long term administration of I3C in the diet inhibits
DEN-initiated hepatocarcinogenesis in the infant mouse
model. And in rainbow trout, where some observers
claimed to find I3C promotion of hepatocarcinogenesis,
other researchers failed to confirm such promotion
(see the study of Takahashi and the Oregon State University
team (Takahashi et al., Food Chem Toxicol (1995):
Induction of hepatic CYP1A
by indole-3-carbinol in protection against aflatoxin
B1 hepatocarcinogenesis in rainbow trout)
With dueling models - rainbow trout versus rat versus
mouse etc. - and potentially differential confounding
factors across studies and models, the safety issue
is left at time of writing rather indeterminate, and
there is certainly insufficient compelling evidence
to propose a clear danger in the human clinical setting.
A second concern surrounding the issue of potential
adverse interactions through the P450 cytochrome family
of enzymes, especially on the hepatic microsomal metabolism
of tamoxifen (TAM): so Daniel Parkin and Danuta Malejka-Giganti
at the University of Minnesota (Parkin et al., Cancer
Detect Prev (2004): Differences
in the hepatic P450-dependent metabolism of estrogen
and tamoxifen in response to treatment of rats with
3,3'-diindolylmethane and its parent compound indole-3-carbinol)
in another rat study found that although metabolism
of TAM was unaffected by DIM, formation of N-desmethyl-TAM
was increased 3-fold by I3C, and since N-desmethyl-TAM
is transformed to a genotoxic metabolite, this appears
to suggest that dietary exposure to I3C may enhance
hepatic carcinogenicity of TAM in the rat.
However, here again, conflicting results exists: so
Dustin Leibelt and colleagues at Oregon State University
(Leibelt et al., Toxicol Sci (2003): Evaluation
of Chronic Dietary Exposure to Indole-3-Carbinol and
Absorption-Enhanced 3,3'-Diindolylmethane in Sprague-Dawley
Rats) failed to detect any direct toxicity
by long-term exposure to I3C and DIM, even at doses
up to approximately 5–7 times the daily dose
recommended by commercial suppliers of I3C supplements,
and at exposure 10 times higher than the current human
dose for DIM, and the researchers concluded that data
from their present study confirms results from short-term
studies indicating that both I3C and DIM are relatively
nontoxic compounds, and furthermore confirm earlier
long-term feeding studies in other models, including
the rainbow trout and the same strain of rat used
in the present study, that I3C is not a complete carcinogen,
a finding also confirmed by Gary Stoner and co-researchers
(Stoner et al., Carcinogenesis (2002): Development
of a multi-organ rat model for evaluating chemopreventive
agents: efficacy of indole-3-carbinol)
who nonetheless warn that I3C may not an appropriate
chemoprotective agent for human use in that it appears
to both inhibit (breast, colon) and promote (liver)
carcinogenesis. And the Leibelt study warns of two
distinct concerns: (1) that the prolonged use of I3C
for cancer chemoprevention exhibits a potential for
promotion of liver neoplasms, although they prudently
admit that the long-term post-initiation effects of
I3C in hepatocarcinogenesis are not consistent across
species (trout, rats, black mice), leaving open what
the real risk is, if any, in the human context; and
(2) the induction of CYP enzymes by I3C, especially
those of the 1A subfamily, could be a cause for concern,
as these play a role in activation of polycyclic aromatic
hydrocarbons (PAH) and aromatic amines with known
toxicities, a concern that appears not to be shared
with DIM. The reason for this may be that in the acidic
conditions of the stomach after oral exposure, I3C
becomes a complex mixture more than 20 different I3C-derived
compounds, including DIM, all having various pharmacological/toxicological
effects, while DIM is relatively more stable in acid
and does not robustly undergo further condensation
reactions, suggesting that the more stable DIM component
may be the safer compound to deploy in the human context.
However, I3C yielded dose-dependent increases in the
hepatic P450 level according to the research of Malejka-Giganti
and coresearchers at the University of Minnesota (Malejka-Giganti
et al., Cancer Epidemiol Biomarkers Prev (2003): Effects
of treatment of rats with indole-3-carbinol or 3,3'-diindolylmethane
on the hepatic P450-dependent metabolism of estrogen
and tamoxifen) who in their animal
study of female Sprague-Dawley rats tested 5, 25 and
250 mg/kg body weight of I3C and DIM at 8.4 and 42
mg/kg body weight, finding that oral intake of I3C
or DIM at lower dose levels did not alter CYP-mediated
metabolism of tamoxifen, and hence, would not alter
its therapeutic efficacy. Since for a human female
weighing 140 lbs, equivalent to about 64 kilograms
(kg), the CYP-mediated TAM metabolism altering dose
(250/mg/kg) would map to 16,000 mg, which is easily
40 times greater than the recommended I3C dosing of
400mg/daily, and from these findings it would appear
that doses up to 1600mg/daily would be without adverse
interactions on tamoxifen metabolism and efficacy,
assuming the same 140 lbs female. Therefore 400mg/daily
IC3 ingestion is at a level to assure no oncotherapy
interference with tamoxifen.
In summary, we note the conclusions of a recent comprehensive
review by EG Rogan with the Eppley Institute for Research
in Cancer and Allied Diseases at the University of
Nebraska Medical Center (EG Rogan, In Vivo (2006):
The
natural chemopreventive compound indole-3-carbinol:
state of the science) who notes that
"although I3C has been shown to protect against
tumor induction by some carcinogens, it has also been
observed to promote tumor development in animal models"
and that in humans, concerns have been raised that
I3C "might increase the formation of estrogen metabolites
that induce or promote cancer" they nonetheless
conclude that this has not been demonstrated in any
way.
Therefore given the contradictory findings of
harm across divers species, and the complete lack
of any human clinical data to suggest any potential
promotion of hepatocarcinogenesis, we must conclude
that there is no convincing evidence of such adverse
potential of I3C and DIM in humans. Furthermore, the
in vivo component of I3C, 3,3'-diindolylmethane (DIM)
is unlike, its precursor, I3C itself, not highly enzyme-inducing,
where it appears from the evidence base that it is
the unwanted enzyme induction by I3C that accounts
for any perceived adverse tumor promotion activity
by I3C, and lacking these unwanted enzyme-inducing
effects, DIM, which appears to share the positive
efficacy of I3C in breast and cervical carcinomas,
would be suggested as the safer compound in human
use (and in keeping with the conclusion of Leibelt,
cited above, that "Long-term exposure to DIM
produced no observable toxicity, and comparison to
I3C indicates that DIM is a markedly less efficacious
inducer of CYP in the rat at doses relevant to human
supplementation").
Clinical Conclusions:
I3C/ DIM
However, we cannot sustain sufficient balance of
evidence to suggest supplementation of I3C/DIM, given the
relatively large number of continuing serious
concerns, as cited above (as in the studies of Dashwood, Tilton,
Oganesian, Parkin, Malejka-Giganti, and Rogan
among others) left unresolved. And further
concerns have been voice by Frank Johnson and James
Huff at the National Institute of Environmental
Health Sciences (Johnson F, Huff J.
Development of a multi-organ rat model for
evaluating chemopreventive agents: efficacy of
indole-3-carbinol. Certain health supplements may
cause both carcinogenic and anticarcinogenic
effects. Carcinogenesis 2002 Oct; 23(10):1767-8) concerning an I3C-induced combination of anticarcinogenic and carcinogenic effects. Likewise, Makato Suzui and colleagues in Japan
have that found that I3C inhibits the growth of human colon carcinoma cells through induction of p27KIP1 and p21CIP1-mediated G1 cell-cycle arrest but that dietary I3C promotes AOM-induced rat colon carcinogenesis via inhibition of the apoptosis of colon tumors, establishing once again an ambivalent Janus-like modulatory activity from I3C (Suzui M, Inamine M, Kaneshiro T, et al.
Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int J Oncol 2005 Nov; 27(5):1391-9),
disallowing based on the current evidence to date
any positive guidance for supplementation.
Issue: The Safety of Garlic
Furthermore, Brian Foster of Health Canada) has further
help to clarify this issue (Foster, J Pharm Pharmaceut
Sci (2001):
An In Vitro Evaluation of
Human Cytochrome P450 3A4 and P-glycoprotein Inhibition
by Garlic); the study tested 6 different
garlic supplements (ranging in dose from 10mg to 20mg,
equivalent to 1000mg to 2000mg fresh garlic content)
inhibited the cytochrome p450 CYP2C19 enzyme by 21%
to 53%, and concludes that "constituents
of garlic may not need to be present in high levels
to elicit a pharmacological effect in order to produce
a systemic or pre-systemic effect on drug disposition.
The potential for the garlic
products examined in this study to affect drug disposition
may increase if used in combination with one or more
conventional therapeutic products"
and more importantly, that "that
the disposition of drugs . . . could be inhibited
after the co-administration with garlic
or garlic products".
Note that the metabolism of the widely deployed endocrine
agent / aromatase inhibitor letrozole (Femara) is
CYP2C19-mediated, and so potentially adversely affected
by garlic coadministration.
In contrast with these in vitro findings, David Greenblatt
and his colleagues at Tufts evaluated 8 water-soluble
components of aged garlic extract in order to asses
potential to inhibit cytochrome-P450 (CYP) enzyme
activity, for the CYP1A2, CYP2B6, CYP2C9, CYP2C19,
CYP2D6, and CYP3A, observing that none of the 8 garlic
components produced >50% inhibition even at high
concentrations, except for S-methyl-L-cysteine and
S-allyl-L-cysteine, which produced 20–40% inhibition
of CYP3A compared to control. They conclude from this
that drug interactions involving inhibition of CYP3A
enzymes by aged garlic extract are very unlikely.
However, Breast Cancer Prevention
Watch notes:
(1) that although their observation there is no available
clinical evidence for CYP3A inhibition in vivo by
garlic or Allium components is accurate, it should
be remember that there is no such in vivo data because
no in vivo trial has been conducted to settle the
matter one way or the other, so the absence of data
for an in vivo inhibitory effect is not to be construed
as the presence of positive data that shows no such
effect occurs in fact.
(2) that they consider the two exceptions (the S-methyl-L-cysteine
and S-allyl-L-cysteine garlic components) of significant
20–40% inhibition of CYP3A as "modest",
but a reduction this large, were it to be evidenced
in vivo with oncotherapy, would be considered quite
dramatic and of grave concern given the narrow therapeutic
index of oncotherapeutic agents, and this suggests
at least a potential for adverse interaction with
such endocrine agents as anastrozole (Arimidex) whose
metabolism is CYP3A-mediated, exemestane (Aromasin)
which is CYP3A4-mediated, and the CYP3A4-mediated
chemotherapy agents the taxanes docetaxel (Taxotere),
paclitaxel (Taxol), nab-paclitaxel (Abraxane), or
any of the Vinca alkaloids vinorelbine (Navelbine),
vinblastine (Velban), and vincristine (Oncovin), and
the platinum agent carboplatin. Without in vivo data
to demonstrate no clinically significant impact of
this CYP3A/3A4-inhibitory activity, the potential
for adverse interaction remains (not that although
on at least one of these agents, docetaxel (Taxotere)
Michael Cox and coresearchers (Cox et al., Clin Cancer
Res (2006): Influence
of Garlic (Allium sativum) on the Pharmacokinetics
of Docetaxel) found that garlic did
not significantly affect the disposition of docetaxel,
nonetheless as the authors admit, it cannot be excluded
that garlic decreases the clearance of docetaxel in
patients carrying a CYP3A5*1A allele, and hence coadministration
is still problematic, as can not typically pre-identify
these populations).
(3) the Greenblatt findings, with respect to CYP2C19
appear to be in direct contradiction to the Foster
findings cited above, although Breast Cancer Prevention
Watch notes this may be an artifact of the overly
permissive and broad definition of significant interaction
in the Greenblatt study, which is > 50% inhibition.
In contrast the Foster study found that the 6 garlic
supplements (ranging in dose from 10mg to 20mg, equivalent
to 1000mg to 2000mg fresh garlic content) inhibited
the cytochrome p450 CYP2C19 enzyme by 21% to 53%,
amounts they observe correctly could
"elicit a pharmacological effect in order to
produce a systemic or pre-systemic effect on drug
disposition".
We see here a classical difference of disposition:
for Greenblatt, potential interaction appear to have
to exert very large effects (> 50%) before perceived
as clinically significant, while for Foster a potential
20% or higher reduction in the activity of a drug
(and possibly lower) is taken as significant in reductive
capability; more in contrast. Greenblatt takes an
optimistic approach
to the issue of potential adverse interaction (based
on in vitro findings), not observing a notable hazard
unless there are explicit data that show an in vivo
adverse interaction, while Foster takes a cautionary
perspective until in vivo data were to show that the
potentially adverse interaction in vitro is not also
found in vivo, and absent such evidence, as here,
views coadministration as problematic.
Given the narrow therapeutic index of oncotherapy
agents, and their potential impact on mortality, Breast
Cancer Prevention Watch would suggest erring on the
side of caution: after all, for years we have known
about a well-documented potentially adverse compromise
of tamoxifen efficacy when coadministered with SSRI
antidepressants, but many oncologists (but not David
Flockhart, a principal in these findings) argued that
proactive data of a clinically adverse interaction,
coadministration should continue without change (while
as many said "the jury is still out".
Others, including ourselves at
Breast Cancer Prevention Watch, reasoned otherwise,
noting that the absence of demonstration of harm is
not equivalent to the demonstration of no harm, and
that given the vital operation of tamoxifen, typically
administered over years, it would be imprudent to
chance coadministration with an SSRI only to learn
that indeed the interaction is significant, and adverse,
at the clinical level, as this may entail tamoxifen
failure, and even consequent patient mortality or
disease recurrence due to deployment of an efficacy-compromised
endocrine agent like tamoxifen.
On the basis therefore of the above considerations,
we agree with the conclusion of Sonnichsen and colleagues
(Sonnichsen et al., MMW Fortschr Med (2005): Food-drug
interactions: an underestimated risk)
who conclude that "Certain
foodstuffs or food constituents, such as, for example,
grapefruit, Seville orange juice, red wine, alcoholic
drinks in general, or large quantities of caffeine
and garlic should be avoided during drug treatment",
in keeping also with the results of Alex Sparreboom's
and colleagues at the NCI in their review, finding
that garlic was one of the natural agents with the
"potential to significantly modulate the activity
of drug-metabolizing enzymes (notably cytochrome P450
isozymes) and/or the drug transporter P-glycoprotein"
and which "participate[s]
in potential pharmacokinetic interactions with anticancer
drugs" and also with the results of
Zhou et al. (Life Sci (2004): Herbal
bioactivation: The good, the bad and the ugly)
who found potentially adverse interaction of the daily
sulfone component of garlic as a CYP3A4 inhibitor,
although an earlier study by Markowitz et al. (Clin
Pharmacol Ther (2003): Effects
of garlic (Allium sativum L.) supplementation on cytochrome
P450 2D6 and 3A4 activity in healthy volunteers)
found in contradiction that garlic extracts were unlikely
to alter the disposition of coadministered medications
primarily dependent on the CYP2D6 or CYP3A4 pathway
of metabolism. Such not wholly convergent findings
suggest the need for caution concerning coadministration
until in vivo / clinical data are available to settle
the issue.
But recent developments support our cautionary stance:
the results by SK Knox and coresearchers (Knox et
al., 2006 ASCO Annual Meeting Proceedings, in J Clin
Oncol (2006): Cytochrome
P450 2D6 status predicts breast cancer relapse in
women receiving adjuvant tamoxifen (Tam))
just reported at the June 2006 ASCO meeting found
that in patients that coadminister tamoxifen and an
CYP2D6-inhibitory agent such as an SSRI or other inhibitory
agent (fluoxetine (Prozac), paroxetine (Paxil), sertraline
(Zoloft), cimetidine(Tagamet), amiodarone (Cardarone),
doxepin (Adapin/Sinnequan), ticlopidine (Ticlid) and
haloperidol (Haldol) were tested), had significantly
worse time to recurrence(TTR) and disease free survival
(DFS), in the real human clinical setting, settling
the matter. But that puts many oncologists in the
embarrassing position of having countenanced significant
adverse impact on patient outcome on the basis of
an optimistic stance that, after all, only the potential
for harm had priorly been demonstrated, not actual
harm; with the Knox findings we now know retrospectively
that the potential was real and did translate into
adverse impact of patient outcome in terms of both
disease recurrence and survival, and so this seriously
degrades the value of any optimistic stance on these
matters.
Issue: The Safety of Sulforaphane
One final issue on components of brassica vegetables
concerns the component sulforaphane: as Zhou et al.
(Mol Pharmacol (2006): The
dietary isothiocyanate, sulforaphane is an antagonist
of the human steroid and xenobiotic nuclear receptor
(SXR) [pdf]) observe, this biologically
active phytochemical found abundantly in broccoli,
can significantly down-regulate cytochrome P450 3A4
(CYP3A4) expression in human primary hepatocytes,
and although this mechanism serves as part of the
foundation for its anticancer and chemopreventive
activity, there may
be some potential for adverse interaction with
CYP3A4-mediated agents such as exemestane (Aromasin),
and we await clinical studies to determine whether
such interaction exerts clinically significant impact
on concurrent administration (see also Maheo et al.,
Cancer Res (1997: Inhibition
of cytochromes P-450 and induction of glutathione
S-transferases by sulforaphane in primary human and
rat hepatocytes, who first reported
the CYP3A4 enzyme operation in sulforaphane).
And the review of Paolini & Nestle (Mutat Res
(2003): Pitfalls
of enzyme-based molecular anticancer dietary manipulations:
food for thought; full text (as pdf)
on www.foodpolitics.com: http://www.foodpolitics.com/pdf/pitfallenzebase.pdf)
found that "cruciferous
isothiocyanates such as sulforaphane, most often considered
as beneficial phase-II detoxifying system inducers,
turn out to be genotoxics or strong promoters of urinary
bladder and liver carcinogenesis as well as inducing
cell cycle arrest and apoptosis".
Sulforaphane is an isothiocyanate (isothiocyanates
being the family of compounds found in large amounts
in cruciferous vegetables in the form of the thioglucoside
precursors (glucosinolates)) that has been isolated
from SAGA broccoli as the major phase II enzyme inducer
present in organic solvent extracts of this vegetable.
The (chemo)protective effect of sulforaphane, an isothiocyanate
- - which is liberated from glucoraphanin (GRP), its
glucosinolate precursor, by myrosinase hydrolysis,
is believed to involve the induction of Phase-II metabolizing
enzymes which are active in the detoxification of
many carcinogens and ROS (reactive oxygen species),
and by this protecting cells against DNA damage and
subsequent malignant transformation. However, as discovered
by Paolini et al (Carcinogeneis (2004): Induction
of cytochrome P450, generation of oxidative stress
and in vitro cell-transforming and DNA-damaging activities
by glucoraphanin, the bioprecursor of the chemopreventive
agent sulforaphane found in broccoli)
that:
(1) in some cases these enzymes also bioactivate several
hazardous chemicals, and
(2) that despite sulforaphane's projected benefits,
overlooked is its unknown effects on the Phase-I enzyme
systems involved in the bioactivation of a variety
of carcinogens, where not only has sulforaphane been
shown to inhibit the CYP2E1 cytochrome P-450 enzyme
involved in the activation of a variety of carcinogen,
but also to down-regulate CYP3A4 expression (as shown
by the separate Zhou and Maheo studies, cited above),
and this raises issues of potential significant and
possibly adverse interaction with CYP3A4-mediated
oncotherapy agents such as endocrine agent exemestane
(Aromasin), taxanes (docetaxel (Taxotere), paclitaxel
(Taxol)), and nab-paclitaxel (Abraxane) or any of
the Vinca alkaloids (vinorelbine (Navelbine), vinblastine
(Velban), vincristine (Oncovin)), and the platinum
agent carboplatin (Paraplatin), suggesting caution
of coadministration of high-sulforaphane-content dietary
or supplemental sources with any of the CYP3A4-dependent
classes of oncotherapy just notes, until further in
vivo or ideally human clinically studies can demonstrate
compellingly the safety ands non-problematic nature
of such coadministration.
Independent of this, there is another disturbing aspect
of sulforaphanes induction of Phase-I CYP bioactivating
enzymes: sulforaphane is as we noted above liberated
from its glucosinolate precursor glucoraphanin (GRP),
and there is some evidence that GRP may possess co-carcinogenic
properties. Indeed, by inducing Phase-I CYP bioactivating
enzymes, GRP may trigger the conversion of benzo[a]pyrene
to carcinogenic reactive intermediates like diol-epoxides,
and recent studies have shown that a cruciferase diet
containing a selection of brassicaceous vegetable
that includes broccoli, Brussel sprouts or cauliflower,
leads to a significant increase in Phase-I enzymes
such as CYP1A1/2, which can bioactivate PAHs, dioxins,
aromatic amines and nitrosamines (as reported by Paolini
et al (Carcinogeneis (2004): Induction
of cytochrome P450, generation of oxidative stress
and in vitro cell-transforming and DNA-damaging activities
by glucoraphanin, the bioprecursor of the chemopreventive
agent sulforaphane found in broccoli),
and priorly confirmed as well in the study by Vistisen
et al. (Carcinogenesis (1992): Foreign
compound metabolism capacity in man measured from
metabolites of dietary caffeine) who
found that in nine healthy volunteers daily ingestion
of 500 g of broccoli for 10 days increased the CYP1A2
ratio adversely by an average of 12% compared to a
comparable diet of non-cruciferous green vegetable,
see also Lampe et al. (Carcinogenesis (2000): Brassica
vegetables increase and apiaceous vegetables decrease
cytochrome P450 1A2 activity in humans: changes in
caffeine metabolite ratios in response to controlled
vegetable diets).
The adverse impact of the brassica diet hinges on
CYP1A2: CYP1A2 activity is increased by cigarette
smoke, well-cooked meat, and unfortunately by cruciferous
vegetables and this is adverse, since CYP1A2 metabolizes
various environmental procarcinogens, such as heterocyclic
amines (HCAs), nitrosamines and aflatoxin B1, in keeping
with the research of Lampe et al. (Carcinogenesis
(2000): Brassica
vegetables increase and apiaceous vegetables decrease
cytochrome P450 1A2 activity in humans: changes in
caffeine metabolite ratios in response to controlled
vegetable diets)), where it was found
that that under controlled dietary conditions, at
moderate levels of intake (428 g), brassica vegetables
increased (while apiaceous vegetables decreased, and
allium vegetables did not change) CYP1A2 activity
by 18 - 37%, when compared with a basal, vegetable-free
diet.
A Possible Solution
Against this adverse impact of brassica vegetables,
Breast Cancer Prevention Watch
finds intriguing the fact that apiaceous vegetables
(carrots, parsnips, celery, dill and parsley) decreased
mean CYP1A2 activity by ~13–25%, which suggest
to us that the differential CYP1A2 response to the
brassica and apiaceous vegetable diets may be leveraged
to in largely part cancel out or nullify the adverse
CYP1A2 impact of the brassica components by co-consumption
with apiaceous vegetables.
-
Phytoestrogens
Phytoestrogens are
plant polyphenol compounds exhibiting structural resemblance
to the mammalian
estrogen hormone 17ß-oestradiol.
Three classes of phytoestrogens can be distinguished:
(1) isoflavones, found
in concentrated form in soybeans and soy products
and also in other legumes;
(2) lignans, from seeds
(especially flax), whole grains, fruits and berries,
vegetables, and nuts;
(3) coumestans, found
in broccoli and sprouts.
It has been observed that in Asian nations the staple
consumption of phytoestrogen-rich foodstuffs correlates
with a reduced incidence of breast cancer, suggesting
that phytoestrogen consumption
is associated with a favorable hormonal profile.
It has further been observed in this connection that
historically, breast cancer rates in the United States
are typically as much as 4–7 times higher than
those in Asia, with US isoflavone intake at less than
1% of that in Asian populations (which may range from
20 to 80 mg/daily).
However, as Wu et al have noted, "it is difficult
to be certain that soy intake is not a marker of other
factors related to Western lifestyle that are causally
associated with risk of breast cancer", so that
high soy consumption may be only one of many potentially
protective lifestyle factors that distinguish Asian
and Western women (Wu et al, Am J Clin Nutr: Soy
intake and risk of breast cancer in Asians and Asian
Americans).
Although several human dietary intervention trials
have suggested a direct relationship between phytoestrogen
ingestion and decreased breast cancer risk, such trials
were not sufficiently powered to identify the exact
effect of dietary phytoestrogens on mammary
tissue proliferation. Epidemiological and
animal studies crucially have found that the benefit
of breast cancer chemoprevention by dietary phytoestrogen
compounds is chronologically dependent, with pre-puberty
consumption being required, as it is known that at
this time the mammary gland is relatively immature,
but phytoestrogen supplements are typically marketed
commercially
for as natural HRT alternatives in
postmenopausal women.
Therefore, the critical issue is the effect of phytoestrogens
on the growth of preexisting breast tumors. Here,
however, the findings to date are contradictory and
not dispositive. One the one hand, cell culture studies
fairly consistently report the estrogenic stimulation
of estrogen receptor-positive breast cancer cell lines,
as well as antagonism of tamoxifen activity at physiological
phytoestrogen concentrations. On the other hand, rodent
phytoestrogen consumption is typically associated
with less aggressive breast tumor development, with
decreased metastatic potential.
In this connection, Limer and Spiers suggest a potential
benefit of phytoestrogens in breast cancer chemoprevention
and therapy (Limer & Spiers, Breast Cancer Res:
Phyto-oestrogens
and breast cancer chemoprevention),
whereas Atkinson et al. found that a red clover isoflavone
dietary supplement demonstrated no effects
estradiol in postmenopausal women, or on hot flushes
or other menopausal symptoms
and, unlike
conventional HRT, did not increase
mammographic breast density. They conclude that the
isoflavone supplement at the dose given was not acting
as an estrogen or as an anti-estrogen (see Atkinson
et al., Breast Cancer Res: Red
clover-derived isoflavones and mammographic breast
density: a double-blind, randomized, placebo-controlled
trial).
Furthermore, Harris et al. have found that dietary
flavonoids may be able to influence the bioavailability
of endogenous estrogens, and disrupt endocrine balance,
by increasing the ratio of active estrogens to inactive
estrogen sulfates in human tissues (see Harris et
al., J Clin Endocrinol Metab: Phytoestrogens
Are Potent Inhibitors of Estrogen Sulfation: Implications
for Breast Cancer Risk and Treatment),
and similarly, Linseisen et al. found that dietary
intake of certain phytoestrogen components (daidzein,
genistein, and matairesinol, as well as mammalian
lignans reduces premenopausal breast cancer risk (Linseisen
et al., Int J Cancer: Dietary
phytoestrogen intake and premenopausal breast cancer
risk in a German case-control study).
In contrast, Keinan-Boker et al have in their recent
research concluded that "in Western populations,
a high intake of isoflavones or mammalian lignans
is not significantly related to breast cancer risk"
(Keinan-Boker et al, Am J Clin Nutr:
Dietary
phytoestrogens and breast cancer risk),
and Yamamoto et al in a prospective cohort study in
Japan found that although high miso soup and isoflavone
consumption reduced the risk of breast cancer, there
was no evidence for such an association for intake
of soyfoods (Yamamoto et al, J Natl Cancer Inst: Soy,
Isoflavones, and Breast Cancer Risk in Japan);
these findings are in conflict with many others cited
above, and with the recent epidemiologic study of
Bosetti et al. (Cancer Epidemiol Biomarkers Prev (2005):
Flavonoids
and breast cancer risk in Italy)
who found an inverse association between flavones
and breast cancer risk, confirming the results of
an earlier Greek study.
Finally a recent assessment of Regina Ziegler, of
the National Cancer Institute concluded that "at
present, scientific research does not support increasing
phytoestrogen intake among US women to Asian levels,
nor does it suggest that the typical US phytoestrogen
intake is problematic for healthy women" (Ziegler,
Am J Clin Nutr: Phytoestrogens
and breast cancer).
Similarly, Kienan-Boker(Am J Clin Nutr (2004): Dietary
phytoestrogens and breast cancer risk)
concluded more broadly still that a high intake of
isoflavones or mammalian lignans (not naturally occurring
in plant foods) is not significantly related to breast
cancer risk.
Evidencewatch
Commentary:
However, one methodological problem with the Ziegler
and Kienan-Boker studies is the failure to control
for or segregate menopausal status: Hirose et al.
(Br J Cancer (2005): Soybean
products and reduction of breast cancer risk: a case-control
study in Japan)
who found a statistically inverse association between
tofu or isoflavone intake and risk of breast cancer
in Japanese premenopausal women, while no statistically
significant association was evident with the risk
among postmenopausal women. But Boyapati et al. (Breast
Cancer Res Treat (2005): Soyfood
intake and breast cancer survival: a followup of the
Shanghai Breast Cancer Study) found
that soy intake prior to cancer diagnosis was unrelated
to disease-free breast cancer survival, and did not
differ according to ER/PR status, tumor stage, age
at diagnosis, body mass index (BMI), waist to hip
ratio (WHR), or menopausal status, concluding that
soyfoods do not have an adverse effect on breast cancer
survival. And Wood et al. (Cancer Res (2006):
Dietary
soy isoflavones inhibit estrogen effects in the postmenopausal
breast) found
that in the presence of estrogen higher doses of dietary
soy isoflavones may alter ER signaling and induce
selective antagonistic effects in the breast, but
not in lower-estrogen environments.
And some early studies had suggested
that components of soy phytoestrogens may be stimulatory
to breast cancer, later evidence argues against this,
at least not for short-term consumption: see Gallo
et al. (Carcinogenesis (2006): Lack
of stimulatory activity of a phytoestrogen-containing
soy extract on the growth of breast cancer tumors
in mice) who found that a phytoestrogens-containing
soy extract could be not harmful for women with a
history of or at high risk for breast cancer, at least
for short treatment-periods. It
appears that the issue is one of complex and potentially
confounding factors, with the form of isoflavone used
(purified vs soy products), dose (low vs high), timing,
and duration of exposure of isoflavones all playing
major roles in determining overall agonistic or antagonistic
effects (Kumar et al., Front Biosci (2004): Isoflavones
in breast cancer chemoprevention: where do we go from
here?), so further more closely controlled
studies are required to be dispositive.
Breast Cancer prevention Watch Conclusions:
Phytoestrogens
To
date, Evidencewatch therefore concludes that the weight
of the evidence
(1) strongly suggests that
soyfoods do not adversely effect breast cancer survival,
and
(2) subgroup analysis suggests that increased consumption
of soy isoflavones is associated with reduced risk
of breast cancer, but only in premenopausal
women; in postmenopausal women there was no no statistically
significant association. This is in part confirmed
and explained by the findings of Wood and colleagues
(Cancer Res (2006): Dietary
soy isoflavones inhibit estrogen effects in the postmenopausal
breast) which established that
in the presence of estrogen, higher doses of dietary
soy isoflavones alter estrogen receptor signaling
and induce selective antagonistic (beneficial) effects
in the breast, but not in lower-estrogen environments,
including those of natural menopause, or an oncotherapy-induced
menopausal state (see also the review of Rice &
Whitehead, Endocr Relat Cancer (2006): Phytoestrogens
and breast cancer –promoters or protectors?
who concluded that high consumption of phytoestrogens
are associated with a lower incidence of breast cancer).
Warning:
Research on drug interactions in the breast cancer
setting suggests that although soy isoflavone phytoestrogens
are associated with reduced breast cancer risk solely
for premenopausal women, there is still a caution:
the soybean components daidzein and genistein, as
well as other CAM agents, most notably black cohosh,
St. John's Wort, teas and extracts of goldenseal,
chamomile, sage, thyme, licorice and cloves, and grapefruit
juice, can interfere with the bioavailability of certain
oncotherapies, in particular taxanes (docetaxel (Taxotere),
paclitaxel (Taxol)) or any of the Vinca alkaloids
(vinorelbine (Navelbine), vinblastine (Velban), vincristine
(Oncovin)), and goldenseal and St. John's Wort can
in addition, like SSRI type antidepressants, interfere
with tamoxifen bioavailability. Other chemotherapies
are not affected significantly, nor are any aromatase
inhibitors (anastrozole (Arimidex), letrozole (Femara)
and exemestane (Aromasin)). For details, see our
Herbal/Drug Interactions in Breast Cancer Therapy;
the tamoxifen/antidepressants interaction issue is
summarized separately at:
Antidepressants (SSRIs) & Tamoxifen: New Warnings.
-
The
Safety of Soy in Breast Cancer
There is some provisional data to suggest that soy
or isoflavones may be associated with increased breast
cancer risk, for example, exposure to physiologic
concentrations of genistein
in vitro activates ER-a
and induces normal and malignant cell proliferation
in vitro and in vivo. So on this pro-risk perspective,
see especially Ju et al (J Nutr (2001): Physiological
Concentrations of Dietary Genistein Dose-Dependently
Stimulate Growth of Estrogen-Dependent Human Breast
Cancer (MCF-7) Tumors Implanted in Athymic Nude Mice),
Allred et al (Carcinogenesis (2004): Dietary
genistein results in larger MNU-induced, estrogen-dependent
mammary tumors following ovariectomy of Sprague–Dawley
rats;
Chen & Wong (J Clin Endocrinol Metab (2004): Genistein
Enhances Insulin-Like Growth Factor Signaling Pathway
in Human Breast Cancer (MCF-7) Cells);
Allred et al (Carcinogenesis (2004): Soy
processing influences growth of estrogen-dependent
breast cancer tumors) who concluded,
narrowly, that for postmenopausal women with estrogen-dependent
breast cancer, the consumption of foods containing
soy flour is more advisable than consuming isoflavones
in more purified forms (such as purified genistein,
soy protein isolate, isoflavone-rich soy extracts,
or isoflavone capsules, or soy that is ground, defatted
and toasted); and Ju et al. (Carcinogenesis (2006):
Genistein
stimulates growth of human breast cancer cells in
a novel, postmenopausal animal model, with low plasma
estradiol concentrations).
[new:
5/05/07] However, our systemic
review suggests that methodologically problems render
much of this literature - and three researchers in
particular, Clinton Allred, Kimberley Allred, and
Young Ju (all at University of Illinois at Urbana)
have pretty much made a career of trying to prove
the dangers of soy / phytoestrogens / genistein in
a breast cancer setting - inconclusive, and in conflict
with other studies findings of no significant increased
risk, and we often end up with the "dueling studies"
phenomenon: for example, we have Young Ju and colleagues
(Carcinogenesis (2006): Genistein
stimulates growth of human breast cancer cells in
a novel, postmenopausal animal model, with low plasma
estradiol concentrations)) with the
pro-risk perspective, while in the same journal, same
year, we have the Italian researchers of Daniella
Gallo and colleagues ((Carcinogenesis (2006): Lack
of stimulatory activity of a Phytoestrogen-containing
soy extract on the growth of breast cancer tumors
in mice) on the opposite anti-risk
side. Furthermore a protective effect of genistein
is also documented in some studies: Mai and colleagues
at Beth Israel in Boston determined that genistein
may synergistically sensitize the response of ER+
and HER2-overexpressing breast cancer cells to TAM
treatment in vitro (Mai Z, Blackburn GL, Zhou JR.
Genistein
sensitizes inhibitory effect of tamoxifen on the growth
of estrogen receptor-positive and HER2-overexpressing
human breast cancer cells. Mol Carcinog.
2007 Feb 12). And Martijn Verheus and colleagues investigated
the association between plasma phytoestrogen levels
and breast cancer risk in a prospective nested case-control
study using the Prospect cohort within the European
Prospective Investigation into Cancer and Nutrition,
finding that high genistein circulation levels were
associated with reduced breast cancer risk, with no
difference across premenopausal, perimenopausal women,
and in postmenopausal women (Verheus M, van Gils CH,
Keinan-Boker L, Grace PB, Bingham SA, Peeters PH.
Plasma
phytoestrogens and subsequent breast cancer risk.
J Clin Oncol. 2007 Feb 20; 25(6):648-55).
Now, note also that all these studies issue, necessarily,
a large numbers of provisos and qualifications that
essentially render generalizing to a clear and decisive
conclusion one way or the other just about impossible,
especially given the narrow scope of product form
and formulation (which soy?) and trial design particularities,
and of course these studies are often preclinical
animal model-based or epidemiological, intrinsically
not inspiring the high confidence of tightly controlled
and designed prospective RCTs or better yet, systematic
reviews of high-quality RCTs.
And all fail to control for stage-dependent effects
of specific dietary components on carcinogenesis,
where there may be wide variety of results, and conclusions,
contingent on whether the design or model is dealing
with early, middle and late stages of tumorogenesis
(what I call the tumor-stage
fallacy; see Jennifer Fenton and Norman Hord's
thoughtful discussion of this issue (Carcinogenesis
(2006): Stage
matters: choosing relevant model systems to address
hypotheses in diet and cancer chemoprevention research),
in addition to confounding as to equol versus non-equol
producers, pre- and post-menopausal status, receptor
status (ER/PR) and degree of receptor positivity of
negativity, other co-dietary consumption, etc. Thus,
a rare study that controlled for equol - the intestinal
bacterial metabolite of daidzein, which together with
genistein form the two main isoflavones in legumes
- to evaluate the estrogenic potential of daidzein
and equol, finding that dietary daidzein had a slight
but significant stimulatory effect on tumor growth,
whereas equol did not stimulate the growth of estrogen-dependent
breast tumor growth nor increase the cell proliferation
in tumors, and therefore that pharmacokinetic and/or
metabolic factors may mute or weaken the estrogenic
effects of daidzein and equol in vivo, and since most
people consume complex combinations of these various
components, the final overall impact on risk is indeterminate
and may be an increase or a decrease indifferently,
unless we can control, concurrently, for all
relevant components, tumorogenesis stages, receptor
and menopausal status, form of soy or isoflavone,
co-dietary factors, age, and numerous other parameters.
Therefore even if these studies were to weakly suggest
an estrogenic effect, and more importantly (since
such an effect may be clinically nonsignificant) a
theoretical potential for increased breast
cancer risk, nonetheless the estrogenic activity of
soy appears to be minimal, even in the most susceptible
populations, that of postmenopausal women (as first
shown by DD Baird and colleagues at the National Institute
of Environmental Health Sciences, J Clin Endocrinol
Metab (1995): Dietary
intervention study to assess estrogenicity of dietary
soy among postmenopausal women [pdf],
and most recently in the meta-analysis of Bruce Trock
and colleagues, J Natl Cancer Inst (2006): Meta-Analysis
of Soy Intake and Breast Cancer Risk).
In addition, these studies commit another fallacy,
that of failing to recognize and control for potential
cross-neutralization: so for example many of the above
cited pro-risk studies focus on putative proliferation-stimulative
activity of genistein and more specifically on a potential
interference effect on tamoxifen efficacy; but Andreas
Constantinou and colleagues at University of Illinois
at Chicago (Eur J Cancer (2005): The
soy isoflavone daidzein improves the capacity of tamoxifen
to prevent mammary tumours) in a cleverly
designed study showed conclusively that the combination
of daidzein with tamoxifen produces increased protection
against mammary carcinogenesis, in contrast to the
combination of genistein with tamoxifen which produces
an opposing/ compromising effect when compared with
tamoxifen alone. Given that soybeans contain both
isoflavone components, net effect is unlikely to be
either strongly positive or negative on tamoxifen
activity.
Furthermore, although the recent meta-analysis of
Trock and colleagues (J Natl Cancer Inst (2006): Meta-Analysis
of Soy Intake and Breast Cancer Risk)
suggest that soy intake is associated with a modest
reduction in the risk of breast cancer, this is muted
by the basic limitation of most meta-analyses, that
of broad and potentially statistically significant
heterogeneity across the underlying studies aggregated,
and in addition can be no stronger than the data type
analyzed which is epidemiologic (see also the thoughtful
commentary by María Elena Martínez of
the Arizona Cancer Center and colleagues, J Natl Cancer
Inst (2006): Soy
and Breast Cancer: The Controversy Continues).
Essentially, the Trock meta-analysis examined 18 epidemiologic
studies (12 case–control and six cohort or nested
case–control) published between 1978 and 2004
to determine the association of soy exposure and breast
cancer risk, and found among all studies a small reduction
in risk of breast cancer with high soy intake versus
low intake.
Breast Cancer Prevention Watch:
Conclusions
Upon systematic review and critical appraisal, we
find on the weight of the evidence that there is weak
but not sufficiently dispositive data to support a
modest protective effect of the standard American
soy diet on breast cancer, with best guidance suggesting
that the safest soy consumption is that of foods containing
soy flour, in preference to more purified forms of
isoflavones such as purified genistein, soy protein
isolate, isoflavone-rich soy extracts, or isoflavone
capsules, or soy that is ground, defatted and toasted,
and that furthermore whole soybean products by virtue
of their containing both the genistein and daidzein
isoflavone components are unlikely to have any net-adverse
impact on tamoxifen activity.
-
Black
Cohosh:
Hormone replacement therapy is contraindicated in
women with breast cancer. Extracts from the rhizomes
of Cimicifuga racemosa, have gained acceptance as
a natural alternative for the treatment of menopausal
symptoms. In the present study we investigated the
antiproliferative activity of C. racemosa extracts
(isopropanolic and ethanolic) on the estrogen receptor
positive MCF-7 and estrogen receptor negative MDA-MB231
breast cancer cells. These results indicate that C.
racemosa extract exerts no proliferative activity,
but kills the estrogen receptor positive MCF-7 as
well as estrogen receptor negative MDA-MB231 cells
by activation of caspases and induction of apoptosis
(Hostanska et al., Breast Cancer Res Treat: Cimicifuga
racemosa extract inhibits proliferation of estrogen
receptor-positive and negative human breast carcinoma
cell lines by induction of apoptosis).
One study found that black cohosh contains constituents
that inhibit the growth of human breast cancer cells,
and therefore might eventually be useful in the prevention
or treatment of breast cancer. (Einbond et al., Breast
Cancer Res Treat: Growth
inhibitory activity of extracts and purified components
of black cohosh on human breast cancer cells).
For complete coverage of
(1) the use of black cohosh for menopausal vasomotor
symptoms, especially hot flashes,
(2) its safety in the breast cancer setting,
(3) its bone osteoprotective activity, and
(4) the issue of interaction with oncotherapeutic
agents,
see Black
Cohosh Issues: Hot Flashes, Osteoprotection, Breast
Cancer on our special Menopause
page.
-
Essiac
Tea
This product, and the Essiac
based Flor-Essence, created
by a Canadian nurse, Renèe M. Caisse (‘Caisse’
spelled backwards is ‘Essiac’), has been
in use for over 70 years both to ameliorate the adverse
effects of traditional oncotherapies and as a putative
cancer therapy itself. Essiac tea contains four herbals:
(1) burdock root, (2) Indian rhubarb root, (2) sheapshead
sorrel, and (4) slippery elm bark, while Flor-Essence
adds: (5) watercress (6) blessed thistle (7) red clover
and (8) kelp.
With respect to Essiac tea, one systematic review
conducted by the Task Force
on Alternative Therapies of the Canadian Breast Cancer
Research Initiative (CBCRI) concluded that although
some weak evidence of its effectiveness may exist,
the nature and quality of studies reporting benefit
are such that the findings can only be regarded as
preliminary (E. Kaegi, CMAJ (1998): Unconventional
therapies for cancer: 1. Essiac [pdf]).
A second more recent systematic review (Boon &
Wong, Expert Opin Pharmacother (2004): Botanical
medicine and cancer: a review of the safety and efficacy)
concluded that additional research is needed in order
to determine the efficacy of essiac, and both reviews
failed to uncover any published clinical trial of
essiac.
See also National Cancer Institute, NCI Cancer Topics
(2005):
Essiac/Flor•Essence (PDQ®)
[health professional version]; Memorial Sloan-Kettering
Cancer Center (MSKCC) About Herbs (2005): ESSIAC
(Burdock root (Arctium lappa), sheep sorrel (Rumex
acetosella), slippery elm bark (Ulmus fulva), turkish
rhubarb root (Rheum palmatum)); MD
Anderson Cancer Center, CIMER (Complementary/Integrative
Medicine Education Resources) Reviews of Therapies
(2005): Herbal
/ Plant Therapies: Essiac.
Breast Cancer Prevention Watch
Conclusion: Essiac Tea
Although some researchers such as Leonard et al. (J
Ethnopharmacol (2006): Essiac
tea: Scavenging of reactive oxygen species and effects
on DNA damage) have found that Essiac
tea possesses potent antioxidant and DNA-protective
activity, properties that are speculated to be common
to natural anticancer agents (see also Cheung et al.,
Oncol Rep (2005): Antioxidant
and anti-inflammatory properties of ESSIAC and Flor-Essence),
and at least one uncontrolled case report (Can J Urol
(2005): Remission
of hormone-refractory prostate cancer attributed to
Essiac) has suggested a response by
one 64-year-old man with hormone-refractory prostate
cancer from Essiac tea, nonetheless such non-clinical
considerations and isolated uncontrolled case reports
are uncompelling and given this, Breast
Cancer Prevention Watch concludes on the balance
of the evidence that there is currently insufficient
evidence to establish the efficacy and safety of Essiac
tea or Flor-Essence in any aspect of cancer therapy.
In addition, researcher at the University of Toronto
found that essiac tea failed to demonstrate significant
hypoglycemic, hepatoprotective, or immunomodulatory
properties (Leonard et al., Anticancer Res (2006)
An in vivo analysis of the
herbal compound essiac).
Breast Cancer Prevention Watch
Warning:
Furthermore, Breast Cancer Prevention Watch notes
that Flor-Essence - which contains in addition to
the four herbs of Essiac, also watercress, blessed
thistle, red clover, and kelp - can actually promote
mammary tumor development in the Sprague-Dawley rat
model (Bennett et al. Breast Cancer Res Treat (2005):
Flor-Essence herbal tonic
does not inhibit mammary tumor development in Sprague
Dawley rats), suggesting caution in
human application, especially contraindicated in women
with existing breast carcinoma. And recently findings
(Kulp et al., Breast Cancer Res Treat (2006): Essiac((R))
and Flor-Essence((R)) herbal tonics stimulate the
in vitro growth of human breast cancer cells)
suggest that even the simpler compound of Essiac tea
as well as Flor-Essence herbal tonic adversely increase
the growth of human breast cancer cells: Essiac tea
and Flor-Essence stimulated cell proliferation relative
to untreated controls in both ER-positive and ER-negative
cell lines (also producing a dose-dependent increase
in ER dependent luciferase activity in MCF-7 cells),
showing that both herbal tonics can stimulate the
growth of human breast cancer cells through ER mediated
as well as ER independent mechanisms of action.
-
Mistletoe
(Iscador):
Extracts of mistletoe (Viscum album L.), a semi-parasitic
plant living on various trees such as oak, pine, fir,
elm and apple, are marketed under several trade names,
mainly in Europe (Iscador, Helixor, Eurixor, Isorel),
and have been extensively studied for antitumor activity
in laboratory, animal and human clinical trials.
Postoperative complementary treatment of breast cancer
patients with lectin-standardized
mistletoe extract (sME)
proved to be a well tolerated optimization of standard
tumor-destructive therapies, mainly improving quality
of life and relapse-free intervals in defined UICC
stages (Schumacher et al., Anticancer Res: Influence
of postoperative complementary treatment with lectin-standardized
mistletoe extract on breast cancer patients. A controlled
epidemiological multicentric retrolective cohort study).
And in a comprehensive epidemiological study, Bock
et al. (Arzneimittelforschung (2004): Efficacy
and safety of long-term complementary treatment with
standardized European mistletoe extract (Viscum album
L.) in addition to the conventional adjuvant oncologic
therapy in patients with primary non-metastasized
mammary carcinoma. Results of a multi-center, comparative,
epidemiological cohort study in Germany and Switzerland)
confirmed the safety of a standardized mistletoe extract
in patients with primary, non-metastatic breast cancer,
with reduced disease and treatment-associated symptoms,
and prolonged overall survival in the mistletoe extract
group as compared with controls. Similarly Grossart-Maticek
et al. in their review (Altern Ther Health Med (2001):
Use of Iscador, an extract
of European mistletoe (Viscum album), in cancer treatment:
prospective nonrandomized and randomized matched-pair
studies nested with a cohort study
[pdf]) in their review of a mistletoe extract preparation
(Iscador) found that
prospective controlled nonrandomized and randomized
matched-pair studies nested within a cohort study
of 10,226 cancer patients treated with Iscador and
derivatives suggested that survival time was longer
in patients treated with Iscador.
A recent cell study by Dutch researchers Harmsma and
colleagues (Harmsma et al., Arzneimittelforschung
(2006): Effects
of mistletoe (Viscum album L.) extracts Iscador on
cell cycle and survival of tumor cells)
found that both formulations of Iscador Quercus Spezial
and Iscador Malus Spezial induced apoptotic activity
after early cell cycle inhibition in a dose dependent
manner, with a stronger response exerted by Iscador
Malus than Iscador Quercus; and the in vitro cell
study of Swiss researchers Kovacs and colleagues (Arzneimittelforschung
(2006): Cytostatic
and cytocidal effects of mistletoe (Viscum album L.)
quercus extract Iscador)
on the Viscum album Quercus extract form confirmed
mistletoe operation as first a cell proliferation
inhibitory effect followed by apoptosis, with the
greatest activity seen in cells having a high proliferation
rate, and the French research team of Elluru and colleagues
summarized the mechanisms underlying the antitumoral
activity of mistletoe to involve apoptosis and angiogenesis,
as well as immunomodulation.
And in one of the few human trials, an EORTC international
research team (Schöffski et al., Ann Oncol (2004):
Phase
I trial of intravenous aviscumine (rViscumin) in patients
with solid tumors: a study of the European Organization
for Research and Treatment of Cancer New Drug Development
Group) designed the very first study
for the i.v. administration of the recombinant protein
form of mistletoe, aviscumine, an escherichia coli-derived
recombinant type II ribosome-inactivating protein
which is the recombinant counterpart of natural mistletoe
lectin-l, in patients with advanced cancers refractory
to conventional treatment, including colorectal, ovarian,
renal cell and breast cancer patients. The best response
obtained was stable disease in 11 patients, lasting
for two to eight cycles, and on the basis of their
findings they recommended 5600 ng/kg twice weekly
as the optimal dose.
Note that the preparation of mistletoe extract can
be important: of two forms, lectin-rich form (Iscador
Qu and a lectin-poor but viscotoxin-rich form
(Iscador Pini (Weleda
Company, Germany), the lectin rich form may induce
eosinophilia [abnormal levels of eosinophils, a type
of white blood cell], unobserved in the viscotoxin-rich
form (Huber et al., J Altern Complement Med (2002):
Effects
of a lectin- and a viscotoxin-rich mistletoe preparation
on clinical and hematologic parameters: a placebo-controlled
evaluation in healthy subjects).
Nonetheless, as pointed out by a recent extensive
review conducted by NCI (National Cancer Institute,
NCI Cancer Topics (2006):
Mistletoe Extracts PDQ),
almost all surveyed studies exhibited methodological
problems and weaknesses compromising the ability to
draw decisive conclusions, and as of this writing
mistletoe extracts require further confirming trials
to achieve a compelling level of evidence for efficacy
in various human cancers. Similarly, an early systematic
review (E. Kaegi, CMAJ (1998): Unconventional
therapies for cancer: 3. Iscador [pdf])
concluded that although there is laboratory evidence
of biological activity that may be beneficial to cancer
patients, the evidence of clinical benefit from human
studies remains weak and inconclusive, and the same
conclusion of insufficient or methodologically compromised
evidence of the efficacy of mistletoe as anticancer
therapy has been drawn in other systematic reviews:
Bar-Sela et al. (Harefuah (2006): Mistletoe
(Viscum Album) Preparations: An Optional Drug for
Cancer Patients?), Ernst et al. (Int
J Cancer (2003): Mistletoe
for cancer? A systematic review of randomised clinical
trials), and Kienle et al. (Eur J Med
Res (2003): Mistletoe
in cancer - a systematic review on controlled clinical
trials).
Mistletoe is presently under several clinical trials,
including one NCCAM (National Center for Complementary
and Alternative Medicine)-sponsored study (NIH Clinical
Trials: Mistletoe
Extract and Gemcitabine for the Treatment of Solid
Tumor Cancers) of mistletoe extract
and gemcitabine in patients with solid tumor cancers
including breast carcinoma.
See also Memorial Sloan-Kettering Cancer Center (MSKCC)
About Herbs (2005): MISTLETOE
(EUROPEAN) (Viscum album, Viscum coloratum),
and MD Anderson Cancer Center, CIMER (Complementary/Integrative
Medicine Education Resources) Reviews of Therapies
(2005): Herbal
/ Plant Therapies: Mistletoe.
Breast Cancer Prevention Watch
Conclusion: Mistletoe
Breast Cancer Prevention Watch
concludes on the balance of the evidence that there
is currently insufficient evidence to establish the
efficacy and safety of Essiac tea or Flor-Essence
in any aspect of cancer therapy.
-
Calcium
d-glucarate:
Calcium-D-glucarate is the calcium salt of D-glucaric
acid, a substance produced naturally in small amounts
by mammals, including humans. Glucaric acid is also
found in many fruits and vegetables with the highest
concentrations to be found in oranges, apples, grapefruit,
and cruciferous vegetables. Oral supplementation of
calcium-D-glucarate has been shown to inhibit beta-glucuronidase,
an enzyme produced by colonic microflora and involved
in Phase II liver detoxification. Elevated beta-glucuronidase
activity is associated with an increased risk for
various cancers, particularly hormone-dependent cancers
such as breast, prostate, and colon cancers. Other
potential clinical applications of oral calcium-D-glucarate
include regulation of estrogen metabolism and as a
lipid-lowering agent. (See Altern Med Rev: Calcium-D-glucarate
[pdf]).
-
Vitamin D
+ Calcium
It has been recently found that higher intakes of
vitamin D and calcium (400 IU vitamin D and 1,000
mg calcium) from food and supplements are associated
with lower levels of breast density among premenopausal,
but not postmenopausal, women, and given that breast
density is one of the strongest breast cancer risk
indicators, this suggests that increased intake of
vitamin D and calcium may represent a safe inexpensive
strategy for breast cancer prevention (Berube et al.,
Cancer Epidemiol Biomarkers Prev (2005): Vitamin
D and Calcium Intakes from Food or Supplements and
Mammographic Breast Density).
This has also been confirmed in the prospective study
of McCullough et al. (Cancer Epidemiol Biomarkers
Prev (2005): Dairy,
calcium, and vitamin D intake and postmenopausal breast
cancer risk in the Cancer Prevention Study II Nutrition
Cohort)
who found that women with the highest intake of dietary
calcium (>1,250 mg/daily) were at a lower risk
of breast cancer than those reporting <=500 mg/daily;
however, it is important to note that neither use
of supplemental calcium nor vitamin
D intake was associated with risk. Consumption starting
at two or more servings of dairy products per day
was likewise inversely associated with risk, compared
with less than a half a servings/daily), with associations
slightly stronger in women with estrogen receptor–positive
tumors, supporting the hypothesis that dietary calcium
and/or some other components in dairy products may
modestly reduce risk of postmenopausal breast cancer.
-
Vitamin E
Many observational studies have suggested that vitamin
E from dietary sources (a-tocopherol with or without
other related tocopherols and tocotrienols) may provide
women with at least modest protection from breast
cancer, through antiproliferative and pro-apoptotic
effects: so Schwenke, J Nutr Biochem (2002): Does
lack of tocopherols and tocotrienols put women at
increased risk of breast cancer?) found
in his review, noting however that there is no evidence
that non-dietary vitamin E supplements confer any
protection whatever against breast cancer (animal
studies suggest that a-tocopherol supplementation
alone has little effect on mammary tumors; see also
Kimmick et al. (Nutr Cancer (1997): Vitamin
E and breast cancer: a review).
The exact impact of Vitamin E on breast cancer risk
has not wholly been clarified, but a recent study
sheds some considerable light on the matter and may
help account for inconsistent fin dings to date. Charmas
et al. (Nutr Cancer (2005): Novel
interactions of vitamin E and estrogen in breast cancer)
investigated the effect of vitamin E (alpha-tocopherol)
on breast cancer cell growth, finding a dose-dependent
inhibition of cell proliferation in estrogen receptor
(ER)-positive cells, reducing significantly the response
of breast cancer cell lines to estrogen. However,
no growth inhibition was observed when cells were
grown in the absence of estrogen, and indeed vitamin
E altered and decreased the growth inhibition induced
by tamoxifen, suggesting an effect of vitamin E on
the expression of ER. Thus, vitamin E may inhibit
ER-positive cell growth by altering the cellular response
to estrogen, but may compromise the antitumor efficacy
of tamoxifen due tamoxifen's anti-estrogen activity.
As Vitamin E is known to be a complex group of compounds,
research is investigating what compounds are most
active in antiproliferative activity.
It appears that one compound known as alpha-TEA (alpha-tocopherol
ether linked acetic acid analogue) is a potent inducer
of apoptosis (inducing cancer cells but not normal
cells to undergo a form of programmed cell death)
in a wide variety of epithelial cancer cell types,
including breast, prostate, lung, colon, ovarian,
cervical, and endometrial, and in combination with
the COX-2 inhibitor celecoxib (Celebrex) and the chemotherapeutic
agent 9-nitro-camptothecin (9NC, an analogue of Camptothecin
(CPT)) decreases breast cancer animal model tumor
burden and inhibits metastasis significantly better
than do single-agent treatments (Kline et al., J Nutr
(2004): Vitamin
E and Breast Cancer), suggesting that
Vitamin E's antitumor activity may require for maximal
expression combination with other antitumor or cell-expressive
agents.
[new] However,
Breast Cancer Prevention Watch
notes that at least some recent evidence appears to
suggest potential interference between Vitamin E and
tamoxifen: supplemental antioxidant vitamin E (alpha-tocopherol)
acts at the plasma membrane to alter the effectiveness
of tamoxifen in ER-positive breast cancer cell lines,
as confirmed in the cell study of Elizabeth Peralta
and colleagues (Surgery (2006): Effect
of vitamin E on tamoxifen-treated breast cancer cells)
reported at the 63rd Annual Meeting of the Central
Surgical Association, Louisville, Kentucky (March
9-11, 2006), who found that that supplemental vitamin
E decreased the proliferation-inhibitory effect of
tamoxifen on ER+ breast cancer cells and nullified
the rapid rise in intracellular calcium leading to
apoptosis stimulated by tamoxifen; hence, the use
of such vitamin E acetate supplements would appear
to be inadvisable for ER+ breast cancer patients on
tamoxifen.
Vitamin C and Vitamin E, Selenium:
Summary
Several studies have suggested an inverse association
between Vitamin C and Vitamin E, as well as selenium,
and breast cancer risk (i.e., higher consumption is
associated with reduced risk), primarily through increasing
serum levels of a lignan called enterolactone. Lignans
are phytonutrients that exhibit strong antioxidant
properties, and can modulate hormone levels. The human
lignan enterolactone is a mammalian lignan produced
by intestinal bacteria from plant components obtained
in the diet. Enterolactone, and certain other lignans
- especially flaxseed (see below) and the lignans
found concentrated in berries - and have been associated
with a reduced risk of breast cancer for both premenopausal
and postmenopausal women, as well as with a reduced
risk of other hormone-dependent cancers (like prostate
cancer), reduced risk of acute coronary events, and
possibly also reduced risk of osteoporosis.
However, except
for selenium, there are other contradictory studies
with respect to supplementary Vitamins C and E, so
that on the balance of the evidence, supplementation
with the antioxidant vitamins C and E is not established
to be associated with a beneficial reduction in breast
cancer risk (in part due to possible interfering interactions
with certain oncotherapies), and pending further more
decisive trials, breast cancer patients should avoid
such supplementation and restrict intake to quality
dietary sources in fruits and vegetables. On the other
hand, selenium supplementation is well-established
as beneficial in hormone-dependent cancers, including
breast cancer, at a level of 200 micrograms daily.
-
Green
Tea:
Although there is substantial in vitro and in vivo
evidence suggestive of tea polyphenols as chemopreventive
agents against various cancers, epidemiologic data
is not clearly supportive of the chemoprotective role
of tea in breast cancer etiology. Thus, in one pooled
analysis of two prospective studies green-tea intake
was not associated with a lower risk of breast
cancer (see Suzuki et al., Br J Cancer: Green
tea and the risk of breast cancer: pooled analysis
of two prospective studies in Japan).
However, Anna Wu and colleagues (Int J Cancer:
Green
tea and risk of breast cancer in Asian Americans;
also Wu et al., Cancer Res: Tea
Intake, COMT Genotype, and Breast Cancer in Asian-American
Women)
at the Department of Preventive Medicine, University
of Southern California discovered a significant trend
of decreasing risk with increasing amount of green
tea intake in their population-based, case-control
study of breast cancer among Los Angeles county Chinese,
Japanese and Filipino women. Their study found that
although breast cancer risk was not related to consumption
of black tea, green tea drinkers showed a significantly
reduced risk of breast cancer, maintained even after
adjusting for age, specific Asian ethnicity, birthplace,
age at menarche, parity, menopausal status, use of
menopausal hormones, body size and total caloric and
black tea intake, and other potentially confounding
factors such as smoking, alcohol, and coffee intake,
breast cancer family history, physical activity, and
intake of soy and dark green vegetables. They also
noted that although both green tea and soy intake
had significant, independent protective effects on
breast cancer risk, the benefit of green tea was primarily
observed among low soy consumer subjects, while the
protective effect of soy was primarily observed among
nondrinkers of green tea. Therefore, at least as to
In Asian-American women, there appears to be an important
role for both green tea and soy intake in relation
to breast cancer risk.
And Seely et al. (Integr Cancer Ther (2005): The
effects of green tea consumption on incidence of breast
cancer and recurrence of breast cancer: a systematic
review and meta-analysis) conducted
a systematic review and meta-analyses of observational
studies, concluding on the basis of the evidence that
(1) to date, the epidemiological data indicates that
consumption of 5 or more cups of green tea a day shows
a non-statistically significant trend towards the
prevention of breast cancer development, and (2) that
evidence indicates that green tea consumption may
possibly help prevent breast cancer recurrence in
early stage (I and II) cancers, but that further studies
are needed before clinical guidance can be put forth
on the potential therapeutic application of green
tea in breast carcinoma. In addition, Sun et al. (Carcinogenesis
(2005): Green
tea, black tea and breast cancer risk: a meta-analysis
of epidemiological studies) examined
populations in eight countries with respect to consumption
of either green tea or black tea, or both, in relation
to breast cancer risk, finding that for green tea,
a meta-analysis of the studies shows a reduced risk
of breast cancer for highest versus non/lowest intake,
while in contrast for black tea, there appears to
be a possible late-stage, promotional effect of black
tea on breast carcinogenesis.
Given the conflicting results and conclusions of the
recent Suzuki analysis cited above on the one hand
and the work of Wu and colleagues just cited, it is
clear that further studies are needed to more precisely
determine the relationship, if any, of green tea consumption
and risk of breast cancer. Evidencewatch notes in
this context that Wu's observation of the benefit
of green tea primarily among low soy consumer
subjects is intriguing, and may suggest that in high
soy consumption populations, as found in Japanese
subjects resident in Japan, the potential chemopreventive
may be muted. Nonetheless, the balance of the evidence
suggests at least that high green tea consumption
(> 5 cups/daily) appears to exert beneficial effect
on breast cancer prevention and possibly also recurrence.
Another possible explanation of conflicting effects
is suggested in the study of Yuan et al. (Carcinogenesis
(2005): Green
tea intake, ACE gene polymorphism and breast cancer
risk among Chinese women in Singapore)
where they hypothesized that the effect of polyphenols
should be more prominent among women possessing high-activity
ACE (angiotensin-converting enzyme) genotype than
women with low-activity ACE genotype, given that it
is known that women with low-activity genotype of
the ACE gene had a reduced risk of breast cancer compared
with those possessing high-activity ACE genotype;
they further reasoned the inhibition of angiotensin
II-induced reactive oxygen species production by green
tea polyphenols may be one mechanism by which these
polyphenols protect against human breast cancer, and
so conducted a nested case–control study to test
these hypotheses. They indeed found that no association
between intake frequencies of green tea and risk of
breast cancer among all women or those with low-activity
ACE genotype, but among women with high-activity ACE
genotype, intake frequency of green tea was associated
with a statistically significant decrease in risk
of breast cancer; black tea intake was unrelated to
breast cancer risk irrespective of the ACE genotype.
Thus, this study highlights the importance of genetically
determined factors in evaluating the role of green
tea intake in breast cancer development.
Issues of Safety and Interaction
Sherry Crow and and colleagues at the Arizona Cancer
Center (Cancer Epidemiol Biomarkers Prev (2006): Effects
of Repeated Green Tea Catechin Administration on Human
Cytochrome P450 Activity) observed
that preclinical studies suggested that green tea
or green tea catechins can modulate the activities
of drug-metabolizing enzymes, and they conducted a
clinical study to determine the effect of repeated
green tea catechin administration on human cytochrome
P450 (CYP) enzyme activities, finding that Repeated
green tea catechin administration (at a dose that
contains 800 mg epigallocatechin gallate (EGCG) daily)
is not likely to result in clinically significant
interference with the disposition of drugs metabolized
by CYP enzymes (CYP1A2, CYP2D6, CYP2C9, and CYP3A4).
Synergy
with Chemotherapy and
Reversal of Drug Resistance
Yuying Mei et al. (Landes Biosci (2005): Reversal
of Multidrug Resistance in KB Cells with Tea Polyphenol
Antioxidant) explored the reversal
effects on multidrug resistance (MDR) via the antioxidant
capacities of tea polyphenols, and EGCG in particular,
based on the observation that drug resistance cells
undergo oxidative stress, confirmed in doxorubicin
(Adriamycin)-induced intracellular concentration of
ROS (reactive oxygen species), and this MDR was reversed
by tea polyphenols and EGCG. This was confirmed in
the study by Feng Qian and colleagues at the East
China University of Science and Technology (Boimed
Pharmacotherap (2005): Modulation
of P-glycoprotein function and reversal of multidrug
resistance by (–)-epigallocatechin gallate in
human cancer cells) who investigated
the molecular mechanism of EGCG and its activity in
the reversal of P-glycoprotein (P-gp) mediated MDR
(multidrug resistance), finding that in vitro EGCG
potentiated the cytotoxicity of doxorubicin to drug-resistant
KB-A1 cells, and that in a KB-A1 cell xenograft model,
EGCG addition enhanced the efficacy of doxorubicin,
increasing the concentration of doxorubicin in resistant
tumors, suggesting that EGCG modulates the function
of P-gp and reverses P-gp mediated multidrug resistance
in human cancer cells. And these findings themselves
further confirm the earlier in vivo results of Qiang
Zhang and colleagues who found that EGCG increased
by 51% the concentration of doxorubicin in resistant
tumors and also increased doxorubicin-induced apoptosis
in those tumors, with the doxorubicin/EGCG combination
being well-tolerated, and concluded therefore that
EGCG chemosensitizes resistant tumor cells to doxorubicin
(Zhang et al., Cancer Letters (2004):
In vivo reversal of doxorubicin resistance by (?)-epigallocatechin
gallate in a solid human carcinoma xenograft).
Similar results were established in animal studies
of leukemia, with doxorubicin-resistant (P388) leukemia
cells by Yasuyuki Sadzuki and colleagues at the University
of Shizuoka Japan, who found that green tea components
(including caffeine, theanine, and EGCG) increased
the doxorubicin-induced efficacy against these cells
via an increase in the doxorubicin concentrations
in the tumors and hence increasing the doxorubicin-induced
antitumor activity (Sadzuki et al. (2000): (Efficacies
of tea components on doxorubicin induced antitumor
activity and reversal of multidrug resistance).
These results were confirmed and extended in the research
of the Mayo Clinic (Rochester, MN) team of Yean Lee
and colleagues who observed that it has been previously
established that CLL (chronic lymphocytic leukemia)
cells synthesize and release VEGF (vascular endothelial
growth factor) under normoxic and hypoxic conditions,
and that CLL B cells also express VEGF membrane receptors
(VEGF-R1 and VEGF-R2) which are spontaneously phosphorylated
on these cells, suggesting that these cells are using
VEGF as a survival factor, given that VEGF significantly
increases the apoptotic resistance of CLL B cells.
They therefore evaluated the impact of EGCG (epigallocatechin-3-gallate)
(), a known receptor tyrosine kinase (RTK) inhibitor,
on the VEGF receptor status and viability of CLL B
cells, finding that EGCG significantly increased apoptosis/cell
death in 8 of 10 CLL cell samples and suppressed both
the Bcl-2 (B-cell leukemia/lymphoma-2), XIAP (X-linked
inhibitor of apoptosis protein), and Mcl-1 (myeloid
cell leukemia-1) proteins in the CLL cells, as well
as VEGF-R1 and VEGF-R2 phosphorylation (incomplete
suppression); they concluded from these findings that
VEGF signaling regulates CLL cell survival signals
and that interruption by EGCG of this autocrine pathway
results in caspase activation and subsequent leukemic
cell death (Lee at al., Blood (2004): VEGF
receptor phosphorylation status and apoptosis is modulated
by a green tea component, epigallocatechin-3-gallate
(EGCG), in B-cell chronic lymphocytic leukemia).
And more recently TD Shanafelt and colleagues at the
Mayo Clinic (Rochester, MN) confirmed the ability
of EGCG to induce apoptotic cell death in the leukemic
B-cells in patients with CLL (chronic lymphocytic
leukemia (CLL)). Indeed, the researchers document
several patients with low grade B-cell malignancies
seen in clinical practice at the clinic with steady
clinical, laboratory, and/or radiographic evidence
of progression who on their own initiative, began
EGCG consumption and subsequently developed objective
clinical response (Shanafelt et al., Leukemia Res
(2006): Clinical
effects of oral green tea extracts in four patients
with low grade B-cell malignancies).
Tae heung Kang and Chinese and Korean colleagues and
researchers at Johns Hopkins found that a multimodality
treatment regimen using DNA vaccination in combination
with EGCG was effective in inhibiting large tumor
growth, inducing tumor cellular apoptosis in a dose-dependent
manner and enhanced tumor-specific T-cell immune response
and enhanced antitumor effects, resulting in a higher
cure rate than either immunotherapy or EGCG alone,
as well as providing long-term antitumor protection
in cured mice (Kang et al. Cancer Res (2007): Epigallocatechin-3-Gallate
Enhances CD8+ T Cell–Mediated Antitumor Immunity Induced
by DNA Vaccination).
Mechanisms of EGCG Antitumor
and Chemopreventive Activity
EGCG is known to act at numerous points regulating
cancer cell growth, survival, and metastasis, including
effects at the DNA, RNA, and protein levels (Ann Beltz
et al., Anticancer Agents Med Chem (2006): Mechanisms
of cancer prevention by green and black tea polyphenols).
Thus EGCG exerted caspase activation and altered Bcl-2
family member expression to induce cell cycle arrest
or apoptosis; inhibited telomerase activity; reduction
of nitric oxide production by means of the suppression
of inducible nitric oxide synthase via blocking nuclear
translocation of the transcription factor nuclear
factor-kB; metastasis inhibition via effects
on urokinase and matrix metalloproteinases; reduction
of angiogenesis, in part by decreasing VEGF (vascular
endothelial growth factor) production and receptor
phosphorylation; reduction of dihydrofolate reductase
activity affecting nucleic acid and protein synthesis;
antagonism of aryl hydrocarbon receptor by directly
binding the receptor's molecular chaperone, HSP-90
(heat shock protein 90). See also Zigang Dong at the
University of Minnesota, BioFactors (2000): Effects
of food factors on signal transduction pathways);
and Nihal Ahmed and colleagues at the Case Western
Reserve University (Arch Biochem Biophys (2000): Green
Tea Polyphenol Epigallocatechin-3-Gallate Differentially
Modulates Nuclear Factor ?B in Cancer Cells versus
Normal Cells), who suggests that EGCG-induced
cell cycle deregulation and apoptosis of cancer cells
may be mediated through NF-kB inhibition.
In the breast cancer specific context, it has been
shown that EGCG is an inhibitor of VEGF induction
and breast cancer angiogenesis (Maryam Artippour,
J Nutr (2002):
Green Tea Inhibits Vascular
Endothelial Growth Factor (VEGF) Induction in Human
Breast Cancer Cells, who concluded
that inhibition of VEGF transcriptionappears to be
one of the molecular mechanism(s) involved in the
antiangiogenic effects of green tea, which may contribute
to its potential use for breast cancer treatment and/or
prevention). And Young-Joon Surh and colleagues at
the Seoul National University, Mutat Res (2001): Molecular
mechanisms underlying chemopreventive activities of
anti-inflammatory phytochemicals: down-regulation
of COX-2 and iNOS through suppression of NF-kB activation)
found that curcumin, EGCG and resveratrol suppress
activation of NF-kB.
Hye-Kyung Na and Young-Joon Surh at Seoul National
University found that EGCG blocked each stage of carcinogenesis
by modulating signal transduction pathways involved
in cell proliferation, transformation, inflammation,
apoptosis, metastasis and invasion (Na & Surh,
Mol Nutr Food Res (2006: Intracellular
signaling network as a prime chemopreventive target
of (-)-epigallocatechin gallate), including
via transcription factors such as NF-kappa B (NF-kB).
And EGCG inhibits the expression of VEGF (vascular
endothelial growth factor) by breast, colon, and head
and neck squamous cell carcinoma (HNSCC) carcinoma
cells (Joshua Lambert and Chung Yang, J Nutr (2003):
Mechanisms of Cancer Prevention
by Tea Constituents).
Components
The benefits of green tea polyphenols, especially
EGCG, appears to be part and parcel of the entire
class of polyphenols, that includes the flavonoids,
a large and diverse family of compounds synthesized
by plants, with flavonoid subclasses of
- anthocyanidins in berries and grapes with
active components cyanidin, delphinidin, malvidin,
pelargonidin peonidin, and petunidin,
- flavanols in tea with catechin, epicatechin,
epigallocatechin, epicatechin gallate, epigallocatechin-3-gallate
(EGCG) and theaflavins, thearubigins, proanthocyanidins
being the principle components of this flavanols subclass,
- flavanones in citrus fruits with principle
hesperetin, aringenin and eriodictyol components,
- flavonols in onions that include principle
components of quercetin, kaempferol, myricetin, and
isorhamnetin,
- flavones in herbs and peppers with apigenin
and luteolin as principle components, and
- isoflavones in soy, especially the daidzein
and genistein components (see Roderick Dashwood, J
Nutr (2007): Frontiers
in Polyphenols and Cancer Prevention).
One question that arises is whether concurrent administration
of two (or more) polyphenols, that is, dual polyphenols,
or a polyphenol and another antitumor nutritional
component, would yield synergistic activity. It would
appear this is not always the case: although both
sulforaphane, an isothiocyanate from broccoli, and
the green tea component EGCG are highly across a number
of cancers, no synergistic effects were seen when
both agents were combined - on the contrary, one agent
counteracted the beneficial effects of the other,
yielding no significant aggregate chemopreventive
action (Myzak et al., FASEB (2006): Sulforaphane
inhibits HDAC activity in vivo and suppresses tumorogenesis
in Apcmin mice). What we don't know
is if this applies across the board to combinations
of polyphenols and other nutritional agents operating
over similar underlying pathways, or is an agent-with-agent
specific interaction that must be explored for each
potential synergy, or lack thereof, questions the
new field of epigenetics is beginning to explore.
-
Curcumin
Curcumin is the most active
component of the Curcuma longa (turmeric) plant, and
within curcumin, curcuminoids
are responsible for the yellow color of turmeric and
curry powder, and exhibits a broad range of biological
effects ranging from antioxidant and anti-inflammatory
/ COX-2 inhibitory, to inhibition of angiogenesis
(likely due to down regulation of proangiogenic genes
such as VEGF and angiopoitin and a decrease in migration
and invasion of endothelial cells), and antitumoral
activity; at the molecular level, the active curcuminoids
components exhibit multiple pathways of anticancer
activity (Aggarwal et al: Curcumin
Derived from Tumeric (Curcuma longa): A Spice for
All Seasons [pdf],
In: Preuss H, ed. Phytopharmaceuticals in Cancer Chemoprevention
(CRC Press, 2005) including:
-
Exhibits
tumorogenesis
-
Antiproliferative
activity against Cancer Cells
-
Down-Regulates
Activity of EGFR and Expression of HER2/neu
-
Down-Regulates
Activation of Nuclear Factor kappa-b (NF-kappa-b)
(factors implicated in chemoresistance and induced
chemosensitivity)
-
Down-Regulates
the Activation of STAT3 Pathway
-
Activates
Peroxisome Proliferator-Activated Receptor-gamma
(PPAR-gamma)
-
Down-Regulates
the Activation of Activator Protein-1 (AP-1)
and C-Jun Terminal Kinase (JNK)
-
Suppresses
the Induction of Adhesion Molecules
-
Down-Regulates
Cyclooxygenase-2 (COX-2) Expression
-
Inhibits
Angiogenesis
-
Suppresses
the Expression of MMP9 and
Inducible Nitric Oxide Synthase (INOS)
-
Down-Regulates
Cyclin D1 Expression
-
Exhibits
Chemopreventive Activity
-
Inhibits
Tumor Growth and Metastasis in Animals
-
Inhibits
Androgen Receptors and AR-Related Cofactors
-
Induces
apoptosis via the p53 pathway
-
mTOR (mammalian
target of rapamycin) inhibitor (as recently found
by Beevers et al., Carcinogenesis (2006): Curcumin
inhibits the mammalian target of rapamycin-mediated
signaling pathways in cancer cells)
In addition,
curcumin can make susceptible to apoptosis cell lines
that are resistant to certain apoptotic inducers and
radiation (Singh & Khar, Anticancer Agents Med Chem
(2006): Biological
Effects of Curcumin and Its Role in Cancer Chemoprevention
and Therapy) who conclude their review
observing that "Curcumin . . . has emerged as one
of the most powerful chemopreventive and anticancer
agents"). And the recent study of the Spanish research
team of Montagut et al (Endocr Relat Cancer (2006):
Activation
of nuclear factor- B is linked to resistance to neoadjuvant
chemotherapy in breast cancer patients)
suggests that curcumin's well-established activity as
a NF-kappa-B inhibitor can be used to prevent
or overcome chemoresistance in breast cancer.
Preclinical findings also suggest that curcumin play
play a critical role in the treatment and potential
chemoprevention of organ/visceral breast cancer metastases.
In this connection, note the findings of Aggarwal and
his team at the Cytokine Research Laboratory of M.D.
Anderson Cancer Center (Clin Cancer Res (2005): Curcumin
Suppresses the Paclitaxel-Induced Nuclear Factor-B Pathway
in Breast Cancer Cells and Inhibits Lung Metastasis
of Human Breast Cancer in Nude Mice who
hypothesized that because curcumin suppresses nuclear
factor-kappa-B (NF-kappa-B) activation,
and since most chemotherapeutic agents activate NF-kappa-B
that mediates cell survival, proliferation, invasion,
and metastasis, curcumin would potentiate the effect
of chemotherapy in advanced breast cancer and inhibit
lung metastasis, and their preclinical findings validated
that hypothesis, showing that dietary administration
of curcumin significantly decreased the incidence of
breast cancer metastasis to the lung and suppressed
the expression of NF-kappa-B, COX-2, and MMP-9 (matrix
metalloproteinase-9), indicating that curcumin has a
strong therapeutic potential in preventing breast cancer
metastasis, probably through suppression of NF-kappa-B
and NF-kappa-B–regulated gene products.
For the lay reader, note that this study is discussed
in the ACS News story: A
Cancer Treatment in the Spice Cabinet? Researchers See
Promise in Turmeric.
It is highly interesting to note that our research suggests
that this ability of curcumin to inhibit lung metastasis
may also be shared by oral silibin
(the active component of Silymarin
/ Milk Thistle), already in human use as a hepatoprotective
drug, via the same mechanism of suppression of NF-kappa-B
(see the study of Singh et al. at the University of
Colorado: Clin Cancer Res (2004): Oral
Silibinin Inhibits Lung Tumor Growth in Athymic Nude
Mice and Forms a Novel Chemocombination with Doxorubicin
Targeting Nuclear Factor B–Mediated Inducible Chemoresistance)
who found that silibinin inhibits in vivo lung tumor
growth and reduces systemic toxicity of doxorubicin
with an enhanced therapeutic efficacy most likely via
an inhibition of doxorubicin-induced chemoresistance
involving NF-kappa-B signaling, concluding that
silibinin is a potential agent for lung tumor growth
inhibition, alone and in combination chemotherapy with
antineoplastic agents including anthracycline drugs,
and also exhibits preventive effects against doxorubicin-caused
systemic toxicity. An more intriguing is the potential
for silibin and related natural NF-kappa-B suppressors
such as green tea polyphenols to form a multifocal angiostatic
regimen (see Block, Integr Cancer Ther (2005): Multifocal
Angiostatic Therapy: An Update).
And other related research suggests that NF-B and its
associated genes may also be relevant therapeutic targets
in osteolytic tumor burden (Gordon et al., Cancer Res
(2005): Nuclear
Factor-B–Dependent Mechanisms in Breast Cancer
Cells Regulate Tumor Burden and Osteolysis in Bone)
thus suggesting that curcumin may have anti-metastatic
activity in bone as well as lung breast cancer metastases.
Besides inhibiting the activation of NFkappaB,
it also inhibits the expression of HER-2 (Wu et al.,
Acta Pharmacol Sin (2006): Down-regulation
of p210bcr/abl by curcumin involves disrupting molecular
chaperone functions of Hsp90); see also
Kim et al (Oncology Rep (2002): The
role of HER-2 oncoprotein in drug-sensitivity in breast
cancer [pdf]) who notes that curcumin
reduces the tyrosine kinase activity of HER-2, which
corresponds to the growth inhibition of HER-2 overexpressing
breast cancer cell lines. Similarly, Hong et al., Clin
Cancer Res (1999): Curcumin
Inhibits Tyrosine Kinase Activity of p185neu and Also
Depletes p185neu) have observed that
curcumin also has anti-tyrosine kinase activity and
has been shown to inhibit ligand-induced activation
of the EGFR (epidermal growth factor receptor) tyrosine
phosphorylation, leaving the protein level unaffected,
and that curcumin was at that time the only natural
compound known to inhibit tyrosine kinase activity and
also to deplete the tyrosine kinase protein itself (see
also Atalay et al., Ann Oncol (2003): Novel
therapeutic strategies targeting the epidermal growth
factor receptor (EGFR) family and its downstream effectors
in breast cancer; and Dorai & Aggarwal,
Cancer Let (2004): Role
of chemopreventive agents in cancer therapy
[pdf]).
In conclusion, we agree with the summary observation
of Aggarwal
et al. (Curcumin
Derived from Tumeric (Curcuma longa): A Spice for All
Seasons [pdf],
In: Preuss H, ed. Phytopharmaceuticals in Cancer Chemoprevention
(CRC Press, 2005) that it is clear
that curcumin exhibits activities against cancer, cardiovascular,
diseases, and diabetes and that epidemiological evidence
is further supportive, given that in countries like
India with exceptional high consumption of dietary curcuminoids
in the form of the Turmeric spice, the incidence of
breast cancer is one eighth of that in the US, and interesting
ovarian cancer rate in India is one fourth that of the
US, while the incidence of lung cancer is one sixteenth
of that of the US, and brain cancer one third of the
US incidence level (and melanoma is 1/260th the level
of that in the US).
These observations on the efficacy and safety of curcumin
have been similarly confirmed in the literature review
of approx. 1500 papers on curcumin by Stig Bengmark
of the Institute of Hepatology at the London Medical
School (S Bengmark, JPEN J Parenter Enteral Nutr (2006):
Curcumin, An Atoxic Antioxidant
and Natural NFB, Cyclooxygenase-2, Lipooxygenase, and
Inducible Nitric Oxide Synthase Inhibitor: A Shield
Against Acute and Chronic Diseases )
who found that curcumin " . . . has been shown
to be non-toxic, to have antioxidant activity, and to
inhibit such mediators of inflammation as NF-kappaB,
cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible
nitric oxide synthase (iNOS)" and therefore that
"there is ample evidence to support its clinical
use, both as a prevention and a treatment".
Safety of Curcumin: Issues of
Drug Interference
Researchers at the Lineberger Comprehensive Cancer Center
at the University of North Carolina (Sivagurunathan
et al, Cancer Res (2002): Dietary
Curcumin Inhibits Chemotherapy-induced Apoptosis in
Models of Human Breast Cancer) used an
in vivo model of human breast cancer, finding that dietary
supplementation with curcumin significantly inhibited
cyclophosphamide-induced tumor regression, via a decrease
in the activation of apoptosis by cyclophosphamide,
as well as decreased JNK activation, supporting the
hypothesis that dietary curcumin consummation and supplementation
can inhibit chemotherapy-induced apoptosis through inhibition
of ROS generation and blockade of JNK function.
Breast Cancer Prevention Watch
has reviewed these claims and has determined them to
be against the overwhelming balance of the evidence,
and the study on which these claims are purportedly
founded exhibits severe methodological flaws that render
the drawn conclusions wholly illicit: curcumin has distinct
and sometimes contrary behavior that is acutely dose-related
and it would appear that the level used in the study
(10 µM) is insufficient to (1) produce superoxide
radicals and (2) induce apoptosis especially as reactive
oxygen species (ROS) appears to be necessary for curcumin’s
apoptotic effect, setting in at levels of 50 µM
and above, a fact further evidenced recently by the
Polish team of Sikora et al. (Mol Cancer Ther (2006):
Curcumin
induces caspase-3-dependent apoptotic pathway but inhibits
DNA fragmentation factor 40/caspase-activated DNase
endonuclease in human Jurkat cells) who
observed that curcumin's ability to induce cell death
in many cancer cells depends on the cell type and curcumin
concentration, and that in Jurkat cells, 50 µmol/L
curcumin was required to severely lower cell survival.
Furthermore, curcumin has been shown to augment the
cytotoxic effects of chemotherapeutic drugs, including
tamoxifen (Nolvadex) , doxorubicin (Adriamycin, Doxil),
cisplatin (Platinol), camptothecin (CPT) , daunorubicin
(Cerubidine, Daunomycin), vincristine (Oncovin), and
melphalan (Alkeran)(see TM Mitchell's critique of the
study in Cancer Res (2003): Correspondence
re: Somasundaram et al., Dietary Curcumin Inhibits Chemotherapy-induced
Apoptosis in Models of Human Breast Cancer),
in direct contradiction of the Lineberger teams findings.
In addition, the bioavailability issue is wholly ignored
by the researchers: in humans after a dose of 2 g curcumin
serum levels were either subtherapeutic being either
wholly undetectable, or extremely low, but concomitant
administration of piperine,
an inhibitor of hepatic and intestinal glucuronidation,
at 20 mg/kg produced much higher concentrations within
15 min to 1 hour later, with an increase in bioavailability
of 2000%, demonstrating that piperine enhances the serum
concentration, degree of absorption, and bioavailability
of curcumin in humans (and with no adverse effects)
(Shoba et al., Planta Med (1998): Influence
of piperine on the pharmacokinetics of curcumin in animals
and human volunteers). And even more unaccountably
the Lineberger team used a maximum time limit of just
15 hours, despite the fact that curcumin’s cytotoxic
effects typically do not occur for at least 48 hours
(Hanif et al., J Lab Clin Med (1997): Curcumin,
a natural plant phenolic food additive, inhibits cell
proliferation and induces cell cycle changes in colon
adenocarcinoma cell lines by a prostaglandin-independent
pathway), with maximal growth inhibition
at 72 hours (Goel et al., Cancer lett (2001): Specific
inhibition of cyclooxygenase-2 (COX-2) expression by
dietary curcumin in HT-29 human colon cancer cells).
Therefore, for these reasons and the weight of the evidence,
that we conclude that there is no compelling evidence
curcumin exhibits any interference with established
anticancer agents, with the further weight of the fact
that to date, there are no animal or human data to corroborate
the finding of Sivagurunathan and the Lineberger team.
Safety of Curcumin: Safety in
Human Clinical Trials
Numerous human clinical trials have further attested
to the safety of curcumin. Christopher Lao at the University
of Michigan (UM)/Ann Arbor) headed a research team from
UM, UCSD, and NCI/NIH who conducted a systematic dose
escalation study (Lao et al., BMC Complement Altern
Med (2006): Dose
escalation of a curcuminoid formulation)
of the pharmacology and safety / toxicology of standardized
curcumin (from Sabinsa corporation) in humans to determine
the MTD (maximum tolerated dose) and safety of a single
dose of standardized curcumin extract, concluding that
the safety and tolerance of curcumin in high oral dose
appears to be excellent, with no significant toxicity
in a dose step-through from 500, 1,000, 2,000, 4,000,
6,000 up to 8,000 mg., with no limiting maximum tolerated
dose. Similarly, researchers at the National Taiwan
University College of Medicine (Cheng et al., Anticancer
Res (2001):
Phase I clinical trial of curcumin, a chemopreventive
agent, in patients with high-risk or pre-malignant lesions)
reported no treatment-related toxicity of curcumin in
doses up to 8,000 mg/day for 3 months, in a high-risk
population of subjects with urinary bladder cancer,
arsenic Bowen's disease of the skin, uterine CIN (cervical
intraepithelial neoplasm) (CIN), oral leucoplakia, and
intestinal metaplasia of the stomach. In another dose-escalation
study to determine the pharmacology and safety of curcumin
in humans, Ricky Sharma at the University of Leicester
and coresearchers (Sharma et al., Clin Cancer Res (2001):
Pharmacodynamic and Pharmacokinetic
Study of Oral Curcuma Extract in Patients with Colorectal
Cancer) studied Sabinsa-standardized
curcumin doses between 0.45 and 3.6 g daily for up to
4 months in advanced refractory colorectal cancer patients,
finding that curcumin was well tolerated at all dose
levels, with only manageable mild diarrhea in some subjects,
and with no dose-limiting toxicity observed. And Nita
Chainani-Wu at UCSF conducted a systematic review (J
Altern Complement Med (2003): Safety
and Anti-Inflammatory Activity of Curcumin: A Component
of Tumeric (Curcuma longa)) of the literature
on the safety of curcumin, noting that in addition to
the the seminal studies cited here, five other human
trials using curcumin in a dose range of 1125 to 2500
mg per day have also concluded it's high safety, observing
that just as of 2003, curcumin has been demonstrated
to be safe in six human trials.
And recently Hanai and colleagues at the Hamamatsu University
School of Medicine (Clin Gastroenterol Hepatol (2006):
Curcumin Maintenance Therapy
for Ulcerative Colitis: Randomized, Multicenter, Double-Blind,
Placebo-Controlled Trial) evaluated 2
grams of curcumin daily for 6 months as maintenance
therapy in patients with quiescent ulcerative colitis,
finding clinical significant efficacy with no significant
toxicity. And confirmatory, Ishita Chattopadhyay of
the Indian Institute of Chemical Biology and coresearchers
at the Central Drug Research Institute (Curr Sci (2004):
Turmeric and curcumin: Biological
actions and medicinal applications [pdf])
conducted another review of curcumin's safety and efficacy,
concluding that "safety evaluation studies indicate
that both
turmeric and curcumin are well tolerated at a very high
dose without any toxic effects".
All these findings are in agreement with the conclusions
on human toxicology of curcumin by IPCS (International
Programme on Chemical Safety) and WHO, prepared by Dr.
D Benford with the United Kingdom Food Standards Agency
in behalf of JECFA - Joint Expert Committee on Food
Additives (Benford, IPCS / JECFA Monograph 1084: Curcumin
- WHO Food Additives Series 52 (2004)).
-
Grape
Seed Extract (GSE)
Researchers at the University of Colorado
Health Sciences Center (Sharma et al., Breast Cancer
Res Treat (2004): Synergistic
Anticancer Effects of Grape Seed Extract and Conventional
Cytotoxic Agent Doxorubicin Against Human Breast Carcinoma
Cells) examined the antitumor and chemotherapy-synergistic
activity of grape seed extract (GSE) with the anthracycline
doxorubicin (Adriamycin) in estrogen receptor-positive
human breast carcinoma cells, confirming a synergistic
efficacy of GSE and doxorubucin for breast cancer
treatment, and this was independent of estrogen receptor
status of the cancer cell. More recently, a team of
researchers at the University of Alabama at Birmingham
(Mantena et al., Carcinogenesis (2006): Grape
seed proanthocyanidins induce apoptosis and inhibit
metastasis of highly metastatic breast carcinoma cells)
investigated the effects of grape seed proanthocyanidins
(GSPs) on a highly metastatic mouse mammary carcinoma
cell line, finding that GSPs exhibit chemotherapeutic
efficacy against breast cancer including inhibition
of metastasis, with particularly prominent inhibition
of metastasis of tumor cells to the lungs benefiting
overall survival.
And researchers at the Beckman Research Institute
/ City of Hope Comprehensive Cancer Center (Kijima
et al, Cancer Res (2006): Grape
Seed Extract Is an Aromatase Inhibitor and a Suppressor
of Aromatase Expression) sought to
confirm previous findings that the high levels of
procyanidin dimers contained in grape seed extract
(GSE) are potent inhibitors of the aromatase enzyme
that converts androgen to estrogen; the new study
found that GSE inhibited aromatase activity in a dose-dependent
manner and reduced androgen-dependent tumor growth
in an aromatase-transfected MCF-7 breast cancer xenograft
model, which the researchers concluding that "We
believe that these results are exciting in that they
show GSE to be potentially useful in the prevention/treatment
of hormone-dependent breast cancer through the inhibition
of aromatase activity as well as its expression".
Optimal consumption levels need for antitumor activity
await the results of a dose-finding study (ClinicalTrials
(2006): IH636
Grape Seed Extract in Preventing Breast Cancer in
Postmenopausal Women at Risk of Developing Breast
Cancer).
-
Lignans
and Flax:
Flaxseed, also known as linseed, is a concentrated
source of omega-3 fatty acids and phytoestrogenic
lignans. Recent studies (in vitro, animal, and epidemiological)
suggest that dietary lignans may be chemopreventive
by virtue of anti-estrogenic, anti-angiogenic, pro-
apoptotic, and anti-oxidant mechanisms (see Webb &
McCullough (2005): Nutr Cancer (2005): Dietary
Lignans: Potential Role in Cancer Prevention,
who found the most support for a role of lignans in
cancer for premenopausal breast cancer;
see also Godnough, Nutrition Bytes (2005): Antitumorigenic
Effects of Flaxseed and Its Lignan, Secoisolariciresinol
Diglycoside (SDG).
Although MD Anderson Cancer Center, CIMER (Complementary/Integrative
Medicine Education Resources) Reviews of Therapies
(2005): Herbal
/ Plant Therapies: Flaxseed & Flaxseed Oil (Linum
usitatissimum) cautiously concluded
that there is not sufficient human evidence to make
a recommendation concerning flaxseed consumption and
breast cancer risk reduction, another systematic review
- Memorial Sloan-Kettering Cancer Center (MSKCC) About
Herbs (2005): FLAXSEED
( Linum usitatissimum. Family: Linacae)
- concluded that flaxseed has been shown to have chemoprotective
effects and that mice studies have shown that flaxseed
inhibits the growth and metastasis of human breast
cancer, prostate cancer, and melanoma, and that furthermore
flaxseed was also as effective as hormone replacement
therapy in improving mild menopausal vasomotor symptoms.
McCann et al., Int J Cancer (2004): Dietary
lignan intakes and risk of pre- and postmenopausal
breast cancer
found that premenopausal women in the highest quartile
of dietary lignan intake had reduced breast cancer
risk, but no association was observed between lignan
intakes and postmenopausal breast cancer, concluding
that dietary lignans may be important in the etiology
of breast cancer, particularly among premenopausal
women).
More recently, the RCT study of Thompson et al. (Clin
Cancer Res (2005): Dietary
Flaxseed Alters Tumor Biological Markers in Postmenopausal
Breast Cancer)
examined the effects of dietary flaxseed (daily intake
of 25g flaxseed-containing muffin) on tumor biological
markers and urinary lignan excretion in postmenopausal
newly diagnosed breast cancer patients, finding reductions
in two biological markers (Ki-67 labeling index and
c-erbB2 expression) used to measure cancer cell growth,
and an increase in apoptosis, suggesting that dietary
flaxseed has the potential to reduce tumor growth
in patients with breast cancer; the researchers suggest
that the anti-proliferative action of flax was comparable
to results for tamoxifen and aromatase inhibitors
in other studies. And the review of Hanf & Gonder
(Eur J Obstet Gynecol Reprod Biol (2005): Nutrition
and primary prevention of breast cancer: foods, nutrients
and breast cancer risk) observed that
lignans from traditionally made sourdough rye bread,
linseed/flaxseed and berries are local sources of
potentially cancer-protective phytoestrogens. We note
that the bioavailability of the antitumor component
of flaxseed, the enterolignans, was 28% greater with
ground flaxseed compared to whole flaxseed, and furthermore
crushed or milled flaxseed was 43% more bioavailable
compared with ground flaxseed, so it is clear that
crushing and milling of flaxseed substantially improves
the bioavailability of the antitumor enterolignans
(J Nutr (2005): The
Relative Bioavailability of Enterolignans in Humans
Is Enhanced by Milling and Crushing of Flaxseed).
And population-based studies have tended to confirm:
so in their case-control study among women who resided
in Nassau and Suffolk counties on Long Island, Brian
Fink and colleagues found that intake of flavonols,
flavones, flavan-3-ols, and lignans was associated
with reduced risk of incident postmenopausal breast
cancer among this sample population (Fink BN, Steck
SE, Wolff MS, et al. Dietary
Flavonoid Intake and Breast Cancer Risk among Women
on Long Island. Am J Epidemiol. 2007;165(5):514-523).
And the prospective study of Marina Touillaud and
her colleagues at the National Institute of Health
and Medical Research in France examined the associations
between the risk of postmenopausal invasive breast
cancer and dietary intakes of the four plant lignans
pinoresinol, lariciresinol, secoisolariciresinol,
and matairesinol) and estimated exposure to the two
enterolignans, enterodiol and enterolactone, in 58,049
postmenopausal French women for a median follow-up,
7.7 years, finding that both high dietary intake of
plant lignans and high exposure to enterolignans were
associated with reduced risks of ER- and PR-positive
postmenopausal breast cancer (Touillaud MS, Thiébaut
AC, Fournier A, Niravong M, Boutron-Ruault MC, Clavel-Chapelon
F. Dietary
lignan intake and postmenopausal breast cancer risk
by estrogen and progesterone receptor status.
J Natl Cancer Inst. 2007 Mar 21; 99(6):475-86).
Evidencewatch Commentary on
Lignan Consumption and Breast Cancer
Although these findings, especially those of the Thompson
study (above) are highly promising, the quite small
number of subjects studied (19 and 13 respectively
in the treatment and placebo groups) as well as the
very short study duration (approx. one month) caution
against drawing definitive conclusions concerning
long-term flaxseed consumption benefits for women
with breast cancer, and it is certainly highly premature
to suggest that flax/lignan consumption may be a substitute
for tamoxifen and/or aromatase inhibitors.
However, that said, given the well-known healthful
benefits of flax/lignan consumption, and the potential
for other positive health benefits independent of
breast cancer risk, suggests that incorporation of
high fiber flaxseed/lignan components into the diet
appears to be without harm and may be healthful overall,
especially for premenopausal women.
And for menopausal women, there may also be a benefit:
the randomized blinded crossover trial of Dr. Lorraine
Turner reported at the annual breast cancer symposium
sponsored by the Cancer Therapy and Research Center
held in San Antonio (Turner et al., 27th Annual San
Antonio Breast Cancer Symposium (2004): Does
flaxseed relieve vasomotor symptoms?)
found that flaxseed (40g daily consumption) significantly
relieved vasomotor hot flashes in 85 postmenopausal
women treated for breast cancer, with the fall in
hot flushes correlating with a rise in urinary lignan
markers, an important finding suggesting that lignans
may potentially be deployed as an alternative for
hot flash relief in women who have undergone breast
cancer treatment, and possibly other postmenopausal
women in general; the median number of hot flashes
- from a baseline of 208 per month - was reduced by
38% during flaxseed supplementation. Furthermore,
despite some previous studies appearing to suggest
that isoflavones can cause hypothyroidism, the study
found that flaxseed was not associated with any thyroid
function abnormalities.
The Thompson study is confirmative of the earlier
work of Brooks et al. (Am J Clin Nutr (2004): Supplementation
with flaxseed alters estrogen metabolism in postmenopausal
women to a greater extent than does supplementation
with an equal amount of soy) which
found that dietary supplementation in postmenopausal
women with 25 g ground flaxseed (but not with 25 g
soy flour) significantly alters the metabolism of
estradiol in favor of the less biologically active
estrogen metabolite (2OHE1).
Furthermore, given the fact that enterolactone is
quantitatively the most important circulating lignan,
Pietinen et al. (Cancer Epidemiol Biomarkers Prev
(2001): Serum
Enterolactone and Risk of Breast Cancer: A Case Control
Study in Eastern Finland) examined
the association between serum enterolactone and risk
of breast cancer, finding a significant inverse association
between serum enterolactone and risk of breast cancer
was seen both among premenopausal and postmenopausal
women, and noting that high enterolactone levels were
associated with higher consumption of rye products,
tea and higher intake of dietary fiber and vitamin
E.
And following up their earlier research, McCann et
al. (Breast Cancer Res Treat (2006): Dietary
lignan intakes and risk of breast cancer by tumor
estrogen receptor status) have further
established that the observed inverse association
of lignans with breast cancer may be limited to ER-
tumors.
-
High-fiber
Diet:
Although some studies fail to support a strong association
between fiber intake and breast cancer risk (Cho et
al., Cancer Epidemiol Biomarkers Prev: Premenopausal
dietary carbohydrate, glycemic index, glycemic load,
and fiber in relation to risk of breast cancer),
more recently, and more definitively, found that a
high-fiber, low-fat diet intervention is associated
with reduced serum bioavailable estradiol concentration
in women who have breast cancer, with increased fiber
intake independently related to the reduction in serum
estradiol concentration (see Rock et al., Clin Oncol:
Effects
of a High-Fiber, Low-Fat Diet Intervention on Serum
Concentrations of Reproductive Steroid Hormones in
Women With a History of Breast Cancer;
see also Mattison et al, Br J Cancer: Intakes
of plant foods, fibre and fat and risk of breast cancer
- a prospective study in the Malmo Diet and Cancer
cohort,
where it was found that high fiber intakes was associated
with a significant 40% reduction in breast cancer
risk, and that the lowest risk of breast cancer was
associated with the combination high fiber-low fat).
Note however that intake of dietary fat per se has
not been conclusively established as associated with
higher breast cancer risk. Nonethel |
