|
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
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