CR versus human breast cancer

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Hi All,

To me, the below pdf-available represents great CR studies. Notably,

anorexia

nervosa is characterized by CRHN (caloric restriction with horrible

nutrition).

Animal studies using rodents have shown that CR is highly effective

against cancers.

The paper appears to me to have much for many in the COMMENT for

CRers:

IGF-1 related factors, growth factors and live human beings that

pathologically but intentionally lose, not loose, weight.

True, though, it is a retrospective cohort study, not a prospective

study. Randomized control studies are impossible, I believe, for

CR. How can someone be randomized to go against accepted medical

practice. The Human Investigation Committee would not approve such a

study and subjects would not be found.

JAMA, March 10, 2004—Vol 291, No. 10

Caloric Restriction and Incidence of Breast Cancer

Karin B. Michels, Anders Ekbom

Context Restricting caloric intake is one of the most effective

ways to extend lifespan

and to reduce spontaneous tumor occurrence in experimental animals,

but whether

similar associations hold in humans has not been appropriately

studied....

Design, Setting, and Participants Retrospective cohort

study ....

Participants were 7303 Swedish women hos-pitalized

for anorexia nervosa prior to age 40 years between 1965 and 1998.

Women were excluded (n=31) if they were diagnosed with cancer prior

to their first discharge from hospitalization for anorexia nervosa....

Results Compared with the Swedish general population, women

hospitalized for

anorexia nervosa prior to age 40 years had a 53% (95% confidence

interval [CI],3%-81%) lower incidence of breast cancer; nulliparous

women with anorexia ner-vosa had a 23% (95% CI, 79% higher to 75%

lower) lower incidence, and parous women with anorexia nervosa had a

76% (95% CI, 13%-97%) lower incidence.

Conlusions Severe caloric restriction in humans may confer

protection from inva-sive breast cancer. Low caloric intake prior to

first birth followed by a subsequent pregnancy appears to be

associated with an even more pronounced reduction in risk.

RESTRICTING CALORIC INTAKE

is one of the most effective ways to extend lifespan and

to reduce spontaneous tumor occurrence in experimental

animals.1,2 Caloric restriction has an

important protective role in experi-mental

mammary carcinogenesis.3,4 A

recent meta-analysis summarized the

available evidence of the effect of

energy restriction on spontaneous

mammary tumors in mice.5 The com-bined

estimate for the 14 included

studies implied that the energy-restricted

animals developed 55%

(95% confidence interval [CI], 41%-69%)

fewer mammary tumors than

did those in the control groups, irre-spective

of the type of restricted nutri-ent.5 The authors called for dietary

cohort studies to gain insight into the

effects of energy restriction on devel-opment

of breast cancer in humans.5

Reduced caloric intake in experi-mental

animals has been found to be

accompanied by lower levels of circu-lating

insulin, insulin-like growth fac-tors

I and II, and epidermal growth

factor, as well as by modified cellular

responsiveness to estrogens, en-hanced

immunologic responsiveness,

alterations in cell cycle regulation, lower

rates of cellular proliferation, in-creased

DNA repair, reduced expres-sion

of oncogenes, and enhanced ex-pression

of tumor suppressor genes.5-10

Energy restriction may be crucial

during early life and prior to first preg-nancy,

when mammary tissue is espe-cially

susceptible to carcinogenic pro-cesses.

11,12 This hypothesis is supported

by the observation that greater height,

which although genetically influ-enced

still reflects nutritional status and

hence caloric intake during growth, is

associated with an increased inci-dence

of breast cancer.13,14

Energy restriction is difficult to study

in humans. One marker of caloric re-striction

is anorexia nervosa, an ill-ness

that occurs generally during ado-lescence

or early adulthood and is

characterized by very low caloric in-take,

low body mass index (BMI), and

amenorrhea....

METHODS

Study Design

....

Anorexia nervosa is defined in this

study as having received inpatient care

for the disease. A hospitalization for an-orexia

nervosa was identified by dis-charge

diagnoses ICD-7 codes 316.99

and 784.09, ICD-8 code 306.50, and

ICD-9 code 307B. This study was re-stricted

to a first hospitalization for an-orexia

nervosa.

We identified 7303 women from the

Swedish Inpatient Registry who were

hospitalized for anorexia nervosa prior

to age 40 years between 1965 and 1998....

Assessment of Effect Modifiers

The Swedish Fertility Registry has in-formation

on every birth in Sweden

among all women born in 1925 and

thereafter. We obtained information on

parity status from this registry for the

members of our anorexia cohort........

standardized incidence ratio (SIR)....

RESULTS

The distribution of women hospital-ized

for anorexia nervosa in our

cohort by age and calendar year of dis-charge

diagnosis is presented in

TABLE 1. The majority of anorexia cases

(73%) were diagnosed prior to age 20 years.

Among the 7303 women who were

diagnosed with anorexia prior to age 40

years, we identified 52 women who

were diagnosed with any type of can-cer

during 96887 person-years of fol-low-

up between 1965 and 2000; the ex-pected

number of cancer cases was 56.6.

The SIR for all types of cancers com-bined

was 0.92 (95% CI, 0.69-1.21) (TABLE 2).

Among women who were diag-nosed

with anorexia prior to age 40

years, the SIR for breast cancer was 0.47

(95% CI, 0.19-0.97) (Table 2). Seven

women in this group developed breast

cancer. The expected number of breast

cancer cases was 14.8; thus, women in

this group had a 53% (95% CI, 3%-81%)

lower incidence of breast cancer

than the Swedish general population.

Among women diagnosed with an-orexia

nervosa prior to age 20 years, no

case of breast cancer occurred; the num-ber

of breast cancer cases expected in

this group was 2.7. Among women di-agnosed

between the ages of 20 and 29

years, 4 cases were diagnosed and 6.4

expected; among women diagnosed

with anorexia between the ages of 30

and 39 years, 3 cases were observed and

5.7 expected.

In our anorexia cohort, 73% of

women remained nulliparous through-out

the observation period. Among

women who remained nulliparous, the

SIR for breast cancer was 0.77 (95% CI,

0.25-1.79) during 78984 person-years

of follow-up; there were 5 cases

diagnosed and 6.5 expected, and thus

women in this group had a 23% (95%

CI, 79% increased to 75% decreased)

reduced incidence of breast cancer. The

corresponding SIR value among par-ous

women was 0.24 (95% CI, 0.03-

0.87) during 17903 person-years of fol-low-

up; there were 2 cases diagnosed

and 8.3 expected, and thus women in

this group had a 76% (95% CI, 13%-97%)

reduced incidence (Table 2).

Analyses of other hormone-dependent

cancers such as uterine or

ovarian cancer did not reveal a signifi-cant

inverse association, but statisti-cal

power was limited (data not shown).

COMMENT

Among this Swedish cohort of women

with a hospital discharge diagnosis of

anorexia nervosa prior to age 40 years,

we found a significant decrease in breast

cancer incidence compared with the

general Swedish female population of

comparable age and birth cohort. Be-cause

anorexia nervosa that requires

hospitalization is associated with se-vere

caloric restriction during a pro-longed

period of early life, we con-clude

that such starvation during

adolescence and early adulthood may

impact on mechanisms crucial for de-velopment

of breast cancer. The ma-jority

of breast cancers in this cohort

arose in premenopausal women due to

the age structure of the cohort.

These findings confirm observations

made in rodents in which caloric re-striction

has been a very effective mea-sure

to reduce cancer incidence. We are

aware of only 1 other study in which the

association between anorexia nervosa

and cancer incidence was considered

among humans. A study conducted in

Denmark took a similar approach, link-ing

the Danish Psychiatric Case Regis-ter

and the National Registry of Pa-tients

to the Danish Cancer Registry.18

The authors report an SIR of 0.80 (95%

CI, 0.52-1.18) for overall cancer inci-dence

among 2151 women with a hos-pital

discharge diagnosis of anorexia ner-vosa

based on 25 observed cases. In this

cohort, statistical power was limited to

consider site-specific cancers. The SIR

observed for breast cancer was 0.8 (95%

CI, 0.3-1.7), but the study population

was not restricted to women who expe-rienced

anorexia prior to age 40 years.18

In another study, prepubertal girls who

were exposed to the Norwegian famine

in World War II and who consumed an

average of 22% fewer calories had a

lower subsequent rate of breast cancer

than women from earlier or later birth

cohorts.19

Among women with anorexia in our

cohort who later had 1 or more chil-dren

the risk of breast cancer was re-duced

by 76%. Among these women, we

mimic the environment of developing

countries where women experience ca-loric

restriction but go on to become

pregnant and deliver children. Rates of

breast cancer in developing countries are

considerably lower than in most afflu-ent

countries.20 It is conceivable that ca-loric

restriction during early periods of

life is associated with decreased devel-opment

of breast parenchyma and that

subsequent differentiation of breast cells

during pregnancy confers stronger pro-tection

than among women in industri-alized

countries. Hence, low rates of

breast cancer in developing countries

may be due to low caloric intake prior

to first birth, and a particularly pro-nounced

protection is conferred by sub-sequent

pregnancy.

Among women with anorexia ner-vosa,

later fertility does not seem to be

compromised, but fecundability is re-duced.

21,22 In general, women with an-orexia

nervosa may have delayed child-birth

and thus lower parity. In our

cohort, only 26% of women gave birth

after a diagnosis of anorexia nervosa,

but due to the age structure of the co-hort

most women are still of childbear-ing

age. In Sweden, the average age at

first birth is currently 30 years.23

A number of possible mechanisms

may underlie our observations. Ca-loric

restriction may have a direct effect

on breast cell growth and develop-ment.

Prolonged caloric restriction can

also affect the _expression of various on-cogenes

and tumor suppressor genes.

Reduced levels of epidermal growth

factor _expression, reduced ERBB2 lev-els,

a decrease in cyclin D1 expres-sion,

and increased p53 and p27 ex-pression

have been found in the

mammary tissue of chronically calorie-restricted

rodents.7-9

Furthermore, caloric restriction and

anorexia have been found to reduce lev-els

of estrogen (which may be mani-fested

in amenorrhea)10,24 and insulin-like

growth factor I (IGF-I).6,25 Recent

research has identified IGF-I as an im-portant

biomarker for the prediction of

breast cancer.26,27 IGF-I is a powerful

growth hormone whose serum and tis-sue

levels peak during adolescence.28 An-orexia

nervosa might lead to lower tis-sue

levels of IGF-I during a crucial phase

of mammary gland development and

thus affect risk of breast cancer.

Anorexia nervosa is associated with

amenorrhea and consequently a re-duced

number of lifetime ovulations,

which might confer protection from

breast cancer. Women with anorexia of-ten

enhance weight loss by strenuous

physical activity. The epidemiologic

data on the association between physi-cal

activity and risk of breast cancer are

not conclusive, but more evidence sup-ports

an inverse relation with post-menopausal

breast cancer 29,30 than with

premenopausal 31,32 breast cancer. Some

studies indicate a reduced risk of breast

cancer among women who exercised

heavily during their teenage years.33,34

Heavy exercise was associated with the

strongest risk reduction in breast can-cer

among women with low BMI in at

least 1 study.35

Anorexia may be associated with con-siderable

weight fluctuations, which

have also been found to protect from

breast cancer in the animal model.36 We

are aware of only 1 epidemiologic study

that has considered weight cycling and

breast cancer among humans.37 In a

population-based case-control study

conducted in the United States, weight

cycling was defined as losing 20 lb (9

kg) or more and gaining at least half of

the lost weight back within 1 year; 1

cycle was sufficient to qualify an indi-vidual

as a weight cycler. No associa-tion

was found with breast cancer.

The biological pathways of the asso-ciation

between body mass and the risk

of breast cancer are complex, with op-posing

effects of a high BMI on pre-menopausal

and postmenopausal risk

of breast cancer.38,39 A number of re-

ports have related a high BMI during

adolescence with a decreased risk of

breast cancer.40-43 Coates and col-leagues

44 have reported a U-shaped re-lation

between relative weight in ado-lescence

and later risk of breast cancer:

women who were either much heavier

or much thinner than average were at

reduced risk. Both anorexia nervosa and

obesity during adolescence may be as-sociated

with anovulation and thus a

delayed onset of menarche. Alterna-tively,

mechanisms underlying the pro-tection

conferred by low and high ca-loric

intake may differ; while very low

circulating levels of estrogen and other

growth hormones might be protec-tive,

fairly high levels might induce early

differentiation of breast cells.43

Our study has a number of limita-tions.

The number of cases observed in

our cohort is limited. Furthermore,

there is the possibility of unmeasured

confounding. It is unlikely, however,

that established risk factors for breast

cancer, such as family history, would

be related to anorexia nervosa. While

our cohort of women with anorexia may

differ from the general population in

some aspects other than total caloric in-take,

women with anorexia who go on

to become pregnant are more similar to

the general population, which lends

support to our conclusions. Reproduc-tive

factors (eg, age at menarche, par-ity,

age at first birth) and anthropomet-ric

variables (eg, height, BMI) might be

in the causal pathway of the associa-tion

of interest; thus, we would not

want to adjust for them. Furthermore,

lower parity and a later age at first birth

would place women with anorexia at

a higher risk of breast cancer. In this

Swedish cohort, exposure and out-come

were ascertained with high ac-curacy.

Neither differential nor non-differential

misclassification of exposure

or disease are probable. Therefore, it is

unlikely that our results are due to bias.

Our observations suggest an impor-tant

role for caloric intake in the etiol-ogy

of breast cancer and call for fur-ther

research exploring the underlying

mechanisms of this association to elu-cidate

whether it is primarily due to di-

rect effects of caloric restriction on

breast cell growth and development, to

amenorrhea and associated hypoestro-genism,

or to a decreased level of

growth factors.

Cheers, Alan Pater, PhD; 4849 Swanson St., Port Alberni, BC, V9Y 6M7;

phone: 250 724-0596; email: old54200@...