Breast

cancer

risk

factors

in

relation

to

breast

density

-LRB-

United

States

-RRB-

Objectives

Evaluate

known

breast

cancer

risk

factors

in

relation

to

breast

density

Introduction

Numerous

studies

have

shown

that

breast

density

as

assessed

through

mammography

is

an

important

breast

cancer

risk

factor

-LSB-

-RSB-

Relative

to

the

lowest

classification

of

breast

density

-LRB-

fatty

tissue

-RRB-

women

with

the

highest

classification

-LRB-

extreme

density

-RRB-

may

have

a

to

increased

risk

of

breast

cancer

-LSB-

-RSB-

In

addition

to

its

role

in

breast

cancer

risk

breast

density

reduces

mammographic

accuracy

-LSB-

-RSB-

potentially

increasing

the

risk

of

a

later

stage

breast

cancer

diagnosis

Previous

studies

indicate

that

established

breast

cancer

risk

factors

including

family

history

of

breast

cancer

age

at

first

birth

parity

and

postmenopausal

hormone

use

have

similar

associations

with

breast

density

In

contrast

the

influence

of

age

at

menarche

which

in

most

studies

is

inversely

related

to

breast

cancer

risk

-LSB-

e.g.

-RSB-

remains

uncertain

Some

studies

have

found

positive

associations

-LSB-

-RSB-

at

least

one

suggests

an

inverse

association

-LSB-

-RSB-

and

others

found

no

relation

between

age

at

menarche

on

breast

density

-LSB-

-RSB-

In

an

effort

to

clarify

inconsistent

results

from

previous

studies

we

evaluated

established

breast

cancer

risk

factors

in

relation

to

breast

density

in

a

large

population

of

women

enrolled

in

a

statewide

mammography

registry

Our

intention

was

to

determine

whether

characteristics

associated

with

breast

cancer

risk

were

also

related

to

breast

density

a

finding

that

would

be

consistent

with

the

notion

that

density

mediates

breast

cancer

risk

We

were

particularly

interested

in

assessing

the

influence

of

menarcheal

age

Methods

The

New

Hampshire

Mammography

Network

-LRB-

NHMN

-RRB-

registers

all

consenting

women

who

undergo

mammography

at

participating

mammographic

facilities

in

our

state

Details

of

the

registry

have

been

described

previously

-LSB-

-RSB-

For

the

present

study

potentially

eligible

women

were

NH

residents

of

ages

who

had

at

least

one

mammogram

registered

in

the

NHMN

from

May

to

June

The

epidemiological

data

used

in

this

analysis

arose

from

three

sources

a

self-administered

questionnaire

completed

by

the

patient

a

patient

intake

form

administered

face-to-face

by

the

radiologic

technologist

and

a

standardized

clinical

assessment

form

completed

by

the

radiologist

The

questionnaire

collected

height

weight

place

of

birth

ethnicity

marital

status

education

insurance

coverage

reason

for

the

current

visit

past

history

of

clinical

breast

examinations

and

mammography

age

at

menarche

parity

and

age

at

first

birth

The

questionnaire

also

queried

women

regarding

the

date

of

their

last

menstrual

period

and

history

of

gynecological

surgery

This

information

was

used

to

classify

women

as

premenopausal

-LRB-

still

having

periods

naturally

-RRB-

or

postmenopausal

-LRB-

periods

had

stopped

permanently

-RRB-

either

naturally

because

of

chemotherapy/radiation

or

surgery

-RRB-

The

patient

intake

form

obtained

date

of

birth

family

history

of

breast

cancer

-LRB-

in

the

subject

's

mother

sister

daughter

or

other

relative

-RRB-

personal

history

of

breast

cancer

history

of

breast

procedures

type

of

exam

conducted

at

current

visit

examination

outcomes

recommendation

for

further

work-up

or

follow-up

and

current

use

of

postmenopausal

hormone

therapy

-LRB-

HT

-RRB-

The

clinical

assessment

form

obtained

the

type

of

exam

conducted

at

current

visit

breast

density

examination

outcomes

and

recommendation

for

further

work-up

or

follow-up

All

three

forms

are

completed

during

the

woman

's

first

NHMN

mammography

visit

Patient

intake

and

clinical

assessment

forms

are

also

completed

at

subsequent

mammography

visits

and

the

questionnaire

is

updated

as

possible

Breast

density

the

outcome

variable

estimates

the

proportion

of

fibroglandular

tissue

in

the

breast

relative

to

fat

Breast

density

was

recorded

on

the

standardized

clinical

assessment

form

by

interpreting

radiologists

using

the

American

College

of

Radiology

Breast

Imaging

Reporting

and

Data

System

-LRB-

BI-RADS

-RRB-

classification

-LRB-

fatty

scattered

density

heterogeneously

dense

and

extremely

dense

-RRB-

-LSB-

-RSB-

In

the

event

of

discordance

in

the

density

of

the

right

and

left

breast

the

woman

was

classified

according

to

the

higher

density

classification

Breast

density

readings

were

available

for

-LRB-

-RRB-

of

the

women

who

had

at

least

one

mammogram

recorded

in

the

registry

To

optimize

temporal

correspondence

between

the

women

's

characteristics

and

the

classification

of

breast

density

the

statistical

analyses

were

when

possible

based

on

the

woman

's

breast

density

on

the

date

of

the

first

recorded

mammogram

When

data

for

variables

-LRB-

other

than

HT

use

-RRB-

were

unavailable

for

the

date

of

the

mammogram

we

searched

forward

in

the

NHMN

records

to

retrieve

replacement

information

corresponding

to

a

subsequent

mammography

visit

Informative

forward

searches

retrieved

information

from

subsequent

mammographic

encounters

occurring

on

average

within

months

of

the

index

mammogram

and

reduced

missing

values

by

Current

body

mass

index

-LRB-

BMI

-RRB-

was

missing

for

women

and

the

analyses

were

confined

to

women

for

whom

this

measure

was

available

Included

in

the

analytic

sample

were

-LRB-

-RRB-

women

with

a

screening

mammogram

-LRB-

-RRB-

with

a

diagnostic

mammogram

and

-LRB-

-RRB-

for

whom

the

reason

for

the

mammogram

was

not

recorded

The

majority

of

women

-LRB-

-RRB-

had

no

personal

history

of

breast

cancer

-LRB-

-RRB-

had

a

prior

history

of

breast

cancer

based

on

NHMN

records

or

the

patient

intake

form

and

-LRB-

-RRB-

had

unknown

breast

cancer

status

We

used

unconditional

logistic

regression

analyses

to

generate

odds

ratios

-LRB-

OR

-RRB-

and

confidence

intervals

-LRB-

CI

-RRB-

-LSB-

-RSB-

for

the

association

between

factors

and

breast

density

dichotomized

as

heterogeneously/extremely

dense

-LRB-

dense

-RRB-

or

fatty/scattered

density

-LRB-

not

dense

-RRB-

Statistical

significance

required

a

probability

value

of

-LRB-

two-sided

test

-RRB-

OR

were

computed

using

the

cutpoints

shown

in

the

tables

Tests

of

trend

and

the

corresponding

OR

were

based

on

the

categorical

-LRB-

age

at

menarche

-RRB-

or

the

continuous

form

of

the

variable

-LRB-

age

BMI

age

at

first

birth

parity

-RRB-

in

accordance

with

the

method

of

data

collection

Because

breast

density

was

inversely

associated

with

age

-LRB-

p

for

trend

-RRB-

and

current

BMI

-LRB-

p

for

trend

-RRB-

terms

for

these

variables

using

the

continuous

form

were

included

in

all

models

We

found

no

evidence

of

confounding

by

the

other

variables

shown

in

Table

-LRB-

fully

adjusted

OR

were

within

of

those

adjusted

for

age

and

BMI

-RRB-

Model

building

began

with

terms

representing

the

main

effects

and

included

interaction

terms

involving

age

BMI

and

menopausal

status

as

suggested

by

visual

inspection

of

the

stratified

analyses

The

presence

of

statistical

interactions

was

formally

tested

using

likelihood

ratio

tests

The

interaction

term

representing

BMI

was

defined

as

BMI

-LRB-

high

BMI

-RRB-

versus

-LRB-

low

BMI

-RRB-

The

final

multivariable

model

based

on

all

women

contained

terms

for

age

and

BMI

in

their

continuous

form

BMI

-LRB-

high

low

-RRB-

family

history

of

breast

cancer

age

at

menarche

age

at

first

birth

parity

menopausal

status

current

use

of

HT

and

terms

for

the

interactions

involving

BMI

-LRB-

high

low

-RRB-

and

age

at

menarche

age

at

first

birth

and

parity

a

term

for

the

interaction

involving

age

and

current

HT

use

and

a

term

for

the

interaction

between

age

at

first

birth

and

menopausal

status

We

repeated

the

analyses

in

parous

women

in

women

with

a

screening

mammogram

and

in

women

who

did

not

have

a

personal

history

of

breast

cancer

Table

of

women

's

characteristics

by

breast

density

dichotomized

as

dense

versus

not

denseCharacteristics

of

study

sample

-LRB-

n

-RRB-

Not

denseDensen

n

Age

-LRB-

years

-RRB-

All

Education

High

High

school

College

Post

Marital

status

Not

Current

BMI

Family

history

breast

cancer

Age

at

menarche

Age

at

first

birtha

Parity

Menopausal

status

HT

useb

aAge

at

first

birth

in

parous

womenbA

small

proportion

of

women

-LRB-

-RRB-

who

reported

whether

they

used

HT

did

not

give

their

menopausal

status

Results

In

all

women

scattered

density

-LRB-

-RRB-

was

most

frequently

recorded

followed

by

heterogeneous

density

-LRB-

-RRB-

fatty

breasts

-LRB-

-RRB-

and

extremely

dense

breasts

-LRB-

-RRB-

The

distribution

of

factors

by

breast

density

classified

as

not

dense

versus

dense

is

shown

in

Table

In

general

based

on

the

cutpoints

shown

there

was

a

tendency

for

younger

women

those

with

higher

education

and

married

women

to

have

denser

breasts

Women

with

lower

BMI

also

had

greater

breast

density

consistent

with

our

use

of

BI-RADS

categories

which

assess

the

proportion

of

fibroglandular

tissue

-LRB-

versus

fat

-RRB-

in

the

breast

Women

with

a

family

history

of

breast

cancer

later

menarcheal

age

later

age

at

first

birth

and

low

parity

had

a

tendency

toward

higher

breast

density

High

breast

density

was

more

common

in

premenopausal

than

in

postmenopausal

women

and

in

women

currently

using

HT

compared

to

nonusers

Age-stratified

analyses

adjusted

for

age

and

BMI

showed

a

weak

positive

influence

of

family

history

of

breast

cancer

across

all

age

groups

assessed

-LRB-

Table

-RRB-

A

small

positive

association

between

age

at

menarche

and

breast

density

appeared

to

vary

by

age

with

weaker

effects

in

the

older

and

youngest

age

groups

There

were

no

clear

age-related

patterns

for

either

the

positive

effect

of

age

at

first

birth

or

the

inverse

effect

of

parity

or

menopausal

status

Current

HT

use

compared

to

nonuse

was

inversely

associated

with

breast

density

in

the

younger

age

groups

and

positively

associated

in

women

of

age

or

more

In

women

of

age

or

more

those

using

HT

compared

to

nonusers

had

twice

the

odds

of

having

dense

breasts

Table

ratios

-LRB-

OR

-RRB-

and

confidence

intervals

-LRB-

CI

-RRB-

for

the

association

with

breast

density

according

to

age

groupCharacteristicaAge

group

n

n

n

n

n

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

Family

history

breast

cancer

NoReferenceReferenceReferenceReferenceReference

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OR

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status

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N/AN/AHT

use

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aAdjusted

for

age

and

current

BMI

as

continuous

variablesbBased

on

the

cutpoints

showncAmong

parous

womendBased

on

the

continuous

form

of

the

variable

Analyses

stratified

on

BMI

suggested

that

the

influence

of

some

factors

was

less

evident

in

women

of

BMI

-LRB-

high

BMI

-RRB-

than

in

those

of

BMI

-LRB-

low

BMI

-RRB-

-LRB-

Table

-RRB-

In

particular

the

positive

influence

of

age

at

menarche

and

age

at

first

birth

and

the

inverse

influence

of

parity

were

least

apparent

in

the

highest

BMI

group

The

data

suggested

an

inverse

effect

of

being

postmenopausal

relative

to

premenopausal

which

decreased

consistently

across

the

BMI

groupings

but

the

change

in

OR

from

the

lowest

to

the

highest

BMI

group

was

slight

Although

the

influence

of

current

HT

use

fluctuated

somewhat

over

BMI

groups

there

were

no

obvious

patterns

Table

ratios

-LRB-

OR

-RRB-

and

confidence

intervals

-LRB-

CI

-RRB-

for

the

association

with

breast

density

according

to

BMI

groupCharacteristicaCurrent

BMI

n

n

n

n

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

OR

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CI

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Family

history

of

breast

cancer

-LRB-

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-RRB-

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-RRB-

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Age

at

menarche

Overall

OR

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CI

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at

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birthc

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CI

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-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Parity

Overall

OR

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

for

trendd

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Menopausal

status

PremenopausalReferenceReferenceReferenceReferenceReference

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

HT

use

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aAdjusted

for

age

and

current

BMI

as

continuous

variablesbBased

on

the

cutpoints

showncAmong

parous

womendBased

on

the

continuous

form

of

the

variable

Analyses

stratified

by

menopausal

status

revealed

largely

similar

results

for

most

variables

but

the

relationship

between

age

at

first

birth

and

breast

density

was

stronger

in

the

postmenopausal

women

-LRB-

Table

-RRB-

Table

ratios

-LRB-

OR

-RRB-

and

confidence

intervals

-LRB-

CI

-RRB-

for

the

association

with

breast

density

according

to

menopausal

statusCharacteristicaMenopausal

status

PremenopausalPostmenopausaln

n

OR

-LRB-

CI

-RRB-

OR

-LRB-

CI

-RRB-

Family

history

of

breast

cancer

NoReferenceReference

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

first

birth

Overall

OR

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

for

trend

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

first

birthb

Overall

OR

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

for

trendc

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Parity

Overall

OR

-LRB-

CI

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

p

for

trendc

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

HT

use

NoNAReference

-LRB-

-RRB-

aAdjusted

for

age

and

current

BMI

as

continuous

variablesbAmong

parous

womencBased

on

the

continuous

form

of

the

variable

We

assessed

risk

factors

and

potential

interactions

in

a

multivariable

model

-LRB-

Table

-RRB-

Only

one

factor

family

history

of

breast

cancer

which

showed

a

weak

but

significant

positive

effect

-LRB-

OR

CI

-RRB-

on

breast

density

was

not

involved

in

an

interaction

The

possible

interaction

involving

age

and

age

at

menarche

suggested

by

the

age-stratified

analyses

was

not

statistically

significant

-LRB-

p

-RRB-

A

statistically

significant

interaction

was

found

between

current

HT

use

and

age

-LRB-

p

-RRB-

Interactions

were

also

present

between

BMI

and

age

at

menarche

-LRB-

p

-RRB-

age

at

first

birth

-LRB-

p

-RRB-

and

parity

-LRB-

p

-RRB-

We

also

noted

a

significant

interaction

between

menopausal

status

and

age

at

first

birth

-LRB-

p

-RRB-

but

the

coefficients

were

inconsistent

across

categories

of

age

at

first

birth

When

the

interaction

between

menopausal

status

and

age

at

first

birth

was

omitted

from

the

multivariable

model

results

for

the

remaining

terms

were

essentially

unchanged

A

possible

interaction

involving

age

menopausal

status

and

HT

was

not

significant

-LRB-

p

-RRB-

Table

-LRB-

β

-RRB-

and

standard

errors

-LRB-

SE

-RRB-

for

the

association

between

factors

and

breast

density

in

all

women

and

in

subgroupsaCharacteristicAll

women

n

Women

without

breast

cancer

n

β

-LRB-

SE

-RRB-

β

-LRB-

SE

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

-LRB-

-RRB-

-LRB-

-RRB-

Current

BMI

-LRB-

-RRB-

-LRB-

-RRB-

Family

history

of

breast

-LRB-

-RRB-

-LRB-

-RRB-

BMI

-LRB-

-RRB-

-LRB-

-RRB-

Postmenopausal

-LRB-

-RRB-

-LRB-

-RRB-

HT

use

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

menarche

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

BMI

Age

at

menarche

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

first

birth

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

BMI

Age

at

first

birth

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Postmenopausal

Age

at

first

birth

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Paritya

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

BMI

Parityb

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

HT

-LRB-

-RRB-

-LRB-

-RRB-

aBased

on

a

multivariable

model

containing

all

terms

shown

in

the

tablebThe

nulliparous

parameter

and

its

interaction

with

BMI

were

set

to

since

these

variables

were

linear

combinations

of

other

variables

We

repeated

the

analyses

in

the

subgroup

of

women

who

did

not

have

a

personal

history

of

breast

cancer

and

found

similar

results

-LRB-

Table

-RRB-

The

findings

were

also

comparable

when

the

analyses

were

confined

to

parous

women

or

to

those

with

a

screening

mammogram

-LRB-

data

not

shown

-RRB-

Discussion

Evidence

accumulating

for

nearly

years

supports

the

association

between

breast

density

and

breast

cancer

-LSB-

-RSB-

Although

the

notion

remains

controversial

breast

density

may

be

a

biomarker

of

risk

-LSB-

-RSB-

In

addition

to

its

influence

on

breast

cancer

risk

breast

density

reduces

the

accuracy

of

screening

mammography

-LSB-

-RSB-

particularly

in

younger

women

-LSB-

-RSB-

who

tend

to

have

denser

breasts

-LSB-

-RSB-

Perhaps

as

a

direct

consequence

of

reduced

screening

accuracy

breast

density

is

associated

with

increased

risk

of

interval

breast

cancers

-LSB-

-RSB-

with

an

adverse

impact

on

breast

cancer

prognosis

Most

studies

of

breast

cancer

risk

have

shown

an

inverse

effect

of

age

at

menarche

-LSB-

-RSB-

but

previous

studies

of

the

relationship

between

age

at

menarche

and

breast

density

have

produced

inconsistent

results

A

positive

association

was

seen

in

two

studies

-LSB-

-RSB-

including

a

large

HMO

population

of

nearly

women

in

Seattle

-LSB-

-RSB-

Studies

of

breast

cancer

family

members

-LSB-

-RSB-

Singaporean

women

-LSB-

-RSB-

and

Hispanic

women

-LSB-

-RSB-

found

no

association

between

menarcheal

age

and

breast

density

Findings

from

the

HMO-based

study

suggested

the

positive

effect

of

age

at

menarche

was

stronger

in

the

youngest

and

oldest

age

groups

-LSB-

-RSB-

whereas

a

study

of

nearly

women

in

Guernsey

found

significant

positive

effects

only

in

postmenopausal

women

-LSB-

-RSB-

In

contrast

our

age-stratified

analyses

suggested

weaker

effects

in

the

oldest

age

groups

although

the

interaction

involving

age

and

age

at

menarche

was

not

statistically

significant

Also

in

this

study

analyses

stratified

on

BMI

suggested

that

age

at

menarche

was

positively

associated

with

breast

density

in

most

BMI

groups

but

the

association

was

tenuous

in

women

with

high

BMI

and

the

interaction

involving

age

at

menarche

and

high

BMI

was

statistically

significant

A

positive

association

between

age

at

menarche

and

breast

density

even

if

confined

to

women

with

lower

BMI

seems

paradoxical

given

the

usual

inverse

association

between

age

at

menarche

and

breast

cancer

and

the

strong

positive

association

between

breast

density

and

breast

cancer

risk

Consistent

with

some

-LSB-

-RSB-

but

not

all

-LSB-

-RSB-

previous

efforts

our

findings

show

that

age

at

first

birth

and

parity

are

generally

associated

with

breast

density

in

a

pattern

resembling

known

associations

with

breast

cancer

risk

However

our

stratified

analyses

indicate

that

the

influence

of

the

reproductive

variables

is

less

pronounced

in

women

with

high

BMI

and

our

modeling

results

confirmed

interactions

involving

BMI

and

both

variables

These

findings

along

with

our

findings

for

age

at

menarche

are

consistent

with

the

possibility

that

hormonal

or

reproductive

events

are

less

influential

in

heavier

women

whose

circulating

hormone

levels

may

be

influenced

by

conversion

in

peripheral

adipose

tissue

We

also

noted

a

stronger

positive

influence

of

age

at

first

birth

in

postmenopausal

women

although

a

previous

study

of

Native

American

women

found

stronger

effects

in

premenopausal

women

-LSB-

-RSB-

Our

sample

was

large

and

the

multivariable

results

were

inconsistent

across

categories

of

age

at

first

birth

thus

it

is

possible

the

interaction

between

menopausal

status

and

age

at

first

birth

was

due

to

statistical

artifact

rather

than

true

effect

modification

Only

one

variable

family

history

of

breast

cancer

was

not

involved

in

interactions

with

age

BMI

or

menopausal

status

Although

previous

studies

have

not

shown

an

effect

of

family

history

on

breast

density

-LSB-

-RSB-

this

is

likely

due

to

limited

power

to

detect

a

weak

association

The

modest

inverse

effect

of

menopausal

status

has

been

noted

previously

-LSB-

-RSB-

Most

previous

reports

although

not

all

-LSB-

-RSB-

found

a

positive

association

between

use

of

HT

and

breast

density

-LSB-

-RSB-

resembling

the

well-known

association

between

use

of

these

hormones

and

breast

cancer

risk

The

large

size

of

our

study

allowed

an

assessment

of

HT

use

in

young

postmenopausal

women

and

these

analyses

showed

a

modest

but

significant

inverse

effect

in

postmenopausal

women

less

than

years

of

age

a

phenomenon

that

has

no

clear

explanation

In

women

of

age

or

more

the

positive

effect

of

HT

on

density

increased

with

age

perhaps

reflecting

a

corresponding

decrease

in

density

in

untreated

women

in

the

same

age

group

Consistent

with

our

findings

at

least

two

previous

studies

of

breast

density

showed

an

increasing

effect

of

HT

use

when

examined

over

increasing

age

groups

-LSB-

-RSB-

A

prospective

study

of

breast

cancer

risk

also

noted

stronger

HT

effects

in

older

women

-LSB-

-RSB-

although

this

is

not

always

seen

-LSB-

-RSB-

The

age-related

increase

observed

in

our

study

could

potentially

reflect

a

longer

duration

of

HT

use

but

at

least

two

studies

have

shown

that

most

of

the

increase

in

breast

density

occurs

soon

after

HT

initiation

-LSB-

-RSB-

and

duration

of

use

was

not

associated

with

increased

breast

density

in

the

HMO

study

-LSB-

-RSB-

In

contrast

the

positive

influence

of

HT

on

breast

cancer

risk

is

usually

observed

for

current/recent

and

long-term

use

-LSB-

-RSB-

While

speculative

it

is

possible

that

sustained

breast

density

associated

with

long

term

HT

use

mediates

the

relationship

between

HT

and

breast

cancer

risk

Finally

our

data

did

not

indicate

a

stronger

effect

of

HT

on

breast

density

in

leaner

woman

but

a

few

studies

-LSB-

-RSB-

including

a

collaborative

analysis

of

studies

-LSB-

-RSB-

suggested

a

stronger

association

between

HT

and

breast

cancer

risk

in

leaner

women

Although

the

type

of

HT

used

-LRB-

estrogen

alone

or

estrogen

combined

with

progesterone

-RRB-

was

not

assessed

in

our

study

a

possible

role

of

progesterone

is

suggested

by

reports

that

breast

density

is

greater

during

the

luteal

phase

of

the

menstrual

cycle

-LSB-

-RSB-

In

addition

at

least

two

studies

have

found

substantially

greater

changes

in

parenchymal

patterns

in

women

initiating

use

of

a

combined

estrogen

plus

progesterone

hormone

regimen

as

opposed

to

single

agent

estrogen

-LSB-

-RSB-

Results

from

the

Women

's

Health

Initiative

randomized

clinical

trials

of

postmenopausal

hormones

also

indicate

that

the

increased

risk

of

breast

cancer

is

due

to

the

combined

regimen

-LSB-

-RSB-

rather

than

single

agent

estrogen

-LSB-

-RSB-

Strengths

of

our

study

include

the

large

size

of

our

sample

allowing

analyses

stratified

by

relatively

refined

age

and

BMI

groups

which

has

not

been

possible

in

most

previous

studies

and

good

representation

of

the

underlying

population

Epidemiologic

data

were

obtained

on

the

time

of

the

mammographic

visit

ensuring

updated

information

and

importantly

a

high

level

of

correspondence

between

use

of

hormone

replacement

therapy

and

the

assessment

of

breast

density

Limitations

of

our

study

include

of

women

for

whom

BMI

is

missing

reliance

of

self-report

for

BMI

and

a

lack

of

information

regarding

the

type

and

duration

of

HT

use

Our

definition

of

family

history

of

breast

cancer

included

second

degree

relatives

which

may

have

attenuated

the

effect

of

this

variable

Also

the

BI-RADS

scores

are

qualitative

as

opposed

to

digital

quantification

of

density

and

were

applied

by

community

radiologists

who

despite

being

trained

to

use

this

system

may

apply

it

differently

Nevertheless

our

general

findings

in

terms

of

the

direction

of

effects

for

reproductive

factors

and

HT

use

were

compatible

with

those

of

most

previous

studies

In

conclusion

our

results

based

on

the

largest

study

to

date

confirm

earlier

findings

that

most

established

breast

cancer

risk

factors

behave

similarly

in

relation

to

breast

density

consistent

with

the

notion

that

breast

density

mediates

breast

cancer

risk

However

our

data

indicated

an

inverse

effect

of

HT

in

younger

women

and

a

positive

influence

in

older

women

which

has

not

been

reported

previously

We

also

noted

effect

modification

by

BMI

in

which

the

positive

effects

of

age

at

menarche

and

age

at

first

birth

and

the

inverse

effects

of

parity

were

less

apparent

in

heavier

women

Further

investigation

including

biological

studies

may

elucidate

the

complex

interrelationships

of

hormones

BMI

breast

density

and

breast

cancer

and

potentially

offer

opportunities

for

breast

cancer

prevention

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

reproductive history
mammographic breast density


Anti-CCP2 Antibodies : An Overview and Perspective of the Diagnostic Abilities of this Serological Marker for Early Rheumatoid Arthritis The literature of the last 4 years confirms that the anti-CCP2 test is a very useful marker for the early and specific diagnosis of rheumatoid arthritis -LRB- RA -RRB- . The anti-CCP2 test is very specific for RA -LRB- 95 -- 99 % -RRB- and has sensitivity comparable to that of the rheumatoid factor -LRB- 70 -- 75 % -RRB- . The antibodies can be detected very early in the disease and can be used as an indicator for the progression and prognosis of RA . In this review , these interesting properties and some future possibilities of this diagnostic test are discussed . The presence of autoantibodies in the serum of patients is a very typical phenomenon for autoimmune diseases . Most of these autoantibodies , however , can also be detected in patients with other conditions and are therefore not specific . A typical example is the rheumatoid factor -LRB- RF -RRB- , which is present in most inflammatory conditions . However , in some cases , autoantibodies can give the clinician a more precise indication of the type of underlying disease because they occur specifically in a certain disease . For example , anti-Sm antibodies are linked almost exclusively to systemic lupus erythematosus -LRB- SLE -RRB- ; whereas anti-DNA topoisomerase-I antibodies are typically present in scleroderma patients . Among the most disease-specific autoantibodies described are the so-called ACPA -LRB- anti-citrullinated protein/peptide antibodies -RRB- . These antibodies occur specifically in RA and can be measured most conveniently via the anti-CCP -LRB- anti-cyclic citrullinated peptide -RRB- antibody test . The first generation CCP test -LRB- CCP1 -RRB- used in early diagnostic studies -LRB- 2000 -- 2001 -RRB- contained a single cyclic citrullinated peptide derived from filaggrin as the substrate -LSB- 1 -RSB- . It could detect ACPA in 68 % of patients with established RA with a very high specificity -LRB- 98 % -RRB- . Because filaggrin is not expressed in the synovium , it is most likely not the natural citrullinated antigen for ACPA . Other peptides , not related to filaggrin , could therefore potentially provide better epitopes for detection of ACPA . Via screening of a number of peptide libraries , novel citrullinated peptides were obtained and incorporated into a second generation CCP test -LRB- CCP2 -RRB- . This test is commercially available , and as all companies use the same type of CCP2 peptides , standardization is achieved quite easily . The diagnostic properties of this test will be discussed below . The CCP2 Test is Sensitive and Highly Specific for RA Since its appearance on the market in the second half of 2002 , the diagnostic properties of the CCP2 test have been studied by many laboratories . This resulted in more than 120 publications dealing with this subject . The accumulated data , including only papers that appeared in PubMed till December 2006 , are given in Table 1 . It is clear that the accumulated data confirm the earliest reports on specificity and sensitivity of the CCP2 test . The anti-CCP2 test demonstrates an RF-like sensitivity with a very high specificity for RA -LRB- see also recent reviews : -LSB- 2 , 3 -RSB- -RRB- . It is also commonly recognized that anti-CCP2 antibody may be present in up to 40 % of RF-negative RA sera -LSB- 4 , 5 -RSB- . Table 1Cumulative anti-CCP2 diagnostic data published between 2002 and 2006Patient groupNumberCCP2 + Sensitivity -LRB- % -RRB- Specificity -LRB- % -RRB- RA total14 ,18310,13571.5 Early3 ,8762,36561.0 Established10 ,3077,77075.4 Controls15 ,1566834.595.6 Non-RA11 ,5026475.694.4 Healthy3 ,654361.099.0 In total , 122 independent studies were included . The selection for early RA has been adopted from the original reports . The anti-CCP2 test enables clinicians to distinguish RA patients from other arthritic diseases , especially in cases where the RF test is not discriminative . This is , for example , the case with chronic hepatitis C virus -LRB- HCV -RRB- infection , a disease that can easily be misdiagnosed as it often reveals RA-like arthropathies and , in many cases , is accompanied by a positive RF . Several examples of such studies are given in recent reviews on this subject -LSB- 6 -RSB- . Recently , there is also an interest to compare the diagnostic potential of anti-CCP2 with novel tests based on the use of a citrullinated antigen -LRB- for example , MCV = anti-mutated citrullinated vimentin -LSB- 7 -RSB- , CPA = citrullinated protein antibodies , VCP = anti-viral citrullinated protein -LSB- 8 -RSB- , antihuman fibrinogen alpha -LSB- 9 , 10 -RSB- , and CCP3 -LSB- 11 -RSB- -RRB- . For a reliable comparison of these tests , it is essential that their performance is assessed under the same conditions , e.g. , the sensitivities of the tests should be determined at the same level of specificity . Good examples of such stratified studies have been carried out recently by van der Cruijssen et al. -LSB- 10 -RSB- and Dejaco et al. -LSB- 7 -RSB- . For example , Dejaco et al. -LSB- 7 -RSB- showed , in a large cohort of patients -LRB- > 600 -RRB- , that at a specificity of 98.7 % , being the specificity of the anti-CCP2 test , the sensitivity of the anti-MCV test is 53.7 % as opposed to 70.1 % for the anti-CCP test . Coenen et al. -LSB- 11 -RSB- compared several commercial tests , including a very recent CCP3 test from Inova . At the cut-offs recommended by the various manufacturers , the positive predictive value of the three commercial CCP2 tests is about 90 % with a specificity of around 96 % . The specificity of the other tests -LRB- CCP3 = 88 % , MCV = 90 % , CPA = 94 % -RRB- is lower as are their positive predictive values -LSB- 11 -RSB- . These numbers may improve a little bit when the cut-off values are adjusted to more realistic data ; nevertheless , the data allow the statement that , in absolute percentages , none of the tests performs better than the anti-CCP2 test . They also seem to indicate that some tests detect RA patient groups that are negative in the anti-CCP test , illustrating again that the autoantibody repertoire of RA patients is very heterogeneous . Another risk for the specificity of a test that is based on a citrullinated antigen is the possibility that antibodies are not directed exclusively to the citrulline-containing epitope but also to other possibly overlapping epitopes present in the substrate antigen . This is particularly important when citrullinated versions of proteins like vimentin or fibrinogen are used . For example , it is known that antibodies to vimentin are present in several diseases different from RA -LSB- 12 , 13 -RSB- . This particular problem has been addressed for CCP2 by Vannini et al. -LSB- 14 -RSB- . They used ELISA plates containing the control CCP2 antigens -LRB- Arg instead of Cit in the same peptide context -RRB- , produced and made available by Euro-Diagnostica , Arnhem , The Netherlands , in parallel to the normal CCP2 test . The results of these comparative studies showed that in RA and most non-RA rheumatic disease sera , anti-CCP reactivity indeed is citrulline-dependent . However , in some patients , particularly autoimmune hepatitis patients , citrulline-independent reactivity with the antigen may occur . A positive CCP test in a rheumatic disease -LRB- almost always citrulline-specific -RRB- may thus suggest the future development of RA as has been suggested by several studies -LSB- 15 , 16 -RSB- . A positive test in a nonrheumatic disease -LRB- very often not citrulline-specific -RRB- , for example , liver disease , should be interpreted with care -LSB- 14 -RSB- . Anti-CCP2 Antibodies are Present Early in Disease and have Predictive Potential Because RA patients at first presentation often do not fulfill the criteria for the diagnosis/classification of RA , an early , highly predictive marker would greatly assist the clinician in reaching an early diagnosis . There are several studies indicating that the anti-CCP2 test provides this help -LRB- reviewed by -LSB- 2 -RSB- -RRB- . In the recently published EULAR recommendations for the management of early arthritis -LSB- 16 -RSB- , a list of factors has been proposed that predict persistent and erosive disease . These factors include : number of swollen and tender joints , ESR or CRP , level of RF and anti-CCP antibodies , and radiographic erosions . Most of these factors were also mentioned as being important in the prediction of early erosive RA -LRB- Visser et al. -LSB- 17 -RSB- -RRB- . Subsequent studies by the same group gave an indication of the relative importance of these factors . When expressed as odds ratios -LRB- OR -RRB- , the data was as follows : arthritis of three or more joints , 5.0 ; radiographic erosions , 8.7 ; positive IgM-RF , 1.7 ; and positive anti-CCP2 , 38.6 -LSB- 18 -RSB- . These and other data -LRB- see also -LSB- 19 -RSB- -RRB- clearly show that the presence of anti-CCP antibodies is an important and independent prognostic factor for radiographic progression in not only early arthritis but also in early rheumatoid arthritis -LSB- 16 , 20 -RSB- . Recently , it has also been shown that IgM-CCP is present in early samples from both patients with undifferentiated arthritis -LRB- UA -RRB- and patients with RA as well as in follow-up samples from patients with RA . These data indicate the development of the anti-CCP isotype repertoire into full usage early in the course of arthritis and a continuous -LRB- re -RRB- activation of the RA-specific anti-CCP response during the further development of the disease -LSB- 21 -RSB- . It is , however , evident that besides the clinical and laboratory parameters mentioned above , some genetic factors are important as well . The effect of the HLA shared-epitope alleles on the development of ACPA has been firmly established . Citrullination is typically a process that occurs in apoptotic cells . Because such dying cells are generally removed from the environment via clearance by phagocytes , a process that is regulated by many genes , the immune system will normally not encounter citrullinated proteins . However , it has been shown that during inflammation , citrullinated proteins are detectable in the inflamed tissue , both in RA and non-RA patients -LSB- 22 -RSB- . This is probably caused by inefficient clearance of the massive numbers of dying cells , a process already described to occur in SLE -LSB- 23 -RSB- . This inefficient clearing could , in principal , also be the consequence of altered genes , i.e. , the genetic background . The mere presence of citrullinated antigens in inflamed synovial tissue does not necessarily result in the occurrence of anti-CCP antibodies in serum or synovial fluid , neither in humans nor in mouse models of arthritis -LSB- 24 , 22 -RSB- . Hill et al. -LSB- 25 -RSB- showed that the generation of anticitrulline antibody in mice actually is linked to the expression of the RA shared epitope -LRB- SE -RRB- , and a similar link was also found in patients because the combination of SE , and anti-CCP has a very high predictive value for the future development of RA -LSB- 26 -RSB- . The specific structure of HLA molecules obviously plays an important role in the induction of autoimmunity to citrullinated proteins . These studies were extended by Huizinga et al. -LSB- 27 -RSB- who found that HLA-DRB1 alleles encoding the SE were only associated with anti-CCP positive RA and not with anti-CCP negative RA . In contrast , anti-CCP negative RA appeared to be associated with HLA-DR3 -LSB- 28 -RSB- . Therefore , the presence of citrullinated antigens , together with the appropriate genetic background -LRB- the SE and probably other types of HLA -RRB- , appears to be the minimum requirement for an immune response to citrullinated polypeptides to be generated -LSB- 29 -RSB- . Next to that , other sensitizing genetic settings resulting from polymorphisms -LRB- e.g. , PTPN22 -LSB- 30 -RSB- -RRB- might , given their association , aid in triggering of ACPA . Conclusions and Future Perspectives The present literature describes and confirms that the anti-CCP2 test is a very useful marker for the early and accurate diagnosis of RA . Anti-CCP antibody is very specific for RA and has a sensitivity comparable to that of RF . These antibodies can be detected very early in disease and may be used as an indicator for the progression and prognosis of RA . Initially , the test was available principally as a manual ELISA method through Euro-Diagnostica and Axis-Shield and their partners . More recently , fully automated anti-CCP assays have also been made available from Phadia -LRB- UniCap Elia CCP -RRB- and Abbott Diagnostics -LRB- AxSYM anti-CCP -RRB- . A very novel format is the CCPoint , a Point-of-Care test for the detection of these antibodies in whole blood in 10 min -LSB- 31 -RSB- . A small drop of whole blood is applied onto the sample well followed by the addition of four drops of running buffer . After 10 min , the result is read by visual inspection of the detection zone for staining of the antigen line . As no special equipment is required to perform the assay , this test will bring the detection of anti-CCP antibodies into the office of the family doctor , facilitating a very fast referral to the rheumatologist when the test gives a positive answer . Such new applications will undoubtedly further enhance the utility of the anti-CCP autoantibody system in clinical practice .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

autoantibodies
rheumatoid factor
ccp2 test