Prophylactic

Mastectomy

in

Mutation

Carriers

and

Women

at

Risk

of

Hereditary

Breast

Cancer

Long-Term

Experiences

at

the

Rotterdam

Family

Cancer

Clinic

Background

mutation

carriers

and

women

from

a

hereditary

breast

-LRB-

ovarian

-RRB-

cancer

family

have

a

highly

increased

risk

of

developing

breast

cancer

-LRB-

BC

-RRB-

Prophylactic

mastectomy

-LRB-

PM

-RRB-

results

in

the

greatest

BC

risk

reduction

Long-term

data

on

the

efficacy

and

sequels

of

PM

are

scarce

Women

with

a

germ-line

or

mutation

as

well

as

risk

carriers

from

a

hereditary

breast

-LRB-

ovarian

-RRB-

cancer

-LRB-

HB

-LRB-

O

-RRB-

C

-RRB-

family

are

at

increased

risk

of

developing

breast

and/or

ovarian

cancer

compared

with

the

general

population

Options

to

reduce

this

risk

are

regular

surveillance

chemoprevention

or

prophylactic

surgery

Prophylactic

surgery

includes

prophylactic

mastectomy

-LRB-

PM

-RRB-

and/or

prophylactic

bilateral

salpingo-oophorectomy

-LRB-

PBSO

-RRB-

PM

implies

either

a

bilateral

prophylactic

mastectomy

-LRB-

BPM

-RRB-

in

high-risk

unaffected

women

as

well

as

in

high-risk

women

with

a

history

of

breast

cancer

-LRB-

BC

-RRB-

previously

treated

with

breast

conserving

therapy

-LRB-

BCT

-RRB-

or

a

contralateral

prophylactic

mastectomy

-LRB-

CPM

-RRB-

after

a

unilateral

therapeutic

mastectomy

Several

studies

have

shown

that

PM

strongly

reduces

the

risk

of

developing

-LRB-

contralateral

-RRB-

breast

cancer

while

PBSO

reduces

the

risk

of

ovarian

as

well

as

primary

breast

cancer

These

strategies

therefore

have

commonly

been

accepted

at

this

moment

as

risk-reducing

strategies

for

women

being

at

increased

risk

of

HB

-LRB-

O

-RRB-

C.

PM

however

is

a

drastic

and

irreversible

intervention

and

in

case

of

breast

reconstruction

-LRB-

BR

-RRB-

is

accompanied

by

a

substantial

complication

rate

Further

issues

of

concern

with

respect

to

PM

include

changes

in

a

woman

's

body

image

and

self-esteem

changes

of

sexual

function

and

in

psychological

distress

At

the

Rotterdam

Family

Cancer

Clinic

of

women

carrying

a

or

mutation

opt

for

either

bilateral

or

contralateral

PM

For

women

who

are

contemplating

this

intervention

it

is

imperative

to

have

reliable

data

on

the

outcomes

of

PM

in

a

well-defined

cohort

to

make

a

good

informed

decision

and

to

minimize

postoperative

feelings

of

deception

At

the

Rotterdam

Family

Cancer

Clinic

there

is

ample

and

long-term

experience

with

sufficient

numbers

of

women

undergoing

PM

We

previously

reported

data

concerning

the

occurrence

of

breast

cancer

after

BPM

in

unaffected

women

with

a

proven

mutation

complications

of

PM

with

breast

reconstruction

and

psychological

aspects

of

PM

in

combination

with

BR

In

the

current

analysis

we

report

on

an

extended

series

with

longer

follow-up

of

women

having

undergone

a

PM

at

the

Rotterdam

Family

Cancer

Clinic

because

of

either

a

proven

mutation

or

a

genetic

susceptibility

-LRB-

risk

carriers

from

a

HB

-LRB-

O

-RRB-

C

family

-RRB-

Our

study

sample

was

large

enough

to

discriminate

between

unaffected

women

and

women

with

a

history

of

BC

-LRB-

affected

-RRB-

Special

attention

is

paid

to

the

prevalence

of

-LRB-

pre

-RRB-

malignant

lesions

in

prophylactically

removed

mastectomy

specimens

Further

we

report

on

the

postoperative

complications

of

PM

in

combination

with

breast

reconstruction

PATIENTS

AND

METHODS

As

of

the

start

of

the

Rotterdam

Family

Cancer

Clinic

in

PM

and/or

PBSO

are

being

discussed

as

risk-reducing

strategies

with

women

at

increased

risk

of

hereditary

BC

and/or

ovarian

cancer

In

early

years

PM

was

discussed

with

mutation

carriers

as

well

as

with

women

from

a

HB

-LRB-

O

-RRB-

C

family

without

a

proven

mutation

-LRB-

so-called

risk

carriers

-RRB-

and

applied

for

unaffected

as

well

as

affected

-LRB-

with

a

history

of

breast

cancer

-RRB-

women

Due

to

the

development

of

more

advanced

mutation-detection

methods

enabling

the

performance

of

a

complete

gene

mutation

screen

there

has

been

a

shift

in

more

recent

years

to

discuss

the

option

of

PM

only

with

identified

mutation

carriers

Before

the

decision

to

undergo

a

PM

and/or

PBSO

was

discussed

individually

by

the

doctor

and

the

woman

in

question

As

of

women

opting

for

either

PM

and/or

PBSO

are

additionally

discussed

in

the

multidisciplinary

Committee

on

Hereditary

Tumors

For

this

purpose

institutional

guidelines

concerning

the

surveillance

schedule

and

indications

regarding

PM/PBSO

have

been

further

elaborated

and

implemented

as

of

which

were

updated

as

knowledge

progressed

and

more

evidence-based

data

became

available

Before

no

additional

examinations

were

performed

before

PM

irrespective

of

the

individual

situation

-LRB-

unaffected/affected

risk

carrier

-RRB-

Women

were

seen

biannually

for

physical

examination

while

a

mammography

was

performed

annually

As

of

institutional

guidelines

from

the

working

party

on

hereditary

tumors

recommended

to

perform

clinical

breast

examination

-LRB-

CBE

-RRB-

and

imaging

examination

within

months

prior

to

PM

to

minimize

the

risk

of

finding

unexpected

malignant

changes

at

PM

At

first

imaging

examination

consisted

of

either

mammography

or

magnetic

resonance

imaging

-LRB-

MRI

-RRB-

scan

while

more

recently

MRI

has

been

preferred

Breast

ultrasound

-LRB-

US

-RRB-

and

if

necessary

fine-needle

aspiration

cytology

-LRB-

FNAC

-RRB-

are

additionally

performed

in

case

lesions

are

found

at

CBE

or

one

of

the

imaging

examinations

Further

the

guidelines

recommend

the

discussion

of

the

case

in

the

multidisciplinary

Committee

on

Hereditary

Tumors

and

a

standard

visit

with

a

psychologist

For

affected

women

the

guidelines

are

extended

with

dissemination

investigations

to

rule

out

recurrent

or

distant

breast

cancer

activity

-LRB-

chest

x-ray

liver

ultrasound

bone

scan

liver

functions

and

determination

of

-RRB-

Where

women

with

a

history

of

ovarian

cancer

were

previously

eligible

for

PM

at

the

moment

this

is

not

discussed

anymore

in

this

setting

because

the

prognosis

is

mainly

dictated

by

the

ovarian

cancer

In

the

sample

these

women

were

classified

as

unaffected

unless

they

also

had

a

history

of

BC

To

evaluate

the

short-term

and

long-term

medical

effects

of

prophylactic

surgery

in

high-risk

women

a

combined

retrospective

and

prospective

longitudinal

study

was

activated

at

our

institution

including

all

genetically

susceptible

women

who

had

opted

for

prophylactic

surgery

-LRB-

either

PM

and/or

PBSO

-RRB-

Women

were

informed

by

oral

and

written

information

and

were

asked

for

written

consent

The

protocol

was

approved

by

the

institutional

review

board

-LRB-

project

EMC-DDHK

-RRB-

Surgical

Technique

At

our

institute

the

oncological

and

plastic

surgeon

perform

the

PM

and

BR

as

a

team

During

the

operation

the

patient

is

under

general

anesthesia

in

a

half-supine

position

A

skin-sparing

mastectomy

is

performed

through

a

vertical

peri-areolar

incision

which

extends

from

just

above

the

nipple

down

the

submammary

fold

The

breast

tissue

including

the

superficial

fascia

-LRB-

creating

thin

skin

flaps

-RRB-

the

axillary

tail

the

inframammary

fold

the

nipple-areolar

complex

and

the

fascia

of

the

pectoral

muscle

are

removed

In

case

of

immediate

breast

reconstruction

either

a

subpectoral

silicone

implant

is

inserted

in

a

pocket

created

below

the

pectoral

muscles

in

a

one-stage

procedure

or

autologeous

tissue

is

used

Autologeous

reconstruction

encompasses

a

broad

range

of

procedures

incorporating

the

patient

's

own

tissues

to

recreate

the

breast

The

transverse

rectus

abdomis

myocutaneous

-LRB-

TRAM

-RRB-

flap

and

latissimus

dorsi

flap

are

two

standard

myocutaneous

flaps

used

for

breast

reconstruction

More

recent

modifications

to

the

traditional

techniques

led

to

the

use

of

the

deep

inferior

epigastric

perforator

-LRB-

DIEP

-RRB-

flap

Nipple

reconstruction

is

offered

after

months

and

consists

of

three

small

transposition

flaps

the

areola

is

mimicked

by

tattooing

the

desired

skin

color

Breast

reconstruction

is

not

always

performed

in

the

same

operation

as

the

mastectomy

the

techniques

for

these

delayed

reconstructions

however

are

as

described

previously

Microscopic

Examination

of

Mastectomy

Specimens

As

of

a

standard

procedure

has

been

followed

for

meticulous

microscopic

examination

of

prophylactically

removed

mastectomy

specimens

to

rule

out

the

presence

of

occult

-LRB-

microscopic

-RRB-

malignant

alterations

The

protocol

prescribes

that

mastectomy

specimens

are

cut

into

slices

of

cm

thickness

whereby

each

slice

is

carefully

inspected

and

palpated

for

abnormalities

Standard

three

randomly

selected

parenchymal

tissue

samples

from

each

quadrant

and

a

transverse

section

through

the

nipple

are

submitted

for

histology

in

addition

to

samples

of

all

visible

or

palpable

abnormalities

Further

three

samples

from

each

quadrant

of

the

mastectomy

specimens

are

snap

frozen

for

the

tissue

bank

Radiographic

examination

of

breast

tissue

specimens

is

not

performed

on

a

routine

basis

Study

Design

The

current

study

included

all

women

at

increased

risk

of

hereditary

BC

according

to

previously

described

criteria

who

underwent

prophylactic

bilateral

or

contralateral

mastectomy

between

January

until

December

Of

our

study

cohort

women

-LRB-

-RRB-

underwent

PM

at

our

clinic

while

women

-LRB-

-RRB-

were

treated

elsewhere

e.g.

due

to

a

waiting

list

at

our

clinic

or

the

fact

that

previous

surgery

was

performed

elsewhere

The

latter

women

were

only

eligible

for

this

analysis

if

the

follow-up

after

PM

took

place

at

our

clinic

and

a

copy

of

the

pathology

report

was

available

In

general

DNA

testing

was

performed

before

the

prophylactic

surgery

although

some

women

choose

for

prophylactic

surgery

without

or

irrespective

of

DNA

testing

DNA

analysis

was

performed

according

to

standard

procedures

as

has

been

previously

described

DNA

testing

was

not

an

inclusion

criterion

for

participation

in

the

study

Proven

noncarriers

from

a

family

BRCA

mutation

were

excluded

from

the

study

Relevant

data

were

extracted

from

the

hospital

records

For

each

woman

including

deceased

women

the

following

information

was

obtained

date

of

birth

death

and

PM

performance

-LRB-

yes/no

-RRB-

and

type

of

breast

reconstruction

PBSO

diagnosis

of

breast

and/or

ovarian

cancer

mutation

status

duration

of

follow-up

after

PM

-LRB-

end

date

being

either

the

date

of

death

or

the

date

of

last

clinic

visit

in

case

of

loss

to

follow-up

or

the

end

date

of

this

study

i.e.

December

-RRB-

and

type

and

number

of

complications

after

breast

reconstruction

Regarding

the

latter

we

distinguished

between

early

-LRB-

within

weeks

-RRB-

and

late

postoperative

complications

-LRB-

after

weeks

-RRB-

Early

complications

consisted

of

infection

necrosis

bleeding

and

luxation

of

the

prosthesis

Late

complications

were

divided

in

surgical

complications

-LRB-

such

as

capsular

formation

infection

necrosis

and

luxation

of

the

prosthesis

-RRB-

and

complaints

related

to

cosmetic

outcome

-LRB-

such

as

poor

symmetry

and

dog

ears

-RRB-

Nipple

reconstruction

is

regarded

as

part

of

the

breast

reconstruction

and

therefore

has

not

been

registered

as

a

cosmetic

complication

A

computerized

database

-LRB-

MS-Access

-RRB-

was

used

to

process

the

data

Data

were

entered

retrospectively

as

well

as

prospectively

after

each

clinic

visit

Statistical

Analysis

Descriptive

statistics

-LRB-

median

range

and

frequency

-RRB-

were

computed

When

appropriate

statistical

significance

testing

between

relevant

subgroups

was

performed

using

the

chi-square

test

for

categorical

variables

and

a

t-test

for

continuous

variables

A

P

value

of

less

then

was

considered

statistically

significant

RESULTS

Study

Population

In

Table

the

characteristics

of

the

women

who

underwent

a

PM

are

shown

A

total

of

women

with

a

median

follow-up

after

PM

of

years

fulfilled

the

study

eligibility

criteria

consisting

of

-LRB-

-RRB-

women

with

a

history

of

breast

cancer

-LRB-

affected

women

-RRB-

and

-LRB-

-RRB-

women

without

a

history

of

BC

-LRB-

unaffected

women

-RRB-

A

total

of

-LRB-

-RRB-

women

were

mutation

carriers

while

the

other

women

-LRB-

-RRB-

were

risk

carriers

from

a

HB

-LRB-

O

-RRB-

C

family

The

unaffected

group

mainly

consisted

of

mutation

carriers

as

compared

with

risk

carriers

-LRB-

vs

P

-RRB-

whereas

the

affected

group

consisted

of

an

equal

number

of

mutation

carriers

and

risk

carriers

-LRB-

mutation

carriers

versus

risk

carriers

P

-RRB-

This

difference

in

distribution

was

highly

significant

-LRB-

P

-RRB-

TABLE

Characteristics

of

the

study

populationHISTORY

OF

BCNo

-LRB-

Unaffected

n

-RRB-

Yes

-LRB-

Affected

n

-RRB-

P

valuedBRCAHB

-LRB-

O

-RRB-

CBRCAHB

-LRB-

O

-RRB-

Cn

-LRB-

-RRB-

an

-LRB-

-RRB-

an

-LRB-

-RRB-

an

-LRB-

-RRB-

aNo

of

women

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

c

e

Death

due

to

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

PM

-LRB-

years

-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-

Duration

of

follow-up

-LRB-

years

-RRB-

Mutation

status

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

PBSO

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

PBSO

-LRB-

years

-RRB-

of

PBSO

Before

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

At

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

After

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Ovarian

cancer

before

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Unexpected

-LRB-

p

-RRB-

MF

at

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Cancer

after

PM

Breast

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Ovarian

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

BC

breast

cancer

HB

-LRB-

O

-RRB-

C

hereditary

breast

-LRB-

ovarian

-RRB-

cancer

PM

prophylactic

mastectomy

PBSO

prophylactic

bilateral

salpingo-oophorectomy

-LRB-

p

-RRB-

MF

-LRB-

pre

-RRB-

malignant

findings.a

Percentage

of

the

number

of

women

in

column

in

question

unless

stated

otherwise.b

Percentage

of

unaffected

women.c

Percentage

of

affected

women.d

Difference

between

unaffected

and

affected

mutation

carriers

unless

stated

otherwise.e

Difference

in

distribution

between

unaffected

and

affected

women

The

median

age

at

PM

in

the

unaffected

and

affected

group

was

significantly

different

being

and

years

respectively

-LRB-

Table

P

-RRB-

In

the

affected

group

mutation

carriers

were

significantly

younger

at

PM

than

risk

women

-LRB-

vs

years

respectively

P

-RRB-

In

the

unaffected

group

we

found

no

significant

difference

in

this

respect

-LRB-

vs

years

respectively

P

-RRB-

A

history

of

ovarian

cancer

was

present

in

four

mutation

carriers

from

the

unaffected

group

-LRB-

-RRB-

and

in

three

women

-LRB-

-RRB-

in

the

affected

group

TABLE

Comparison

between

unaffected

and

affected

womenUnaffectedAffectedP

valueNo

of

women

-LRB-

N

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

PM

-LRB-

years

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

PBSO

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

at

PBSO

-LRB-

years

-RRB-

prophylactic

mastectomy

PBSO

prophylactic

bilateral

salpingo-oophorectomy

In

Fig.

the

number

of

PMs

per

year

separately

for

unaffected/affected

BRCA

mutation

carriers

as

well

as

for

unaffected/affected

risk

carriers

is

shown

In

the

unaffected

group

the

annual

number

of

women

undergoing

PM

was

always

larger

in

mutation

carriers

compared

with

risk

carriers

except

for

the

first

years

-LRB-

-RRB-

Further

the

number

of

unaffected

BRCA

mutation

carriers

undergoing

PM

widely

differed

over

the

years

with

two

peaks

in

and

respectively

In

contrast

the

number

of

unaffected

risk

carriers

undergoing

PM

was

quite

stable

over

the

years

FIG.

Annual

number

of

PM

in

unaffected/affected

mutation

carriers

and

risk

carriers

from

HB

-LRB-

O

-RRB-

C

families

In

the

affected

group

however

the

pattern

was

different

whereby

a

shift

has

taken

place

through

the

years

In

the

early

years

of

the

study

period

-LRB-

-RRB-

mainly

women

without

a

proven

mutation

underwent

PM

in

this

group

Between

and

approximately

as

many

mutation

carriers

as

risk

carriers

underwent

a

PM

As

of

more

mutation

carriers

have

undergone

a

PM

although

the

number

of

PMs

in

again

was

not

different

between

mutation

and

risk

carriers

Prophylactic

Bilateral

Salpingo-oophorectomy

A

considerable

part

of

the

BRCA

mutation

carriers

undergoing

PM

also

opted

for

PBSO

being

in

the

unaffected

versus

in

the

affected

group

respectively

-LRB-

Table

P

-RRB-

In

the

HB

-LRB-

O

-RRB-

C

group

however

only

a

minority

of

the

women

underwent

a

PBSO

being

of

risk

carriers

-LRB-

-RRB-

The

median

age

at

PBSO

was

younger

in

BRCA

mutation

carriers

compared

with

the

risk

carriers

both

in

the

affected

and

the

unaffected

group

This

difference

however

was

not

significant

-LRB-

P

and

P

respectively

-RRB-

Further

the

median

age

at

PBSO

was

lower

in

the

unaffected

compared

with

the

affected

group

being

versus

years

respectively

-LRB-

Table

P

-RRB-

In

addition

unaffected

BRCA

mutation

carriers

underwent

PBSO

at

a

younger

age

compared

with

mutation

carriers

with

a

history

of

BC

-LRB-

vs

years

respectively

P

Table

-RRB-

-LRB-

Pre

-RRB-

malignant

Findings

at

PM

In

of

the

women

-LRB-

-RRB-

abnormal

findings

were

unexpectedly

found

in

the

mastectomy

specimens

-LRB-

table

-RRB-

Prior

to

intended

PM

there

was

no

suspicion

to

justify

an

axillary

nodal

dissection

in

combination

with

the

PM

procedure

This

occurred

in

five

unaffected

-LRB-

-RRB-

as

well

as

in

five

previously

affected

women

-LRB-

-RRB-

and

in

both

mutation

carriers

-LRB-

-RRB-

and

risk

carriers

-LRB-

-RRB-

The

characteristics

of

the

unexpected

-LRB-

pre

-RRB-

malignant

findings

as

well

as

the

preoperative

screening

results

are

chronologically

described

in

detail

in

Table

In

in

one

woman

both

preoperative

clinical

breast

examination

-LRB-

CBE

-RRB-

and

mammography

were

suspicious

for

a

malignancy

However

additional

investigation

consisting

of

ultrasound

and

cytology

did

not

reveal

a

malignancy

Nevertheless

histological

examination

of

the

mastectomy

specimens

revealed

an

invasive

ductal

carcinoma

-LRB-

IDC

-RRB-

eventually

staged

as

a

The

patient

died

of

metastatic

breast

cancer

years

after

the

PM

In

another

two

women

undergoing

PM

in

and

a

lesion

was

found

preoperatively

-LRB-

CBE

and

mammography

respectively

-RRB-

and

classified

as

probably

benign

No

malignant

abnormalities

were

seen

at

subsequent

ultrasound

examination

which

is

the

reason

a

FNAC

was

not

performed

However

histological

examination

of

the

mastectomy

specimens

revealed

a

small

ductal

carcinoma

in

situ

-LRB-

DCIS

-RRB-

in

both

women

In

in

one

woman

preoperative

MRI

revealed

a

lesion

classified

as

probably

benign

Indeed

no

malignant

abnormalities

were

found

at

additional

ultrasound

examination

Histological

examination

of

the

mastectomy

specimens

however

revealed

an

IDC

in

the

right

and

an

invasive

medullar

carcinoma

-LRB-

IMC

-RRB-

in

the

left

breast

Preoperative

screening

in

the

remaining

six

women

performed

months

preceding

PM

did

not

show

suspicious

abnormalities

Still

another

invasive

carcinoma

three

cases

of

DCIS

and

two

cases

of

lobular

carcinoma

in

situ

-LRB-

LCIS

-RRB-

were

found

in

the

mastectomy

specimens

All

unexpected

-LRB-

pre

-RRB-

malignant

findings

in

the

affected

women

were

found

in

the

contralateral

breast

TABLE

Characteristics

of

unexpected

-LRB-

pre

-RRB-

malignant

findings

in

the

PM

specimensPreoperativeYear

of

PMGenetic

risk

groupHistory

of

BC

before

PMHistologyGradeTumor

size

-LRB-

mm

-RRB-

ER/PR

-LRB-

O

-RRB-

CNoIDCNANANASCSCa

-LRB-

O

-RRB-

CNoDCISII

-LRB-

O

-RRB-

prophylactic

mastectomy

BC

breast

cancer

DCIS

ductal

carcinoma

in

situ

LCIS

lobular

carcinoma

in

situ

IDC

invasive

ductal

carcinoma

IMC

invasive

medullar

carcinoma

CBE

clinical

breast

examination

Mx

mammography

MRI

magnetic

resonance

imaging

SC

suspicion

of

cancer

PB

probably

benign

nl

normal

not

applicable.a

Additional

investigation

normal.b

Macroscopic

palpable

tumor

microscopic

no

clear

border

therefore

tumor

size

and

grade

not

determinable.c

Treated

previously

for

BC

at

another

hospital

No

information

about

preoperative

imaging

available

Cancer

During

Follow-up

After

PM

After

PM

no

incident

breast

cancer

cases

were

observed

in

risk

carriers

In

BRCA

mutation

carriers

ovarian

cancer

was

detected

in

two

women

in

the

unaffected

group

and

in

one

woman

in

the

affected

group

-LRB-

Table

-RRB-

One

mutation

carrier

from

the

unaffected

group

presented

in

years

after

PM

-LRB-

no

malignant

findings

at

histological

examination

-RRB-

with

metastatic

adenocarcinoma

in

an

axillary

lymph

node

morphologically

and

immunohistochemically

consistent

with

breast

cancer

Additional

dissemination

examinations

also

revealed

metastases

in

bone

and

liver

Review

of

the

preoperative

data

-LRB-

physical

examination

and

mammography

-RRB-

at

the

presentation

of

metastatic

disease

did

not

show

malignant

alterations

while

meticulous

reexamination

of

all

pathology

slides

and

additional

investigation

of

frozen

tissue

material

did

not

detect

a

primary

breast

cancer

Reconstructive

Breast

Surgery

In

Table

the

numbers

and

types

of

reconstructive

breast

surgery

as

well

as

the

numbers

and

types

of

complications

after

breast

reconstruction

-LRB-

BR

-RRB-

are

shown

Of

the

total

population

-LRB-

n

-RRB-

women

underwent

BR

in

combination

with

PM

being

unaffected

and

affected

women

The

presence

or

absence

of

a

mutation

did

not

influence

the

BR

rate

-LRB-

P

for

unaffected

and

P

for

affected

women

-RRB-

or

the

type

of

BR

-LRB-

P

for

unaffected

and

P

for

affected

women

-RRB-

Unaffected

women

mainly

opted

for

BR

-LRB-

-RRB-

consisting

of

immediate

and

three

delayed

reconstructions

while

a

considerable

part

of

the

affected

women

did

not

opt

for

BR

-LRB-

-RRB-

-LRB-

P

-RRB-

Further

unaffected

women

mainly

opted

for

BR

by

means

of

-LRB-

silicon

-RRB-

prosthesis

-LRB-

-RRB-

In

contrast

affected

women

opting

for

BR

-LRB-

immediate

and

delayed

-RRB-

more

often

had

a

reconstruction

by

means

of

autologeous

tissue

compared

with

unaffected

women

being

versus

respectively

-LRB-

P

-RRB-

TABLE

Breast

reconstruction

-LRB-

BR

-RRB-

in

women

undergoing

PMHistory

of

BCNo

-LRB-

Unaffected

-RRB-

Yes

-LRB-

Affected

-RRB-

P

valueNumber

of

-LRB-

-RRB-

-LRB-

-RRB-

Breast

reconstruction

-LRB-

BR

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Unknown

-LRB-

-RRB-

-LRB-

-RRB-

Type

of

BR

Silicon

-LRB-

-RRB-

-LRB-

-RRB-

Autologeous

-LRB-

-RRB-

-LRB-

-RRB-

Unknown

-LRB-

-RRB-

-LRB-

-RRB-

Therapy

first

BC

b

BCT

-LRB-

-RRB-

BCT/RT

-LRB-

-RRB-

MAST

-LRB-

-RRB-

MAST/RT

-LRB-

-RRB-

Women

with

complications

after

BR

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Total

number

of

complications

after

BR

Early

-LRB-

weeks

after

BR

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Late

-LRB-

weeks

after

BR

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Surgery

due

to

late

complication

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Early

complicationsSurgery

due

to

early

complication

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Type

of

early

complication

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Prosthesis

-LRB-

-RRB-

-LRB-

-RRB-

Poor

arterial

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Late

complicationsSurgery

due

to

late

complication

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Type

of

late

complication

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Capsular

-LRB-

-RRB-

-LRB-

-RRB-

Prosthesis

-LRB-

-RRB-

-LRB-

-RRB-

Poor

cosmetic

appearance

-LRB-

-RRB-

-LRB-

-RRB-

Dog

-LRB-

-RRB-

-LRB-

-RRB-

PM

prophylactic

mastectomy

BC

breast

cancer

BR

breast

reconstruction

BCT

breast

conserving

therapy

BCT/RT

BCT

in

combination

with

radiotherapy

MAST

therapeutic

mastectomy

MAST/RT

MAST

in

combination

with

radiotherapy.a

Surgery

performed

at

another

hospital

not

included

in

P

value

calculation.b

Data

shown

for

women

with

a

BR

after

PM.c

One

woman

can

have

complication.dIncluding

asymmetry

In

of

women

opting

for

BR

-LRB-

-RRB-

one

or

more

complications

were

registered

totaling

complications

Surgical

reinterventions

were

performed

in

cases

-LRB-

for

late

complications

-RRB-

Concerning

the

number

of

complications

this

was

not

different

between

unaffected

and

affected

women

neither

for

the

moment

of

the

complication

-LRB-

i.e.

early

or

late

-RRB-

-LRB-

P

-RRB-

the

necessity

of

reintervention

due

to

the

complication

-LRB-

P

-RRB-

nor

for

the

type

of

complication

-LRB-

P

for

early

complications

and

P

for

late

complications

-RRB-

DISCUSSION

In

this

study

we

updated

and

extended

the

long-term

experiences

at

the

Rotterdam

Family

Cancer

Clinic

with

prophylactic

mastectomy

-LRB-

PM

-RRB-

in

proven

mutation

carriers

and

in

risk

carriers

from

a

HB

-LRB-

O

-RRB-

C

family

We

compared

the

data

of

PM

and

breast

reconstruction

-LRB-

if

performed

-RRB-

in

women

with

-LRB-

affected

-RRB-

and

without

a

personal

history

of

BC

-LRB-

unaffected

women

-RRB-

and

further

distinguished

between

women

with

a

BRCA

or

mutation

and

women

without

a

proven

mutation

While

within

the

unaffected

group

especially

mutation

carriers

opted

for

PM

we

observed

that

within

the

affected

group

an

equal

number

of

mutation

carriers

and

risk

carriers

from

a

HB

-LRB-

O

-RRB-

C

family

opted

for

PM

Women

carrying

a

BRCA

or

mutation

are

known

to

have

an

increased

risk

of

developing

contralateral

primary

BC

which

is

even

more

apparent

among

women

who

are

younger

when

diagnosed

with

a

primary

breast

carcinoma

-LRB-

age

years

-RRB-

For

high-risk

women

without

a

proven

mutation

inconsistent

results

on

the

risk

of

developing

a

contralateral

breast

cancer

-LRB-

CBC

-RRB-

were

reported

Shahedi

et

al.

as

well

as

Kirova

et

al.

reported

an

increased

risk

of

developing

CBC

in

women

while

Tilanus

et

al.

concluded

that

the

rate

of

CBC

was

only

slightly

and

insignificantly

increased

in

compared

with

sporadic

breast

cancer

patients

In

view

of

these

results

one

expects

that

after

a

first

diagnosis

of

breast

cancer

especially

mutation

carriers

will

opt

for

prophylactic

removal

of

the

remaining

breast

tissue

In

our

study

sample

however

also

a

considerable

part

of

the

women

without

a

proven

mutation

opts

for

prophylactic

mastectomy

especially

after

a

history

of

breast

cancer

It

has

to

be

mentioned

that

since

information

on

the

mutation

status

is

not

always

known

in

the

latter

group

and

genetic

testing

is

missing

a

number

of

mutations

it

is

likely

that

some

of

these

patients

are

in

fact

mutation

carriers

Further

the

group

of

women

with

a

history

of

breast

cancer

with

and

without

a

gene

mutation

may

partly

consist

of

women

who

initially

chose

for

surveillance

and

eventually

opted

for

PM

after

the

diagnosis

of

breast

cancer

This

is

in

accordance

with

an

earlier

report

indicating

that

women

may

be

more

likely

to

undergo

PM

after

a

previous

diagnosis

of

BC

This

might

also

partly

explain

the

higher

age

at

the

time

of

PM

in

the

group

with

a

history

of

BC

We

found

that

the

age

at

PM

was

younger

in

unaffected

women

both

for

mutation

carriers

as

for

risk

carriers

Further

we

found

a

significant

difference

between

unaffected

and

affected

mutation

carriers

in

the

distribution

of

the

numbers

of

PM

over

the

various

age

categories

with

the

highest

numbers

of

PM

in

the

age

group

of

for

unaffected

and

for

affected

carriers

respectively

Moreover

the

distribution

of

PM

over

the

various

age

categories

remained

completely

identical

to

the

age

distribution

reported

in

a

previous

study

on

PM

from

our

institute

indicating

consistency

over

time

Our

data

show

that

despite

preoperative

-LRB-

imaging

-RRB-

examination

the

presence

of

unexpected

microscopic

-LRB-

pre

-RRB-

malignant

findings

in

this

group

of

high-risk

women

is

real

-LRB-

-RRB-

Other

studies

reporting

on

high-risk

and/or

pathologic

findings

in

prophylactically

removed

breast

tissues

described

percentages

varying

from

However

the

comparison

of

frequencies

of

unexpected

-LRB-

pre

-RRB-

malignant

findings

between

studies

is

hampered

by

differences

in

population

selection

preoperative

screening

methods

pathological

examination

of

the

specimens

and

definition

of

what

is

considered

-LRB-

pre

-RRB-

malignant

-LSB-

e.g.

lobular

carcinoma

in

situ

-LRB-

LCIS

-RRB-

-RSB-

The

percentage

of

unexpected

invasive

carcinomas

in

these

studies

ranged

from

-LRB-

in

our

study

-RRB-

Most

of

these

studies

however

did

not

provide

information

about

the

outcome

of

preoperative

physical

breast

or

imaging

examination

which

at

the

moment

is

a

standard

procedure

at

our

institution

It

might

be

that

since

the

implementation

of

institutional

guidelines

concerning

preoperative

breast

examination

in

and

the

introduction

of

magnetic

resonance

imaging

-LRB-

MRI

-RRB-

being

more

sensitive

in

detecting

carcinomas

in

high-risk

women

as

detection

tool

the

number

of

unexpected

malignant

findings

in

the

PM

specimens

is

decreasing

With

a

incidence

of

unexpected

microscopic

-LRB-

pre

-RRB-

malignant

findings

the

potential

role

of

sentinel

node

biopsy

-LRB-

SN

-RRB-

for

all

patients

undergoing

PM

has

been

discussed

However

the

majority

of

the

-LRB-

pre

-RRB-

malignant

findings

we

found

in

this

series

represents

DCIS/LCIS

settings

for

which

a

sentinel

node

biopsy

is

not

standardly

indicated

Invasive

cancer

was

found

in

only

of

the

patients

in

this

series

Therefore

in

our

opinion

routine

use

of

SN

in

all

patients

undergoing

PM

is

not

warranted

which

is

also

supported

in

the

paper

by

Boughey

et

al.

A

previous

study

from

our

institution

investigating

the

efficacy

of

PM

in

unaffected

women

with

a

proven

mutation

observed

no

cases

of

breast

cancer

after

PM

The

mean

follow-up

in

that

study

was

years

In

the

current

cohort

one

mutation

carrier

presented

with

metastatic

disease

years

after

PM

-LRB-

no

primary

BC

found

-RRB-

suggesting

the

presence

of

an

occult

primary

tumor

that

was

never

found

despite

a

thorough

reexamination

of

the

specimen

at

the

presentation

of

the

metastatic

disease

This

finding

emphasizes

the

fact

that

despite

thorough

examination

of

the

mastectomy

specimens

the

presence

of

an

occult

breast

cancer

can

not

be

ruled

out

completely

and

indicates

that

a

form

of

surveillance

after

PM

might

be

relevant

The

number

of

reconstructions

after

risk-reducing

mastectomy

was

lower

in

the

affected

group

This

may

be

due

to

the

fact

that

BR

after

previous

radiotherapy

and/or

therapeutic

mastectomy

not

always

leads

to

satisfactory

cosmetic

results

Some

patients

abandon

in

consultation

with

and/or

at

the

advice

of

their

-LRB-

oncological/plastic

-RRB-

surgeon

from

BR

for

this

reason

Other

women

have

accepted

the

mutilation/alteration

of

body

image

caused

by

mastectomy

are

reluctant

to

undergo

renewed

surgery

and

prefer

the

use

of

external

prosthesis

During

the

follow-up

period

of

this

study

of

the

women

with

immediate

or

delayed

BR

after

PM

showed

complications

In

total

complications

were

registered

leading

to

surgical

reintervention

in

cases

These

findings

are

consistent

with

several

other

reports

though

there

are

also

studies

reporting

lower

or

even

complication

rates

after

-LRB-

immediate

-RRB-

BR

However

the

literature

in

this

area

is

difficult

to

compare

in

part

because

not

all

previous

series

compare

bilateral

prophylactic

mastectomy

in

unaffected

women

with

risk-reducing

mastectomies

in

women

after

a

previous

therapy

for

breast

cancer

Furthermore

data

may

not

be

comparable

because

of

different

definitions

of

complications

Moreover

some

studies

describe

the

complication

rate

as

a

percentage

of

the

total

number

of

reconstructions

while

others

like

our

study

present

the

percentage

of

women

with

complications

We

found

no

differences

in

the

numbers

of

complications

after

-LRB-

immediate

-RRB-

breast

reconstruction

in

unaffected

women

compared

with

previously

affected

women

in

this

study

This

finding

appears

to

be

in

contrast

with

earlier

reports

-LRB-

also

from

our

institution

-RRB-

describing

the

occurrence

of

more

complications

after

mastectomy

followed

by

-LRB-

immediate

-RRB-

breast

reconstruction

in

affected

women

These

studies

report

negative

effects

of

preoperative

radiotherapy

on

the

cosmetic

outcome

of

the

reconstruction

in

particular

the

risk

of

capsular

formation

would

be

increased

having

negative

consequences

on

the

symmetry

of

the

breasts

Further

asymmetry

can

be

expected

to

occur

more

often

after

previous

therapeutic

mastectomy

Although

we

have

no

explanation

for

our

findings

it

is

possible

that

the

experience

of

the

surgeons

at

our

institution

is

important

Indeed

where

previously

BR

by

means

of

silicon

prosthesis

after

breast

conserving

therapy

was

performed

this

is

not

done

anymore

In

summary

we

confirmed

our

previous

findings

that

prophylactic

mastectomy

strongly

reduces

the

risk

of

developing

breast

cancer

in

both

mutation

carriers

and

risk

carriers

As

the

frequency

of

unexpected

cancers

in

this

high-risk

group

remains

real

preoperative

imaging

and

careful

histological

examination

is

warranted

Further

we

found

a

substantial

complication

rate

after

breast

reconstruction

which

mainly

concerned

late

cosmetic

issues

almost

always

leading

to

additional

surgery

In

this

respect

patients

should

be

informed

preoperatively

that

an

optimal

cosmetic

effect

can

not

unconditionally

be

achieved

in

just

one

single

operation

Concerning

the

complication

rate

after

BR

we

did

not

find

a

significant

difference

between

affected

and

unaffected

women

In

our

opinion

our

data

are

providing

additional

data

on

this

issue

and

may

help

to

inform

women

considering

prophylactic

mastectomy

and

their

physicians

in

the

complex

process

of

decision-making

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

brca1/2
prevention
unexpected carcinomas