An

overview

of

prognostic

factors

for

long-term

survivors

of

breast

cancer

Background

Numerous

studies

have

examined

prognostic

factors

for

survival

of

breast

cancer

patients

but

relatively

few

have

dealt

specifically

with

year

survivors

Introduction

Breast

cancer

-LRB-

BC

-RRB-

is

the

most

common

cancer

among

women

with

a

lifetime

risk

of

up

to

and

a

risk

of

death

of

up

to

-LSB-

-RSB-

Its

incidence

has

been

increasing

but

after

a

period

of

continuous

rise

in

many

industrialized

countries

BC

mortality

has

been

stable

or

has

even

decreased

in

the

last

years

-LSB-

-RSB-

The

introduction

of

mass

mammographic

screening

programmes

also

resulted

in

earlier

detection

and

diagnosis

of

small

and

less

aggressive

tumours

This

in

combination

with

therapeutic

improvements

has

led

to

a

substantial

increase

in

BC

survivors

over

the

last

few

decades

-LRB-

Fig.

-RRB-

A

long-term

survivor

is

commonly

defined

as

a

person

who

is

still

alive

years

after

cancer

diagnosis

-LSB-

-RSB-

For

BC

the

relative

survival

at

and

years

after

diagnosis

is

and

respectively

both

substantially

higher

than

the

relative

survival

of

all

cancers

together

-LRB-

-RRB-

-LSB-

-RSB-

Thus

it

seems

logical

to

consider

factors

known

to

play

an

important

role

in

predicting

survival

of

BC

patients

and

to

question

their

importance

in

survival

years

after

diagnosis

and

even

longer

Furthermore

in

recent

years

major

advances

in

the

prognostic

value

of

several

molecular

markers

have

been

achieved

hence

the

need

to

incorporate

this

data

into

our

current

knowledge

Therefore

we

have

summarized

available

knowledge

on

the

determinants

of

survival

years

or

more

after

breast

cancer

diagnosis

We

supported

our

analyses

and

considerations

with

data

from

the

population-based

long-standing

Eindhoven

cancer

registry

in

the

Netherlands.Fig

of

breast

cancer

patients

-LRB-

moving

average

-RRB-

diagnosed

between

and

who

survived

years

or

longer

in

Southeastern

Netherlands

Methods

We

initially

searched

PubMed

using

the

search

MESH

term

for

breast

neoplasms

AND

prognoses

AND

long-term

Only

papers

published

in

English

between

and

-LRB-

September

-RRB-

which

researched

female

adults

-LRB-

years

-RRB-

were

included

We

retrieved

articles

and

studied

the

abstracts

-LRB-

sometimes

also

the

methods

section

-RRB-

We

selected

only

articles

that

assess

or

show

the

results

for

those

surviving

years

or

longer

with

cohorts

having

a

mean/median

follow-up

of

years

or

longer

If

mean/median

follow-up

time

was

not

reported

we

examined

the

proportion

of

patients

who

survived

years

after

diagnosis

and

this

ought

to

be

larger

than

If

for

a

specific

topic

of

interest

no

relevant

studies

with

a

follow-up

of

at

least

years

were

found

-LRB-

such

as

BRCA

mutation

or

gene

profiling

which

have

been

studied

only

during

the

last

decade

-RRB-

then

studies

with

the

longest

available

follow-up

were

chosen

Furthermore

the

following

inclusion

criteria

were

used

overall

and/or

BC-specific

survival

was

reported

relative

risk

or

hazard

rate

and

statistical

probability

values

were

given

at

least

BC

patients

included

at

the

beginning

of

study

We

also

searched

the

reference

lists

collected

by

this

search

strategy

and

selected

those

that

were

relevant

to

both

our

study

question

and

inclusion

criteria

Reviews

and

books

that

gave

general

overviews

were

also

included

in

the

reference

list

We

present

data

from

the

Eindhoven

Cancer

Registry

-LRB-

ECR

-RRB-

to

illustrate

the

role

of

factors

such

as

age

tumour

size

lymph

node

involvement

and

time

since

diagnosis

Within

the

Netherlands

ECR

is

unique

because

it

has

collected

follow-up

data

since

including

clinical

aspects

of

cancer

patients

This

is

a

population-based

cancer

registry

covering

a

population

of

almost

million

people

in

-LSB-

-RSB-

Cumulative

survival

proportion

was

calculated

using

the

Kaplan

Meier

method

Relative

survival

was

calculated

by

comparing

the

survival

of

BC

patients

to

the

general

population

Throughout

the

text

the

term

long-term

and/or

survival

will

frequently

be

mentioned

this

corresponds

to

at

least

survival

unless

otherwise

indicated

Results

and

discussions

Determinants

of

survival

BC

years

or

longer

Patient

characteristics

Age

at

diagnosis

Very

young

women

i.e.

younger

than

years

-LSB-

-RSB-

exhibited

a

particularly

poor

survival

as

do

those

older

than

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

Young

BC

patients

were

more

likely

to

have

a

more

negative

clinical

presentation

such

as

affected

lymph

nodes

negative

for

oestrogen

receptors

and

have

large

tumour

with

a

high

fraction

of

nuclei

and

overexpression

of

oncoprotein

-LSB-

-RSB-

However

current

adjuvant

treatment

seems

to

diminish

the

poor

prognostic

value

of

young

age

-LSB-

-RSB-

young

women

who

did

not

receive

adjuvant

treatment

had

a

significantly

increased

risk

of

dying

those

diagnosed

at

years

and

years

had

a

and

higher

risk

of

death

respectively

compared

to

those

of

years

-LSB-

-RSB-

Older

patients

exhibited

higher

mortality

rates

-LSB-

-RSB-

probably

because

of

less

extensive

treatment

-LRB-

either

related

to

advanced

age

itself

or

the

presence

of

serious

concomitant

diseases

-LRB-

comorbidity

-RRB-

-RRB-

-LSB-

-RSB-

Fig.

survival

of

breast

cancer

patients

-LRB-

n

-RRB-

diagnosed

in

and

followed

until

according

to

age

at

diagnosis

in

southeastern

Netherlands

Comorbidity

Concurrent

health

conditions

-LRB-

comorbidity

-RRB-

at

the

time

of

BC

diagnosis

have

a

significant

impact

on

early

-LSB-

-RSB-

as

well

as

long-term

survival

of

BC

patients

-LSB-

-RSB-

The

most

prevalent

conditions

were

cardiovascular

disease

-LRB-

-RRB-

previous

cancer

-LRB-

-RRB-

and

diabetes

mellitus

-LRB-

-RRB-

all

becoming

more

common

with

increasing

age

-LSB-

-RSB-

Compared

to

those

without

comorbidity

whose

relative

survival

was

those

with

diabetes

mellitus

or

cardiovascular

disease

represented

and

of

the

respective

survival

estimates

-LSB-

-RSB-

Patients

with

severe

comorbidity

exhibited

a

higher

risk

of

death

in

years

compared

to

those

without

comorbidity

-LSB-

-RSB-

Period

of

diagnosis

Access

to

care

and

treatment

of

BC

has

improved

over

time

in

most

industrialized

countries

which

is

reflected

in

the

higher

long-term

survival

of

BC

cases

across

all

age

groups

and

the

tumour

characteristics

of

those

diagnosed

more

recently

-LSB-

-RSB-

In

Finland

relative

survival

years

after

diagnosis

among

patients

younger

than

years

increased

from

for

those

diagnosed

in

to

for

the

cohort

-LSB-

-RSB-

Furthermore

of

node-positive

BC

patients

diagnosed

in

in

Italy

survived

years

or

longer

compared

to

the

probability

survival

for

those

diagnosed

in

-LSB-

-RSB-

In

addition

changes

in

BC

diagnosis

e.g.

screening

-LSB-

-RSB-

and

better

staging

-LSB-

-RSB-

may

partly

be

responsible

for

the

observed

increase

in

the

proportion

of

survivors

Time

after

diagnosis

The

longer

a

woman

survives

BC

the

more

the

prognosis

improves

illustrated

by

conditional

survival

-LSB-

-RSB-

Probably

the

subgroup

of

patients

who

survived

longer

had

less

aggressive

tumours

due

to

a

different

genetic

make-up

or

better

life-style

In

Australia

of

women

with

localized

BC

survived

years

after

diagnosis

yet

among

those

still

alive

years

after

diagnosis

had

a

survival

-LSB-

-RSB-

The

respective

values

for

regional

vs.

advanced

BC

were

and

-LSB-

-RSB-

Unlike

other

cancers

relative

conditional

survival

remained

stable

below

after

years

of

survival

and

decreased

again

after

about

years

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

This

may

be

a

consequence

of

late

recurrences

and

metastases

second

cancers

or

late

side-effects

of

treatment

-LSB-

-RSB-

Fig.

relative

survival

-LRB-

calculated

using

period

analysis

-LSB-

-RSB-

of

breast

cancer

patients

diagnosed

in

southern

Netherlands

in

and

followed

until

according

to

age

-LRB-

Dashed

line

-RRB-

diagnosed

at

years

-LRB-

solid

line

-RRB-

diagnosed

at

years

Socioeconomic

status

-LRB-

SES

-RRB-

and

race

A

population-based

study

of

BC

patients

diagnosed

in

in

France

showed

a

diminishing

role

of

SES

on

excess

mortality

among

women

with

BC

over

these

periods

-LSB-

-RSB-

Long-term

follow-up

studies

reported

that

women

with

BC

from

low

social

classes

had

a

poorer

survival

compared

to

patients

from

higher

social

classes

-LSB-

-RSB-

although

others

contradicted

this

-LSB-

-RSB-

Low

SES

patients

were

more

likely

to

be

diagnosed

at

a

later

stage

had

more

aggressive

tumour

characteristics

and

might

have

received

sub-optimal

treatment

However

differences

in

these

prognostic

factors

did

not

fully

explain

the

variation

in

survival

according

to

social

class

-LSB-

-RSB-

This

is

also

the

case

when

breast

cancer

survival

is

studied

according

to

race/ethnicity

Ten

years

after

treatment

of

African

Americans

were

still

alive

compared

to

of

the

white

Americans

After

adjusting

for

other

prognostic

factors

excess

mortality

from

all

causes

was

still

observed

among

African

Americans

compared

to

caucasians

-LSB-

-RSB-

This

suggests

other

residual

factors

such

as

lifestyle

-LRB-

higher

body

weight

was

observed

among

African

Americans

-RRB-

comorbidity

-LSB-

-RSB-

genetics

or

variation

in

the

delivery

of

treatment

which

influence

outcome

beyond

variation

in

tumour

aggressiveness

-LSB-

-RSB-

Tumour-related

characteristics

Tumour

size

Tumour

size

is

one

of

the

strongest

prognostic

indicators

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

even

after

years

of

follow-up

-LSB-

-RSB-

A

larger

tumour

has

been

related

to

more

positive

lymph

nodes

-LSB-

-RSB-

thus

their

interaction

further

influences

the

survival

from

BC

Nonetheless

the

independence

of

survival

by

node

status

is

shown

by

the

lower

overall

survival

rate

found

for

node-negative

patients

with

a

tumour

of

cm

compared

to

those

with

a

tumour

smaller

than

cm

vs.

respectively

-LSB-

-RSB-

Fig.

survival

proportion

of

breast

cancer

patients

diagnosed

in

southern

Netherlands

in

and

followed

until

according

to

tumor

size

-LRB-

based

on

pathological

diagnosis

-RRB-

tumor

size

cm

-LRB-

n

-RRB-

tumor

size

cm

-LRB-

n

-RRB-

tumor

size

cm

-LRB-

n

-RRB-

x

tumor

size

involvement

of

skin

-LRB-

n

-RRB-

and

unknown/not

applicable

tumor

size

Histological

type

The

prognostic

value

of

histological

type

can

be

grouped

into

four

excellent

good

poor

and

very

poor

prognosis

-LSB-

-RSB-

BC

with

an

excellent

prognosis

such

as

invasive

cribriform

tubular

-LSB-

-RSB-

tubulo-lobular

and

mucinous

-LSB-

-RSB-

showed

survival

at

years

-LSB-

-RSB-

Tubular

mixed

mixed

ductal

with

special

type

atypical

medullary

-LSB-

-RSB-

and

alveolar

lobular

carcinoma

have

a

good

prognosis

with

a

survival

Those

with

invasive

papillary

classic

lobular

and

medullary

cancers

have

a

worse

prognosis

Finally

survival

among

those

with

ductal

solid

lobular

mixed

ductal

and

lobular

carcinoma

is

below

-LSB-

-RSB-

In

most

populations

infiltrating

ductal

carcinoma

covers

about

of

all

diagnoses

-LSB-

-RSB-

Inflammatory

BC

has

a

particularly

poor

prognosis

about

survived

years

-LSB-

-RSB-

Histological

grade

The

most

widely

used

grading

systems

are

Scarff-Bloom-Richardson

classification

Fisher

grading

nuclear

system

and

Nottingham

Combined

Histologic

Grade

-LRB-

NCHG

-RRB-

-LSB-

-RSB-

The

validity

of

grading

has

been

subjected

to

inter-observer

reproducibility

and

subjectivity

-LSB-

-RSB-

However

higher

grades

have

been

quite

consistently

associated

with

lower

long-term

survival

-LSB-

-RSB-

Depending

on

other

prognostic

factors

such

as

nodal

status

or

tumour

size

-LSB-

-RSB-

cumulative

survival

among

patients

with

the

lowest

score

was

years

after

diagnosis

and

among

those

with

the

highest

score

-LSB-

-RSB-

Regional

lymph

node

involvement

Lymph

node

involvement

is

a

valuable

indicator

of

long-term

survival

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

Node

positive

patients

have

about

a

times

higher

mortality

than

those

without

nodal

involvement

-LSB-

-RSB-

The

more

nodes

involved

the

worse

the

prognosis

Prognosis

for

patients

with

or

more

involved

axillary

nodes

showed

more

deaths

at

years

than

for

those

with

involved

nodes

-LSB-

-RSB-

The

survival

of

node-positive

patients

improved

due

to

better

staging

procedures

and

application

of

systemic

treatment

-LSB-

-RSB-

Fig.

survival

proportion

of

breast

cancer

patients

diagnosed

in

southern

Netherlands

in

and

followed

until

according

to

nodal

status

-LRB-

based

on

pathological

diagnosis

-RRB-

node

negative

-LRB-

n

-RRB-

node

status

positive

nodes

-LRB-

n

-RRB-

node

status

positive

nodes

-LRB-

n

-RRB-

x

node

status

positive

nodes

-LRB-

n

-RRB-

unknown/not

applicable

node

status

Lymphovascular

invasion

-LRB-

LVI

-RRB-

and

molecular

markers

of

tumours

angiogenesis

At

the

St.

Gallen

meeting

in

LVI

was

added

to

the

prognostics

for

node-negative

patients

-LSB-

-RSB-

Compared

to

patients

having

no

LVI

a

higher

BC

mortality

was

observed

for

node-negative

BC

patients

having

positive

LVI

-LSB-

-RSB-

although

others

did

not

observe

the

independent

role

of

LVI

-LSB-

-RSB-

In

this

line

of

research

studies

have

also

focused

on

the

value

of

microvessel

density

-LSB-

-RSB-

blood

invasion

-LRB-

BVI

-RRB-

-LSB-

-RSB-

and

markers

of

angiogenesis

-LRB-

VEGFR

-LRB-

vascular

endothelial

growth

factor

receptor

-RRB-

-RRB-

-LSB-

-RSB-

in

predicting

long-term

survival

of

BC

patients

although

the

results

are

still

conflicting

Grouped

prognostic

factors

Some

of

the

prognostic

factors

have

been

combined

into

a

prognostic

index

such

as

the

TNM

classification

and

also

the

more

current

Nottingham

Prognostic

Index

-LRB-

NPI

-RRB-

both

highly

predictive

for

estimating

long-term

survival

-LSB-

-RSB-

TNM

staging

consists

of

information

on

primary

tumour

size

involvement

of

the

regional

lymph

node

and

the

presence

of

distant

metastasis

Only

of

patients

with

regional

or

locally

advanced

BC

had

survived

years

after

diagnosis

compared

to

of

those

with

localised

BC

-LSB-

-RSB-

Patients

with

metastasis

-LRB-

stage

-RRB-

at

diagnosis

exhibited

very

poor

survival

-LRB-

-RRB-

-LSB-

-RSB-

Fig.

survival

of

breast

cancer

patients

diagnosed

in

southern

Netherlands

in

and

followed-up

until

according

to

second

cancer

Follow-up

for

patients

with

second

cancer

begins

at

the

date

of

second

cancer

diagnosis

no

second

cancer

-LRB-

n

-RRB-

second

breast

cancer

-LRB-

n

-RRB-

second

non-breast

cancer

-LRB-

n

-RRB-

Tumour

size

grade

and

lymph

node

status

make

up

the

NPI

-LSB-

-RSB-

In

a

large

series

of

BC

patients

survival

proportion

was

for

those

with

the

lowest

NPI

score

and

for

those

with

the

highest

score

-LSB-

-RSB-

Recurrence

metastasis

and

second

cancer

Patients

with

recurrent

metastasized

or

second

cancer

generally

exhibited

lower

long-term

survival

than

those

without

-LSB-

-RSB-

Ten

years

after

surgery

the

probability

for

survival

for

another

years

thus

years

after

diagnosis

for

node-negative

patients

aged

years

tumour

cm

grade

and

without

a

recurrence

or

metastasis

was

If

a

recurrence

occurred

the

probability

of

being

alive

at

years

dropped

to

If

a

metastasis

was

observed

the

probability

of

survival

was

only

-LSB-

-RSB-

The

prognosis

decreases

with

larger

primary

tumour

size

nodal

involvement

-LSB-

-RSB-

higher

grade

-LSB-

-RSB-

early

recurrence

-LRB-

within

years

of

surgery

-RRB-

-LSB-

-RSB-

location

of

recurrence

-LRB-

regional

rather

than

local

ipsilateral

-RRB-

-LSB-

-RSB-

and

inadequate

primary

cancer

treatment

-LSB-

-RSB-

In

the

dataset

of

the

ECR

overall

survival

was

better

for

women

without

second

primary

tumours

than

for

women

who

developed

a

new

primary

cancer

-LRB-

Fig.

-RRB-

Only

of

early

BC

patients

with

second

malignancies

had

survived

years

of

follow-up

compared

to

of

those

without

multiple

cancers

-LSB-

-RSB-

Younger

BC

patients

are

reported

to

have

poorer

survival

and

a

higher

risk

of

second

cancer

-LSB-

-RSB-

Corrected

for

race

and

grade

women

in

the

year

old

category

who

had

a

second

BC

had

a

probability

of

survival

probability

of

only

compared

to

for

those

without

multiple

cancers

Other

tumour

markers

Hormone

receptors

The

presence

of

hormone

receptors

such

as

oestrogen

-LRB-

ER

-RRB-

and

progesterone

-LRB-

PR

-RRB-

receptors

predicts

the

long-term

outcome

of

hormonal

therapy

-LSB-

-RSB-

thus

they

have

been

more

commonly

used

as

a

predictive

marker

rather

than

as

a

prognostic

marker

Thus

given

a

particular

treatment

e.g.

tamoxifen

ER-positive

patients

have

a

considerably

better

prognosis

than

ER-negative

patients

The

prognostic

value

is

weak

-LSB-

-RSB-

or

negligible

-LSB-

-RSB-

particularly

in

the

early

years

after

diagnosis

-LSB-

-RSB-

expression

Node-positive

patients

with

BC

cells

showing

amplification

of

the

gene

for

human

epidermal

growth

factor

receptor

type

-LRB-

-RRB-

and/or

overexpression

of

its

product

had

a

lower

overall

survival

proportion

versus

for

those

without

amplification

-LSB-

-RSB-

After

years

the

difference

in

survival

persisted

although

it

became

somewhat

smaller

-LSB-

-RSB-

Tumours

that

overexpress

are

more

likely

to

contain

abnormalities

to

be

hormone

receptor

and

and

to

have

lymphoid

infiltration

and

a

high

mitotic

index

all

known

to

be

markers

of

poor

prognosis

for

BC

-LSB-

-RSB-

As

for

patients

with

node

negative

tumours

did

not

seem

to

affect

long-term

survival

significantly

-LSB-

-RSB-

expression

has

been

valuable

in

predicting

treatment

responses

to

trastuzumab

certain

endocrine

therapies

and

chemotherapy

adding

to

it

's

role

as

a

predictive

marker

-LSB-

-RSB-

Mitotic

Activity

Index

-LRB-

MAI

-RRB-

MAI

is

an

indicator

of

tumour

proliferative

activity

that

represents

the

mitotic

activity

in

a

given

area

of

the

tumour

Combined

with

another

prognostic

factor

-LRB-

NCHG

-RRB-

MAI

has

proven

to

be

an

accurate

tool

for

assessment

of

long-term

survival

-LSB-

-RSB-

In

a

population-based

study

women

with

node-negative

tumours

cm

and

a

MAI

exhibited

survival

at

years

compared

to

for

an

MAI

-LSB-

-RSB-

Gene

expression

profile

A

very

promising

new

finding

is

the

microarrays

method

in

which

a

set

of

intrinsic

genes

is

clustered

and

segregated

into

major

subgroups

BC

with

a

good

and

poor

prognosis

profile

is

correlated

to

the

probability

of

distant

metastases

-LSB-

-RSB-

or

a

tumour

with

basal

or

luminal

characteristics

which

are

strongly

associated

with

ER

status

-LSB-

-RSB-

In

a

study

of

patients

diagnosed

with

stage

I

or

II

breast

cancer

those

classified

as

having

a

good

prognosis

profile

had

a

overall

survival

rate

compared

to

for

those

with

a

poor

profile

-LSB-

-RSB-

This

classification

predicted

outcome

regardless

of

the

nodal

status

implying

that

more

accurate

criteria

have

become

available

for

administering

adjuvant

systemic

treatment

Various

molecular

markers

mutations

were

first

identified

in

and

are

BC

risk

factors

for

some

specific

groups

-LSB-

-RSB-

Their

role

as

prognostic

indicator

for

long-term

-LRB-

more

than

-RRB-

survival

has

not

yet

been

established

A

study

of

women

-LRB-

median

follow-up

months

-RRB-

of

whom

-LRB-

-RRB-

carried

a

mutation

showed

worse

BC-specific

survival

for

women

with

mutations

than

for

those

without

-LRB-

at

years

versus

P

-RRB-

but

not

for

women

with

the

mutation

-LSB-

-RSB-

However

another

study

which

compared

patients

from

and

families

as

well

as

sporadic

cases

did

not

confirm

the

prognostic

role

of

-LSB-

-RSB-

Long-term

follow-up

studies

have

not

demonstrated

an

independent

effect

of

mutations

on

long-term

survival

The

mutation

was

related

to

a

poor

clinical

profile

for

patients

hence

in

multivariate

analysis

its

role

on

survival

diminished

-LSB-

-RSB-

A

high

level

of

tissue

urokinase-type

plasminogen

activator

-LRB-

uPA

-RRB-

and

its

inhibitors

has

been

correlated

with

poor

outcome

for

node-negative

and

node-positive

patients

Those

having

the

highest

level

of

uPA

have

a

five

times

greater

risk

of

dying

from

BC

compared

to

those

with

the

lowest

level

-LSB-

-RSB-

Other

factors

such

as

-LRB-

-RRB-

cathepsin-D

DNA

ploidy

and

S-phase

have

been

suggested

as

prognosticators

of

survival

with

conflicting

results

particularly

among

long-term

survivors

Their

use

in

general

clinical

settings

is

therefore

not

recommended

-LSB-

-RSB-

Miscellaneous

Lifestyle

Generally

increased

death

rates

due

to

BC

-LRB-

-RRB-

other

causes

-LRB-

-RRB-

and

all

causes

-LRB-

-RRB-

have

been

observed

among

obese

patients

-LSB-

-RSB-

Normal

body

weight

tended

be

more

beneficial

in

death

from

other

causes

than

from

BC

-LSB-

-RSB-

of

obese

patients

died

from

non-BC

causes

compared

to

and

respectively

of

the

normal

or

intermediate

groups

-LSB-

-RSB-

Obesity

was

also

related

to

a

increased

risk

of

postmenopausal

contralateral

BC

and

a

higher

occurrence

of

second

other

cancers

-LSB-

-RSB-

Therefore

normal

weight

may

reduce

the

risk

of

second

post-menopausal

BC

second

other

cancers

and

overall

mortality

-LSB-

-RSB-

Compared

with

women

who

engaged

in

less

than

metabolic

equivalent

task

-LRB-

MET

-RRB-

hours

per

week

of

activity

women

who

engaged

in

or

more

MET-hours

per

week

had

a

lower

risk

of

death

from

all

causes

translating

into

a

absolute

-LRB-

unadjusted

-RRB-

reduction

in

mortality

-LSB-

-RSB-

which

emphasizes

the

need

to

advise

physical

activity

So

far

although

studies

have

not

convincingly

shown

the

positive

influence

of

eating

fruit

vegetables

and

soy

bean

on

long-term

BC

survival

-LSB-

-RSB-

diets

high

in

fruits

vegetables

legumes

poultry

and

fish

and

a

low

intake

of

red

meat

desserts

and

high

fat

dairy

products

are

likely

to

protect

against

mortality

from

non-BC

causes

-LSB-

-RSB-

Modification

of

BC

's

prognostic

factors

Various

studies

have

questioned

the

role

of

BC

risk

factors

in

determining

the

biological

tumour

features

as

mentioned

above

Indeed

BC

risk

factors

seem

to

differ

according

to

histological

type

grade

size

nodal

status

and

ER/PR

receptor

status

-LSB-

-RSB-

For

example

excessive

alcohol

intake

and

obesity

increased

the

risk

for

the

development

of

ER-positive

tumours

-LSB-

-RSB-

As

for

late

age

at

first

full-term

birth

and

obesity

are

related

to

an

increased

risk

of

large

tumours

-LSB-

-RSB-

Hence

risk

factors

for

BC

may

also

affect

breast

biology

and

clinical

behaviour

thus

also

BC

prognosis

Changing

importance

of

prognostic

factors

over

time

after

diagnosis

Commonly

the

value

of

prognostic

factors

decreases

depending

on

the

length

of

the

follow-up

period

-LSB-

-RSB-

Survival

curves

according

to

prognostic

factors

usually

show

a

large

drop

in

survival

for

all

stages

during

the

first

years

afterwards

the

curve

stabilizes

Studies

agreed

on

the

long-lasting

influence

of

tumour

size

at

diagnosis

on

survival

albeit

attenuating

over

time

-LSB-

-RSB-

Grade

nodal

status

and

metastases

were

also

valuable

in

predicting

survival

up

to

years

after

diagnosis

-LSB-

-RSB-

Although

others

have

reported

that

years

after

diagnosis

only

tumour

size

-LSB-

-RSB-

or

nodal

status

-LSB-

-RSB-

or

old

age

-LSB-

-RSB-

remained

as

an

independent

predictor

of

long-term

survival

Similarly

ER/PR

status

and

MAI

only

had

a

significant

prognostic

role

in

the

first

years

after

diagnosis

-LSB-

-RSB-

Because

even

years

after

BC

diagnosis

the

probability

of

survival

for

BC

patients

does

not

seem

to

reach

that

of

the

general

population

the

role

of

other

prognostic

factors

in

determining

survival

for

long-term

survivors

still

needs

to

be

determined

The

role

of

early

detection

Increased

awareness

among

women

and

improvement

in

diagnostic

procedures

have

enabled

earlier

and

better

detection

of

BC

Trials

on

population

screening

have

reported

reduction

in

BC

mortality

for

women

invited

for

screening

within

years

of

follow-up

-LSB-

-RSB-

Screening

identified

tumours

at

an

early

stage

consequently

survival

improved

-LSB-

-RSB-

Screening

also

identified

patients

with

slowly

growing

tumours

who

might

receive

unnecessarily

aggressive

cancer

treatment

Thus

Joensuu

et

al.

-LSB-

-RSB-

examined

recurrence

rates

among

patients

detected

by

screening

compared

to

those

detected

outside

screening

After

adjusting

for

tumour

aggressiveness

-LRB-

tumour

size

nodal

status

grade

age

treatment

PR

status

-RRB-

hence

eliminating

bias

towards

detection

of

indolent

cancers

-LRB-

length

bias

-RRB-

the

benefit

of

screening

for

the

prognosis

for

BC

patients

remained

evident

-LSB-

-RSB-

This

suggests

that

other

factors

explain

the

indolent

behaviour

of

BC

detected

by

screening

Hence

until

this

factor

is

established

detection

mode

should

probably

be

considered

as

a

prognostic

factor

and

thus

be

taken

into

account

in

patient

management

The

role

of

treatment

Improvement

in

BC

treatment

has

undoubtedly

also

increased

the

long-term

survival

of

BC

patients

-LSB-

-RSB-

as

reflected

by

the

improved

overall

survival

across

all

BC

stages

-LSB-

-RSB-

Using

historical

data

from

population-based

studies

in

periods

when

effective

treatment

was

not

available

it

was

estimated

that

without

treatment

only

of

BC

patients

would

survive

years

or

longer

-LSB-

-RSB-

BC

treatment

guidelines

have

been

modified

continuously

in

the

last

years

tailored

to

most

of

the

prognosticators

mentioned

earlier

-LSB-

-RSB-

Effectiveness

of

various

treatment

modalities

has

been

summarized

by

others

who

conclude

that

radiation

chemotherapy

and

hormonal

therapy

may

reduce

long-term

mortality

by

up

to

-LSB-

-RSB-

Emerging

new

therapeutic

approaches

using

a

monoclonal

antibody

directed

against

have

yielded

improved

short-term

survival

for

advanced

stage

-LSB-

-RSB-

as

well

as

operable

BC

patients

-LSB-

-RSB-

Quality

of

treatment

as

indicated

by

loco-regional

failure

-LSB-

-RSB-

surgeon

workload

-LSB-

-RSB-

or

hospital

volume

-LSB-

-RSB-

may

affect

survival

although

its

role

on

long-term

survival

still

needs

confirmation

In

conclusion

on

the

one

hand

we

have

observed

a

shift

in

stage

towards

less

aggressive

cancers

on

the

other

hand

better

and

more

-LRB-

systemic

-RRB-

treatment

has

become

available

leading

to

improved

survival

for

BC

patients

Conclusion

The

prognosis

of

BC

has

become

relatively

good

with

current

relative

survival

about

in

most

western

populations

-LSB-

-RSB-

especially

if

up-to-date

statistical

method

such

as

the

period

analyses

is

used

-LSB-

-RSB-

-LRB-

Table

-RRB-

Even

better

the

longer

patients

survive

their

BC

the

higher

their

survival

chance

-LSB-

-RSB-

Our

review

shows

conventional

prognostic

factors

of

survival

such

as

tumour

size

lymph

node

status

and

grade

remain

the

most

important

determinants

of

survival

for

BC

patients

-LRB-

Table

-RRB-

Most

studies

agreed

on

the

value

of

MAI

and

LVI

for

prediction

of

long-term

survival

The

influence

of

host

factors

including

age

race/ethnicity

or

socio-economic

factors

and

tumour-related

factors

such

as

histological

type

and

angiogenesis

diminishes

after

correction

for

other

factors

For

most

recent

markers

such

as

gene

profiling

mutation

and

uPA

level

longer

follow-up

is

needed

Recurrence

metastases

and

a

second

cancer

double

the

burden

of

disease

thus

increase

risk

of

mortality

Similarly

co-occurrence

with

other

diseases

is

in

no

doubt

decrease

survival.Table

of

studies

reporting

long-term

prognostic

factors

for

breast

cancer

-LRB-

BC

-RRB-

patientsNo.Author

yearNo

of

patientsMean/median

follow-up

-LRB-

yrs

-RRB-

Univariate

-LRB-

UV

-RRB-

analysis

significantMultivariate

-LRB-

UV

-RRB-

analysis

significantNot

and

Jacobsen

-LSB-

-RSB-

MS

T

N

Htyp

MI

G

PR

patients

N

PR

In

N

MI

PR

In

N

MS

survival

was

measured

was

related

to

absence

of

tubular

formation

high

G

ER-negative

high

PCNA

-LRB-

proliferating

cell

nuclear

antigen

-RRB-

-LSB-

-RSB-

N

T

Htyp

tubular

formation

intraductal

growth

margin

formation

necrosis

DNA

ploidy

S-phase

fractionAll

patients

N

T

MI

In

N

T

MI

In

N

T

GOverall

survival

was

measured

is

related

to

younger

age

MI

AI

G

nuclear

-LSB-

-RSB-

G

PCNA

-LRB-

Proliferating

cell

nuclear

antigen

-RRB-

Overall

survival

was

measured

PR

was

only

an

independent

factor

in

N-positive

pts

PCNA

were

related

to

more

positive

N

higher

G

ER

-LSB-

-RSB-

NR

Range

yrsHistological

type

by

stage

-LRB-

localized

regional

BC

-RRB-

Breast

cancer

specific

survival

was

-LSB-

-RSB-

Diagnosed

End

FU

ComorbidityLevel

of

comorbidityAdjusted

for

age

race

stage

N

therapy

Values

for

these

factors

were

not

shownOverall

survival

was

measured

Charlson

comorbidity

index

was

used

There

is

no

difference

in

the

significance

of

comorbidity

on

survival

of

Caucasians

and

African

American

-LRB-

AA

-RRB-

-LSB-

-RSB-

PCNAT

G

PCNA.Overall

survival

was

measured

PR

only

an

independent

factor

for

N

patients

was

related

to

T

MI

-LSB-

-RSB-

Mucinous

BC

Infiltrating

duct

BC

NR

Diagnosed

period

of

diagnosis

Stage

GAgeBreast

cancer

specific

survival

was

-LSB-

-RSB-

age

T

cm

NPIT

G

NAgeOverall

survival

was

measured

Younger

than

yrs

had

higher

grade

more

LVI

and

worse

NPI

group

After

yrs

NPI

did

not

change

and

Tretli

-LSB-

-RSB-

age

End

FU

categorized

by

age

stage

and

follow-up

timeExcess

hazard

from

breast

cancer

was

measured

After

yrs

being

younger

than

does

not

influence

survival

Stage

was

an

important

prognosticator

up

to

-LSB-

-RSB-

by

grade

Treatment

by

gradeOverall

survival

was

measured

The

study

aimed

to

confirm

value

of

Nottingham

grading

system

for

survival

N+G

patients

benefited

from

prolonged

-LSB-

-RSB-

Control

BC

Control

vs.

vs.

controlOverall

survival

was

measured

Case

and

control

were

matched

for

date

of

birth

date

of

diagnosis

and

tumour

size

Patients

with

BRCA

were

younger

Patients

with

had

higher

-LSB-

-RSB-

patients

Whites

African

American

-LRB-

AA

-RRB-

yrs

patients

were

aliveRace

G

N

T

stage

waiting

time

smoking

being

a

widow

having

other

family

as

dependentRace

age

stageUV

alcohol

family

historyOverall

survival

was

measured

AA

is

more

likely

to

be

younger

at

diagnosis

have

larger

tumour

higher

stage

and

more

lymph

-LSB-

-RSB-

Bone

marrow

micrometastasesN

TBone

marrow

micrometastases

LVIOverall

and

breast

cancer-specific

survival

was

measured

Bone

marrow

metastases

may

be

useful

as

prognostic

factor

for

BC

pts

without

information

on

T

and

-LSB-

-RSB-

T

cm

N

LVI

NPIG

NLVIOverall

survival

was

-LSB-

-RSB-

Diagnosed

End

FU

N

G

detection

mode

HTypTXN

age

N

Htyp

N

T

N

GOverall

survival

was

measured

Screening

arrests

disease

progression

Tumour

progression

is

more

rapid

in

BC

patients

yrs

OS

of

-LRB-

mm

-RRB-

vs.

-LRB-

mm

-RRB-

NS

Holmes

-LSB-

-RSB-

BMI

to

quintile

of

protein

protein

intake

after

diagnosis

N

T

GBMI

protein

intake

prior

diagnosis

alcohol

intakeAll

cause

mortality

was

measured

MV

for

BMI

was

corrected

for

age

diet

interval

oral

contraceptive

use

hormone

replacement

therapy

MS

age

at

menarche

aget

at

birth

and

parity

smoking

T

G

N

ER

PR

BMI

and

quintile

of

protein

intake

were

reference

Significant

trend

of

higher

mortality

from

lowest

to

highest

quintiles

of

fibre

lutein

and

zeaxanthin

calcium

and

protein

intake

with

lowest

mortality

in

the

lowest

-LSB-

-RSB-

yrs

stage

cancer

and

recurrenceAge

ER

N

recurrence

second

cancerOverall

survival

was

measuredRecurrence

is

related

to

higher

stage

younger

age

at

diagnosis

Htyp

and

therapy

Second

cancer

is

related

to

younger

age

Death

related

to

recurrence

and

second

cancer

is

increased

yrs

after

diagnosis

Reed

-LSB-

-RSB-

Age

T

GG

T

treatmentUV

treatment

ER

PR

survival

was

measured

was

related

to

PR

ER-negative

G.

was

related

to

PR

Treatment

was

ovarian

locoregional

irradiation

that

had

lower

mortality

-LSB-

-RSB-

pre

vs.

T

G

age

ER+A

ge

EROverall

survival

was

measured

Younger

patients

with

ER

who

were

not

amenorrhoea

had

a

significantly

shorter

-LSB-

-RSB-

ER

ERAge

PR

GBreast

cancer-specific

survival

was

measured

was

related

to

grade

T

ER-negative

was

continuous

-LSB-

-RSB-

age

Diagnosed

Age

T

N

GPeriod

of

treatment

and

surgeryRelative

survival

was

measured

for

excess

mortality

due

to

BC

When

chemotherapy

was

given

BC

at

young

age

does

have

worse

-LSB-

-RSB-

uPA

G

N

PR

by

patients

uPA

N

T

age

In

N

uPA

T

In

N

N

uPA

T

age

survival

was

measured

For

patients

who

received

chemotherapy

uPA

T

N

determined

OS

For

patients

who

received

hormonal

therapy

uPA

N

determined

-LSB-

-RSB-

N

GAMC

T

N

GNecrosisOverall

survival

was

measured

AMC

is

a

good

prognostic

factor

for

N

and

-LSB-

-RSB-

T

N

G

ER

MAI

AIAll

patients

N

T

G

ER

In

N

G

In

N

N

age

ER

age

MV

All

patients

AI

MI

ER

G

MV

in

N

N

AI

MI

ER

G.Breast

cancer-specific

mortality

was

measured

When

patient

FU

was

truncated

at

yrs

MI

was

prognostic

factor

for

N

and

-LSB-

-RSB-

no

adjuvant

therapy

High

risk

group

-LRB-

ER

or

T

cm

-RRB-

vs.

low

risk

-LRB-

ER

and

T

cm

-RRB-

T

risk

group

-LRB-

high

vs.

low

-RRB-

G

MIOverall

survival

was

measured

MI

was

only

significant

when

FU

was

truncated

at

yrs

Grade

was

significant

prognostic

factor

for

short

and

long-term

and

Bracko

-LSB-

-RSB-

G

Tubular

score

MITubular

score

and

MIBreast

cancer-specific

survival

was

measured

This

study

confirmed

the

use

of

Nottingham

grading

system

in

their

Eredita

-LSB-

-RSB-

N

Htyp

G

LVI

NPIT

N

GUV

Age

MS

ER

type

of

surgery

MV

LVI

HtypOverall

survival

was

measured

NPI

gives

similar

survival

prognosis

as

T

N

-LSB-

-RSB-

yrs

about

patients

were

aliveAge

stratified

by

SESIntermediate

vs.

high

SES

group

corrected

for

age

ER

N

T

stageDeprived

vs.

high

SES

group

corrected

for

age

ER

N

T

stageDeprived

women

have

more

ER

tumours

ER

distribution

and

treatment

method

accounted

for

of

disparities

in

-LSB-

-RSB-

stage

N

age

ER/PRMS

therapyOverall

survival

was

-LSB-

-RSB-

T

G

N

ER

necrosisN

necrosis

GUV

Vascular

density

LVI

age

PROverall

survival

was

measured

Intratumoral

vascular

density

was

related

to

larger

tumour

size

and

higher

-LSB-

-RSB-

Familial

BC

BC

Diagnosed

End

FU

age

period

of

BC

diagnosis

FU

time

-LRB-

after

and

yrs

of

diagnosis

-RRB-

relative

survival

was

measured

for

excess

mortality

due

to

-LSB-

-RSB-

BC

type

vs.

other

type

by

nodal

status

and

chemotherapyOverall

survival

was

measured

Tubular

BC

type

had

better

prognosis

than

other

type

This

type

was

more

likely

to

have

low

G

ER

Kato

-LSB-

-RSB-

MI

necrosis

T

N

LVIMI

T

NUV

AIOverall

survival

was

measuredIn

MV

MI

were

independent

prognostic

factors

for

N-patients

only

was

related

to

MI

AI

necrosis

G

T

N

-LSB-

-RSB-

T

N

G

chemotherapyBVI

T

N

G

chemotherapyUV

necrosisOverall

survival

was

-LSB-

-RSB-

N

T

age

ER/PRN

T

ageMS

ER/PRBreast

cancer-specific

survival

was

measured

After

yrs

of

FU

ER

and

PR

were

not

independent

prognostic

-LSB-

-RSB-

in

and

N

T

MS

lymphoid

infiltration

PR-G

T

N

lymphoid

infiltrationOverall

survival

was

measured

was

related

to

large

tumours

higher

G

lymphoid

infiltration

higher

mitotic

index

de

Vijver

-LSB-

-RSB-

age

stage

Gene

profile

-LRB-

Good

vs.

bad

prognosis

-RRB-

for

all

patients

N

N

Gene

profile

T

N

chemotherapyVI

G

age

hormonal

therapyOverall

survival

was

t

Veer

-LSB-

-RSB-

age

classification

of

patients

with

high

risk

of

metastasis

and

in

need

of

-LSB-

-RSB-

OS

year

N

G

recurrence

or

metastasis

OS

yr

G

and

recurrence

or

metastasisAge

TIf

patient

remains

without

recurrence

or

metastasis

effect

of

prognostic

factors

decreases

over

time

With

metastases

this

effect

-LSB-

-RSB-

Gene

profile

-LRB-

luminal

vs.

basal

type

-RRB-

Luminal-like

was

predominantly

ER

Basal-like

and

was

predominantly

-LSB-

-RSB-

N

ER

BMI

and

BMI

higher

total

mortality

and

other

deaths.BMI

on

deaths

after

BC

events.Total

mortality

death

after

BC

events

and

other

deaths

as

well

as

recurrence

rate

and

occurrence

of

a

second

cancer

was

were

measured

MV

was

adjusted

for

treatment

age

MS

race

T

ER

and

PR

Reference

group

was

BMI

Olivotto

-LSB-

-RSB-

stage

BC

Stage

IIIB

and

and

breast

cancer

specific

survival

were

measured

Patients

with

supraclavicular

metastases

had

significantly

better

survival

than

patients

with

Survival

of

these

patients

resembles

that

of

BC

stage

IIB

-LRB-

FU

for

living

patients

yrs

for

all

patients

yrs

-RRB-

-LSB-

-RSB-

N

Chemotherapy

N

-LRB-

vs.

vs.

N

-RRB-

also

by

treatment

and

follow-up

timeN

T

MSMV

NXT

MSXT

additional

vincristine

and

prednisonOverall

survival

was

measured

N

was

related

to

T.

MS

was

related

to

receptor

-LSB-

-RSB-

At

yrs

patients

were

alivePeriod

of

diagnosis

stage

by

age

FU

time

by

stageRelative

survival

was

measured

for

excess

mortality

due

to

BCThe

longer

the

survival

the

better

the

prognosis

Improvement

in

relative

survival

for

all

patients

and

all

stages

since

-LSB-

-RSB-

aged

In

N

vessels

In

all

pts

TekIn

all

pts

G

vessels

ER

In

N

G

vessels

PRIn

all

pts

T

Htyp

PR

age

In

N

T

vessels

ER

ageOverall

survival

was

measured

MV

Tek

showed

significant

role

for

predicting

OS

in

all

patients

and

N

and

Hakulinen

-LSB-

-RSB-

age

Diagnosed

Period

of

diagnosis

stage

stage

period

time

after

diagnosisImprovement

of

prognosis

for

BC

patients

younger

than

over

the

past

decades

Relative

survival

remains

lowered

even

yrs

after

-LSB-

-RSB-

Ashkenazi

T

N

ER

age

T

N

AgeTamoksifen

cancer-specific

survival

was

measured

No

effect

of

BRCA

on

non-BC

death

only

predicted

BC

death

in

patients

without

-LSB-

-RSB-

LVI

N

Adjuvant

systemic

T

GTXGOverall

and

breast

cancer

specific

survival

were

measured

Patients

with

higher

grade

and

size

have

greater

chance

to

die

from

other

those

with

low

risk

disease

greater

chance

of

death

from

-LSB-

-RSB-

NR

Diagnosed

Period

of

diagnosisOver

the

decades

there

were

less

extensive

surgery

and

lymph

node

examination

less

radiotherapy

more

chemo

and

hormonal

-LSB-

-RSB-

age

Comorbidity

N

Therapy

age

comorbidity

NIn

age

comorbidity

N

In

age

comorbidity

ageIn

age

therapy

In

pts

age

N

therapyRelative

survival

was

measured

for

excess

mortality

due

to

BC

Older

patients

with

comorbidity

were

not

treated

differently

but

had

a

worse

-LSB-

-RSB-

LVI

G

N

TherapyLVI

G

NLMVD

-LRB-

Lymphatic

Microvessel

Density

-RRB-

T

Htyp

ER

age

MSOverall

survival

was

measured

LVI

is

related

to

young

premenopausal

BC

lower

G

N

Warwick

-LSB-

-RSB-

N

T

MetastasesG

N

T

MetastasesBreast

cancer

specific

survival

was

measured

All

studied

factors

predicted

long-term

survival

but

their

value

decreased

over

-LSB-

-RSB-

BMI

lower

overall

survivalBMI

survival

and

also

disease

free

survival

were

measured

Reference

group

was

BMI

MV

adjusted

for

ER

T

N

MS

treatment

chemotherapy

hormonal

in

combination

with

-LSB-

-RSB-

N

ER-NRBMI

and

AA

had

higher

overall

mortality

and

non

BC

deathBMI

and

race

on

death

after

BC

eventsTotal

mortality

death

after

BC

events

and

other

deaths

as

well

as

recurrence

rate

and

occurrence

of

a

second

cancer

were

measured

MV

was

adjusted

for

treatment

age

MS

race

T

ER

and

PR

Reference

group

was

BMI

Holmes

-LSB-

-RSB-

monthsPhysical

activity

after

diagnosis

-LRB-

MET

-RRB-

on

BC

and

total

mortalityBreast

cancer

and

total

mortality

were

measured

MV

corrected

for

age

interval

between

diagnosis

and

physical

activity

assessment

smoking

BMI

MS

hormone

therapy

use

age

at

first

birth

parity

energy

intake

stage

and

treatment

MET

metabolic

equivalent

task

hours

per

week

Patients

with

BMI

and

more

physical

activity

before

diagnosis

there

was

a

significant

trend

for

less

breast

cancer

and

Tretli

-LSB-

-RSB-

Diagnosed

End

FU

of

home

age

at

first

child

physical

activity

at

workMV

corrected

for

age

period

of

diagnosis

birth

cohort

educational

levelBreast

cancer-specific

survival

was

measured

Incidence

of

BC

increases

with

higher

educational

level

and

case

fatality

decreases

by

increasing

education

-LSB-

-RSB-

received

breast

conserving

Medullary

BC

vs.

other

BC

typeOverall

survival

was

measured

Medullary

BC

type

had

better

prognosis

than

other

type

This

type

was

more

likely

to

have

ER

PR

less

mutation

Medullary

type

was

only

a

prognostic

factor

for

the

first

-LSB-

-RSB-

stage

I-II

with

local

recurrence

-LRB-

LR

-RRB-

NRNo

LR

treatment

Invasive

LR

time

-LRB-

yrs

-RRB-

to

local

recurrence

age

at

initial

BC

diagnosisT

detection

method

number

of

nodes

sampled

ER/PR

histological

type

G

LVI

marginsMeasure

of

survival

distant

failure

second

malignancy

or

death

Patients

with

a

longer

time

to

recurrence

have

prolonged

-LSB-

-RSB-

BC

with

after

LR

for

living

ptsNRLocation

of

LR

size

of

LR

skin

involvement

of

LR

N

for

primary

tumourOverall

survival

was

measured

Early

detection

of

local

recurrence

may

improve

the

treatment

-LSB-

-RSB-

End

FU

or

more

comorbidities

diabetes

mellitus

and

previous

cancerPrevious

cancer

CVD

DM

cerebrovascular

disease

dementia

or

more

comorbidities

stage

treatment

-LRB-

RT

ST

age

-RRB-

Overall

as

well

as

relative

survival

was

measured

for

excess

mortality

due

to

BC

Primary

treatment

of

BC

patients

with

serious

comorbidity

was

less

extensive

than

treatment

of

those

without

-LSB-

-RSB-

of

severe

comorbidities

race

type

of

comorbidityAll

patients

or

more

comorbidities

adjusted

for

stage

age

ER

surgery

chemotherapy

radiotherapyOverall

survival

was

measured

AA

had

more

diabetes

and

hypertension

After

adjustment

for

these

comorbidities

disparity

-LSB-

-RSB-

age

UV

survival

was

measured

and

were

reported

as

independent

prognostic

factors

corrected

for

T

G

Htyp

in

all

patients

and

-LSB-

-RSB-

Inflammatory

BCNR

Diagnosed

End

FU

of

diagnosisBreast

cancer-specific

survival

was

measured

Prognosis

has

improved

over

the

decades

due

to

more

aggressive

-LSB-

-RSB-

yrsMAIOS

age

T

BCS

MAIOS

HTyp

therapy

period

of

diagnosis

BCS

therapy

period

of

diagnosis

age

T

HtypOverall

-LRB-

OS

-RRB-

as

well

as

relative

survival

-LRB-

BCS

-RRB-

was

measured

for

excess

mortality

due

to

BC

Higher

MAI

was

a

significant

prognostic

factor

for

N

and

N

but

only

during

the

first

yrs

of

-LSB-

-RSB-

T

cm

skin

fixation

muscle

fixation

G

N

ageTotal

FU

T

N

G

age

age

FU

yrs

T

N

G

age

FU

yrs

N

G

age

age

FU

yrs

N

age

FU

yrs

age

survival

was

measured

Long-term

effect

of

prognostic

factors

-LSB-

-RSB-

White

American

AA

Age

stage

SESMeta-analysis

African

American

is

an

independent

predictor

of

poor

outcome

for

overall

survival

and

breast

cancer

specific

-LSB-

-RSB-

women

followed

for

BC

death

-LRB-

N

-RRB-

Women

who

died

of

BC

in

of

education

by

period

of

diagnosisBreast

cancer

death

among

women

with

the

highest

education

compared

to

women

with

the

lowest

education

in

was

and

in

-LRB-

NS

-RRB-

-LSB-

-RSB-

age

Diagnosed

in

corrected

for

age

period

of

diagnosis

marital

status

country

of

birth

Htyp

ER

detection

method

stage

sector

of

care

therapyOverall

survival

was

measured

Lowest

SES

had

less

frequently

screen-detected

cancers

less

stage

I

less

lobular

BC

less

BCT

less

lymph

node

-LSB-

-RSB-

age

Being

in

wheelchair

renal

insufficiency

dementia

CHF

cardiac

arrhythmia

DM

IHD

osteoporosis

PVD

cerebrovascular

disease

COPD

Parkinson

's

disease

valvular

heart

diseaseIn

stage

age

CHF

DM

PVD

stage

cardiac

arrhythmia

Parkinson

's

disease

renal

insufficiency

In

stage

G

stage

N

wheelchair-bound

renal

insufficiency

COPD

age

DMSystemic

therapyOverall

survival

was

measured

CHF

Cardiac

Heart

Failure

DM

Diabetes

Mellitus

IHD

Ischemic

Heart

Disease

PVD

Peripheral

Heart

Disease

COPD

Chronic

Obstructive

Pulmonary

Disease

Role

of

comorbidity

varies

by

-LSB-

-RSB-

premenopausal

N

corrected

for

age

N

ER

type

of

surgeryOverall

survival

was

measured

Those

with

amplified

have

improved

survival

with

-LSB-

-RSB-

-LRB-

A

-RRB-

Adjuvant

therapy

-LRB-

B

-RRB-

Adjuvant

treatment

A

Group

B

LVIGroup

A

T

G

LVI

HtypGroup

B

T

G

LVI

chemotherapy

hormonal

therapyB

ER

age

HtypBreast

cancer-specific

survival

was

measuredFor

patients

without

adjuvant

treatment

role

of

G

in

survival

was

higher

in

the

first

yrs

Role

of

Htyp

was

not

significant

for

the

first

yrs

of

FUaindicates

the

overlapping

patients

used

by

the

same

author

to

answer

another

research

question

yrs

years

UV

Univariate

analysis

MV

Multivariate

analysis

MS

Menopausal

Status

T

Tumour

size

N

Nodal

involvement

Htyp

Histological

type

MI

Mitotic

Index

G

Grade

PR

Progesterone

Receptor

status

ER

Oestrogen

Receptor

status

PCNA

proliferating

cell

nuclear

antigen

mos

months

NR

Not

Reported

AA

African

American

age

is

in

year

and

indicate

age

at

primary

breast

cancer

unless

otherwise

state

NPI

Nottingham

Prognostic

Index

LVI

Lymphovascular

Invasion

-LRB-

Prognostic

factor

-RRB-

-LRB-

Prognostic

factor

-RRB-

interaction

between

two

factors

BMI

Body

Mass

Index

AMC

Average

Microvessel

Count

MAI

Mitotic

Activity

Index

AI

Apoptosis

Index

FU

Follow-up

SES

Socioeconomic

Status

BVI

Blood

vessel

Invasion

LMVD

Lymphatic

Microvessel

Density

LR

local

recurrence

CVD

Cardiovascular

Disease

DM

Diabetes

Mellitus

RT

radiotherapy

ST

Systemic

therapy

VEGFR

Vascular

Endothelial

Growth

Factor

Receptor

OS

Overall

survival

BCS

Breast

Cancer

Specific

Survival

NS

not

significant

CHF

Cardiac

Heart

Failure

IHD

Ischemic

Heart

Disease

PVD

Peripheral

Heart

Disease

COPD

Chronic

Obstructive

Pulmonary

CEF

cyclophosphamide

epirubicin

and

fluorouracilTable

prognostic

factors

for

long-term

overall

mortality

of

breast

cancer

-LRB-

BC

-RRB-

patientsPatient

groups

basedHazard

ratio

-LRB-

HR

-RRB-

for

overall

follow-up

or

survival

probability

-LRB-

S

-RRB-

years

after

diagnosisMorphology

basedHazard

ratio

-LRB-

HR

-RRB-

for

overall

follow-up

or

survival

probability

-LRB-

S

-RRB-

years

after

diagnosisMolecular

basedHazard

ratio

-LRB-

HR

-RRB-

for

overall

follow-up

or

survival

probability

-LRB-

S

-RRB-

years

after

diagnosisAge

at

diagnosis

-LSB-

-RSB-

HR

Lymph

node

status

-LSB-

-RSB-

HR

-LSB-

-RSB-

HR

vs.

-LRB-

P

-RRB-

N

vs.

-LRB-

-RRB-

vs.

-LRB-

-RRB-

vs.

-LRB-

ns

-RRB-

Metastases

vs.

-LRB-

-RRB-

Only

in

node-positive

vs.

-LRB-

P

-RRB-

vs.

-LRB-

P

-RRB-

Period

of

diagnosis

-LSB-

-RSB-

Relative

survivalb

Tumour

size

-LRB-

mm

-RRB-

-LSB-

-RSB-

HR

Cell

proliferation

indexHR

vs.

-LRB-

-RRB-

-LRB-

MAI

-RRB-

vs.

-LRB-

-RRB-

vs.

-LSB-

-RSB-

-LRB-

-RRB-

vs.

-LRB-

-RRB-

Only

in

node-positive

patients

vs.

-LRB-

-RRB-

T

vs.

-LRB-

-RRB-

Time

after

diagnosis

-LSB-

-RSB-

Relative

survival

Tumour

grade

-LSB-

-RSB-

HR

Gene

expression

profile

-LSB-

-RSB-

S

vs.

yrs

after

diagnosis

II

vs.

-LRB-

-RRB-

vs.

Regional

vs.

III

vs.

-LRB-

-RRB-

Poor

vs.

good

signaturef

Locally

advanced

vs.

Socioeconomic

status

-LSB-

-RSB-

HR

Tumour

type

-LSB-

-RSB-

S

ER/PR

status

-LSB-

-RSB-

HR

Intermediate

vs.

-LRB-

-RRB-

Poor

vs.

excellent

d

e

vs.

Positive

vs.

-LRB-

-RRB-

Deprived

vs.

-LRB-

-RRB-

LifestyleHR

Body

Mass

Index

vs.

-LRB-

-RRB-

-LSB-

-RSB-

c

Physical

activity

vs.

-LRB-

-RRB-

-LSB-

-RSB-

HR

Hazard

ratio

calculated

within

multivariate

analysis

of

breast

cancer

patients

followed

for

a

median/mean

of

years

or

longer

a

Metabolic

equivalent

task

hours

per

week

b

Estimates

taken

from

graph

c

Higher

alcohol

intake

no

significant

effect

on

mortality

Significant

trend

of

higher

mortality

for

lowest

compared

to

highest

quintiles

of

fibre

lutein

and

zeaxanthin

calcium

protein

intake

d

Becomes

larger

as

numbers

of

involved

lymph

nodes

increases

-LSB-

-RSB-

e

Excellent

prognosis

tubular

invasive

cribriform

mucinous

tubulolobular

Poor

prognosis

mixed

lobular

solid

lobular

ductal

and

mixed

ductal

lobular

f

unadjusted

estimates

Healthier

lifestyle

generally

increases

long-term

survival

Modifiable

risk

factors

-LRB-

such

as

alcohol

consumption

and

obesity

-RRB-

not

only

affect

incidence

but

also

tumour

clinical

behaviour

and

thus

survival

Although

a

lot

is

known

about

the

prognosis

for

BC

patients

effect

of

traditional

prognostic

factors

appears

to

attenuate

over

time

leaving

room

for

studies

on

the

role

of

other

and

newer

factors

for

long-term

survival

breast cancer
prognostic factors
survival


and

germline

mutation

analysis

in

the

Indonesian

population

Specific

mutations

in

and

genes

have

been

identified

in

specific

populations

and

ethnic

groups

However

little

is

known

about

the

contribution

of

and

mutations

to

breast

cancers

in

the

Indonesian

population

One

hundred-twenty

moderate

to

high

risk

breast

cancer

patients

were

tested

using

PCR-DGGE

and

any

aberrant

band

was

sequenced

Multiplex

ligation-dependent

probe

amplification

-LRB-

MLPA

-RRB-

was

performed

on

all

samples

to

detect

large

deletions

in

the

two

genes

Twenty-three

different

mutations

were

detected

in

individuals

ten

were

deleterious

mutations

and

were

unclassified

variants

with

uncertain

clinical

consequences

Three

of

seven

-LRB-

c.

and

del

exon

-RRB-

and

two

of

four

-LRB-

and

-RRB-

deleterious

mutations

that

were

found

in

and

respectively

are

novel

Several

novel

pathogenic

and

germline

mutations

are

found

in

early

onset

Indonesian

breast

cancer

patients

these

may

therefore

be

specific

for

the

Indonesian

population

Introduction

Breast

cancer

is

the

most

common

cancer

in

women

In

to

of

breast

cancer

cases

the

disease

results

from

a

hereditary

predisposition

-LSB-

-RSB-

which

can

to

a

large

extent

be

attributed

to

mutations

in

either

of

two

tumour

suppressor

genes

-LRB-

MIM

-RRB-

and

-LRB-

MIM

-RRB-

-LSB-

-RSB-

These

genes

are

involved

in

DNA

repair

as

well

as

transcriptional

regulation

-LSB-

-RSB-

Women

carrying

pathogenic

germline

mutations

in

either

of

these

genes

tend

to

develop

breast

cancer

at

an

early

age

-LSB-

-RSB-

The

and

genes

encode

large

proteins

of

and

amino

acids

respectively

Over

distinct

mutations

in

and

have

been

described

-LSB-

-RSB-

These

mutations

are

widely

scattered

across

both

genes

and

most

affect

the

structure

and

function

of

the

gene

Nevertheless

a

significant

proportion

-LRB-

of

and

of

mutations

-RRB-

-LRB-

-RRB-

are

missense

mutations

that

alter

one

amino

acid

but

do

not

truncate

the

protein

and

are

rare

sequence

variants

of

unknown

functional

consequence

Moreover

a

number

of

base

substitutions

do

not

alter

the

amino

acid

sequence

or

result

in

amino

acid

changes

not

associated

with

disease

-LRB-

polymorphisms

-RRB-

-LSB-

-RSB-

Hence

the

biggest

challenge

in

interpreting

the

mutation

analysis

of

and

genes

is

to

distinguish

between

harmless

polymorphisms

and

deleterious

mutations

associated

with

increased

cancer

risk

In

addition

mutations

specific

for

certain

populations

and

ethnic

groups

have

been

identified

in

both

genes

For

example

specific

and

mutations

were

reported

for

Ashkenazi

Jews

-LSB-

-RSB-

Other

common

mutations

were

especially

found

in

Italian

Canadian

Belgian

or

Dutch

breast

cancer

families

-LSB-

-RSB-

In

Indonesia

the

contribution

of

the

mutations

to

the

population

incidence

of

early-onset

breast

cancer

is

largely

unknown

In

one

pilot

study

however

a

new

mutation

was

identified

-LSB-

-RSB-

indicating

that

it

was

worthwhile

to

more

extensively

study

the

Indonesian

population

which

was

the

aim

of

this

study

The

accumulating

knowledge

about

the

prevalence

and

nature

of

and

mutations

in

specific

populations

may

facilitate

the

interpretation

of

genetic

analysis

with

regard

to

breast

cancer

risk

of

individual

patients

Materials

and

methods

Patients

A

total

of

unrelated

breast

cancer

patients

and

of

their

family

members

from

three

Indonesian

cities

-LRB-

Jakarta

and

Jogjakarta

on

the

Java

island

Denpasar

on

the

Bali

island

-RRB-

were

analyzed

Breast

cancer

patients

at

moderate

to

high-risk

of

a

hereditary

predisposition

were

selected

according

to

the

following

criteria

-LRB-

A

-RRB-

Breast

cancer

before

the

age

of

-LRB-

n

-RRB-

-LRB-

B

-RRB-

Two

cases

of

breast

cancer

in

the

same

family

before

the

age

of

-LRB-

n

-RRB-

-LRB-

C

-RRB-

Three

or

more

cases

of

breast

cancer

in

the

same

family

-LRB-

n

-RRB-

-LRB-

D

-RRB-

Bilateral

breast

cancer

-LRB-

n

-RRB-

Subjects

were

asked

to

fill

out

questionnaires

to

evaluate

their

personal

and

family

histories

and

blood

specimens

were

collected

for

determination

of

BRCA

mutations

Informed

consent

was

obtained

from

all

the

subjects

in

this

study

DNA

extraction

and

PCR

amplification

Genomic

DNA

was

isolated

by

the

saturated

salt

extraction

procedure

as

described

in

-LSB-

-RSB-

All

coding

exons

of

and

coding

exons

of

were

amplified

using

primer

sequences

developed

by

the

University

of

Groningen

The

Netherlands

-LSB-

-RSB-

Primers

for

DGGE

were

obtained

from

Ingeny

-LRB-

Goes

The

Netherlands

-RRB-

Genomic

DNA

was

amplified

using

ng

of

template

DNA

pmol

of

the

mixture

of

primers

mM

of

MgCl

mM

dNTPs

-LRB-

Invitrogen

-RRB-

and

unit

of

Platinum

Taq

-LRB-

Invitrogen

-RRB-

in

μl

PCR

reactions

In

order

to

speed

up

the

test

the

PCR

reaction

was

placed

in

well

plates

using

a

pipetting

robot

-LRB-

TECAN

Miniprep

-RRB-

PCR

conditions

were

performed

as

previously

described

-LSB-

-RSB-

Denaturing

Gradient

Gel

Electrophoresis

and

DNA

sequencing

A

μl

aliquot

of

each

PCR

product

with

relatively

large

melting

temperature

differences

were

pooled

as

previously

described

-LSB-

-RSB-

with

some

modifications

for

optimal

results

The

fragment

pool

was

designed

based

on

melting

profiles

and

sequence

Electrophoresis

was

performed

in

TAE

buffer

at

°C

V

for

h

for

gene

and

°C

V

for

h

for

Gels

were

stained

with

ethidium

bromide

and

photographed

under

a

UV

transilluminator

The

aberrantly

migrating

samples

were

re-amplified

using

sequencing

primers

and

sequencing

was

performed

using

Big

Dye

Cycle-sequencing

kit

according

to

the

manufacturer

's

instructions

The

reaction

products

were

analyzed

using

an

ABI

DNA

Sequencer

-LRB-

Applied

Biosystems

Torrence

CA

USA

-RRB-

and

sequence

files

were

edited

using

the

Bio

Edit

program

The

classification

of

gene

alterations

was

performed

in

accordance

with

the

entries

in

the

Breast

Cancer

Information

Core

-LRB-

BIC

Bethesda

MD

-RRB-

Multiplex

ligation-dependent

probe

amplification

-LRB-

MLPA

-RRB-

The

principle

of

the

MLPA

technique

has

been

described

elsewhere

-LSB-

-RSB-

The

MLPA

test

for

-LRB-

-RRB-

and

-LRB-

-RRB-

mutations

were

obtained

from

MRC-Holland

Amsterdam

The

Netherlands

The

fragments

were

analyzed

on

an

ABI

model

capillary

sequencer

-LRB-

Applied

Biosystems

Torrence

CA

USA

-RRB-

using

Genescan-TAMRA

size

standards

-LRB-

Applied

Biosystems

-RRB-

Fragment

analysis

was

performed

with

Genescan

software

Results

and

discussions

We

identified

incident

Indonesian

breast

cancer

cases

diagnosed

before

the

age

of

years

or

having

family

history

of

breast

cancer

or

harboring

bilateral

breast

cancer

during

September

April

-LRB-

Jogjakarta

-RRB-

and

during

July

April

-LRB-

Jakarta

and

Denpasar

-RRB-

In

addition

of

their

family

members

were

analyzed

The

entire

coding

regions

and

exon-intron

junctions

of

and

were

screened

in

these

persons

of

breast

cancer

patients

and

their

families

using

PCR-DGGE

-LRB-

Fig.

-RRB-

followed

by

sequencing

-LRB-

Fig.

-RRB-

for

samples

with

aberrant

migrating

bands

To

optimize

the

screening

MLPA

a

relatively

new

technique

was

also

performed

in

all

samples

-LRB-

Fig.

-RRB-

Here

we

report

on

women

-LRB-

-RRB-

for

whom

analysis

were

completed

The

remaining

four

patients

-LRB-

all

from

group

A

-RRB-

had

to

be

excluded

due

to

the

small

amount

of

extracted

DNA

that

did

not

allow

complete

screening

of

the

and

genes

Fig.

analysis

of

fragments

g

and

of

the

gene

in

ten

unrelated

breast

cancer

patients

The

arrows

show

altered

band

mobility

compare

to

other

patientsFig

electropherogram

of

a

normal

individual

showing

-LRB-

A

-RRB-

wild-type

exon

sequence

and

-LRB-

B

-RRB-

of

breast

cancer

patient

-LRB-

-RRB-

showing

c.

mutationFig

analysis

of

gene

of

patient

sample

-LRB-

blue

-RRB-

compare

to

the

normal

control

-LRB-

red

-RRB-

X

and

Y

axis

represent

peak

size

and

peak

height

respectively

There

are

reduced

peaks

in

the

patient

sample

compared

to

the

normal

control

in

exons

and

-LRB-

arrows

-RRB-

indicating

deletions

and

pathogenic

mutations

The

analysis

of

unrelated

breast

cancer

patients

with

breast

cancer

revealed

that

nine

patients

-LRB-

-RRB-

carried

pathogenic

germline

mutations

especially

the

early

onset

patients

within

-LRB-

-RRB-

and

within

-LRB-

-RRB-

which

is

comparable

to

previous

studies

-LSB-

-RSB-

We

only

found

and

mutations

in

groups

A

-LRB-

early

onset

n

out

of

-RRB-

and

B

-LRB-

two

cases

of

breast

cancer

in

the

same

family

before

the

age

of

n

out

of

-LRB-

-RRB-

-RRB-

-LRB-

Table

-RRB-

There

were

twice

as

many

mutations

as

mutations

Although

the

absolute

numbers

are

low

and

no

firm

conclusions

can

therefore

be

drawn

this

is

comparable

to

other

Asian

regions

-LSB-

-RSB-

but

seems

to

discern

the

Indonesian

population

from

non-Asian

ethnic

groups

where

the

reverse

trend

is

seen

Table

or

germline

mutations

in

Indonesian

women

with

early

onset

breast

cancerPatientAgeageneExonMutationbmutation

typePathogenic

dlarge

rearrangement

CIVS

Leu1209ValMissense?noAZ40BRCA116p.Met1652IleMissense

GIVS?noB731BRCA124p.Arg1835GlnMissense?no21633BRCA124p.Thr1852IleMissense?noP

Gln699LeuMissense?noJ3229BRCA211p.Arg2108CysMissense

CIVS

at

time

of

diagnosisbGen

Bank

Accession

number

of

times

reported

in

BICdnot

determined

detected

by

MLPA

Seven

pathogenic

mutations

were

found

in

nine

probands

three

in

-LRB-

c.

-LRB-

c.

-RRB-

del

exon

-RRB-

and

four

in

-LRB-

c.

-LRB-

c.

T

-RRB-

-LRB-

c.

-RRB-

-LRB-

c.

T

-RRB-

-RRB-

All

these

mutations

were

classified

as

pathogenic

as

they

are

predicted

to

result

in

protein

truncation

The

three

pathogenic

mutations

found

in

were

not

previously

reported

in

the

BIC

database

as

well

as

two

novel

nonsense

mutations

-LRB-

and

-RRB-

identified

in

The

mutation

was

found

in

related

patients

that

had

breast

cancer

above

the

age

of

One

of

seven

pathogenic

mutations

found

in

and

showed

a

significant

clinical

impact

on

the

patient

-LRB-

Table

-RRB-

Patient

AE

with

a

one

nucleotide

insertion

-LRB-

Thymine

-RRB-

between

nucleotide

and

-LRB-

c.

-RRB-

in

exon

of

suffered

from

bilateral

breast

cancer

at

a

relatively

early

age

-LRB-

years

-RRB-

The

insertion

leads

to

frameshift

and

creates

a

premature

stop

codon

in

exon

The

mutation

takes

place

in

the

sequence

within

encoding

for

aminoacids

which

interact

with

protein

that

is

required

for

homologous

recombination

-LRB-

HR

-RRB-

repair

of

double

strand

breaks

-LRB-

DSBs

-RRB-

-LSB-

-RSB-

which

is

one

of

the

most

important

functions

of

the

protein

This

patient

presented

in

a

late

stage

-LRB-

stage

III

for

both

breasts

-RRB-

and

only

survived

for

weeks

after

treatment

Her

mother

did

not

carry

this

mutation

Although

her

father

may

be

carrier

the

mutation

is

probably

de

novo

as

there

was

no

family

history

of

breast

or

other

cancers

Table

features

of

Indonesian

breast

cancer

patients

with

deleterious

or

germline

mutationsPatientAgeaGene

with

germline

mutationMutationbstageDiagnosisMenopausal

statusfamily

history

of

cancerSurvival

IIIAIDC

bilateralpreNoDOD

N

N

preSister

IntDOD

CvDOD

waAge

at

time

of

diagnosisbGen

Bank

Accession

number

determined

detected

by

MLPAIDC

invasive

ductal

carcinoma

DOD

dead

of

disease

bil

bilateral

breast

cancer

N

with

metastatic

to

lymph

node

Int

intestinum

cancer

Br

breast

cancer

Cv

cervical

cancer

The

second

pathogenic

mutation

with

a

significant

clinical

manifestation

was

a

cytosine

for

thymine

substitution

on

nucleotide

of

leading

to

a

premature

stop

codon

in

position

T

-LRB-

-RRB-

Patient

W

presented

at

age

in

a

late

stage

and

survived

for

only

weeks

after

initial

treatment

She

had

no

family

history

of

breast

or

other

cancers

This

mutation

lies

within

exon

of

which

is

the

proposed

site

for

interaction

with

the

protein

that

seems

to

have

a

fundamental

role

in

enabling

the

complex

to

associate

with

sites

of

DNA

damage

-LSB-

-RSB-

The

c.

-LRB-

-RRB-

in

that

has

been

reported

previously

by

us

in

the

Indonesian

population

-LSB-

-RSB-

was

found

in

one

other

patient

in

the

present

study

-LRB-

Table

-RRB-

This

mutation

lies

in

exon

within

the

BRC

repeats

domain

The

truncating

mutation

causes

loss

of

three

quarters

of

the

protein

leading

to

lack

of

interaction

with

the

protein

Different

from

the

repair

of

DSBs

by

HR

is

the

most

important

function

of

the

protein

-LSB-

-RSB-

Patient

was

diagnosed

with

early

stage

breast

cancer

at

age

with

no

family

history

of

breast

or

other

cancers

Her

sister

carried

the

same

mutation

but

with

no

present

clinical

manifestation

as

yet

Patient

AZ

who

was

diagnosed

at

years

of

age

presented

in

late

stage

only

survived

weeks

after

initial

treatment

This

patient

also

harbored

a

mutation

in

exon

of

a

G

to

A

substitution

in

nucleotide

-LRB-

c.

A

-RRB-

which

leads

to

amino

acid

change

from

Methionine

to

Isoleucine

-LRB-

-RRB-

which

has

to

date

been

reported

times

in

BIC

as

a

UV

mutation

As

the

c.

mutation

was

found

in

two

unrelated

patients

this

mutation

could

be

a

good

candidate

as

a

founder

mutation

of

the

families

with

more

than

cases

of

breast

cancer

and

families

with

bilateral

breast

cancer

showed

pathogenic

mutations

in

the

and

genes

Family

U

had

four

first-degree

relatives

that

were

affected

by

breast

cancer

Two

of

four

members

had

bilateral

breast

cancer

In

spite

of

this

high

familial

breast

cancer

incidence

no

mutations

were

found

and

unclassified

variants

Sixteen

-LRB-

and

-RRB-

rare

mutations

of

so

far

unknown

significance

-LRB-

unclassified

variants

UVs

-RRB-

were

detected

in

patients

missense

changes

and

intronic

variants

Of

these

UVs

were

novel

whereas

the

other

UVs

have

been

previously

reported

in

the

BIC

database

-LRB-

Table

-RRB-

From

the

patients

which

carried

UV

mutations

two

patients

were

detected

in

families

from

group

D

one

patient

in

a

group

B

family

and

the

other

fifteen

patients

in

families

from

group

A.

Seven

UV

were

found

in

the

gene

two

mutations

occurring

in

the

intronic

region

between

exons

and

-LRB-

c.

C

-RRB-

and

between

exons

and

-LRB-

c.

G

-RRB-

and

five

missense

mutations

identified

-LRB-

c.

A

-RRB-

-LRB-

c.

G

-RRB-

-LRB-

c.

A

-RRB-

-LRB-

c.

A

-RRB-

and

-LRB-

c.

T

-RRB-

Four

out

of

seven

missense

mutations

-LRB-

c.

G

-RRB-

c.

G

-LRB-

c.

A

-RRB-

and

-LRB-

c.

T

-RRB-

were

have

not

been

described

previously

in

the

BIC

The

may

not

be

a

significant

change

as

both

Leucine

and

Valine

belong

to

the

same

group

of

non

polar

amino

acids

However

is

possibly

an

important

alteration

since

a

positively

charged

Arginine

is

replaced

by

an

uncharged

Glutamine

which

may

have

an

effect

on

the

structure

and/or

function

of

the

protein

Another

potentially

important

alteration

concerns

where

the

hydrophilic

amino

acid

Threonine

is

replaced

by

a

hydrophobic

Isoleucine

The

sites

of

mutation

of

both

and

also

have

to

be

considered

as

they

lie

within

the

site

for

the

activation

domain

of

the

protein

-LSB-

-RSB-

The

intronic

UV

c.

G

also

deserves

further

investigation

as

it

may

theoretically

have

an

effect

on

splicing

However

according

to

splice

site

finder

-LRB-

-RRB-

the

splicing

sites

in

the

wild

type

and

mutant

alleles

are

similar

so

therefore

we

can

suggest

that

the

c.

G

has

no

effect

on

splicing

Nine

different

UVs

of

the

gene

were

found

in

fourteen

patients

-LRB-

-RRB-

and

three

of

them

were

novel

C

G

-RRB-

-LRB-

T

-RRB-

and

-LRB-

A

-RRB-

One

truncating

mutation

near

the

C-terminal

end

of

-LRB-

c.

T

-RRB-

is

probably

not

pathogenic

Since

the

truncating

mutation

is

at

the

very

end

of

the

protein

it

is

possible

that

protein

functions

are

not

affected

Most

of

the

few

entries

in

databanks

describing

nonsense

mutations

near

the

C

terminus

of

between

codon

and

are

described

as

UVs

Thus

the

effect

of

this

truncating

mutation

on

cancer

predisposition

remains

unclear

The

may

not

be

a

significant

change

as

both

Valine

and

Isoleucine

belong

to

the

same

group

of

non

polar

hydrophobic

amino

acids

However

p

and

are

potentially

important

alterations

as

for

a

non

acidic

polar

hydrophilic

Glutamine

is

replaced

by

a

negatively

charged

Glutamic

acid

whereas

for

an

uncharged

hydrophilic

Glutamine

is

replaced

by

a

hydrophobic

Leucine

As

it

takes

place

within

the

BRC

repeats

of

the

protein

the

p

alteration

might

affect

protein

structure

and

function

To

know

more

about

the

importance

of

amino

acid

substitutions

for

protein

function

we

compared

the

amino

acid

sequence

of

interest

in

seven

other

species

i.e.

Mus

musculus

Rattus

rattus

Bos

taurus

Gallus

gallus

Canis

familiaris

Macaca

mullata

and

Monodelphis

domestica

The

missense

mutation

lies

in

the

conserved

region

of

exon

of

the

gene

as

the

sequence

is

maintained

in

seven

other

species

whereas

and

are

only

conserved

in

four

and

three

other

species

-LRB-

comparison

of

and

with

Bos

taurus

sequence

is

not

possible

because

the

gene

is

shorter

-RRB-

Therefore

even

tough

the

Leucine

to

Valine

changes

may

not

give

any

effect

on

amino

acid

charge

its

conservation

in

evolution

is

suggestive

of

a

functional

role

Interestingly

and

of

that

result

in

a

quite

dramatic

amino

acid

subtitution

that

might

lead

to

protein

structure

changes

are

only

conserved

in

four

and

five

species

respectively

As

for

the

the

conservation

in

evolution

is

quite

low

Although

is

less

conserved

we

still

believe

that

Glutamine

to

Glutamic

acid

substitution

may

have

an

effect

on

protein

conformation

as

two

adjacent

acidic

amino

acids

will

be

formed

as

the

result

of

the

substitution

Glycosylation

moiety

of

an

amino

acid

also

plays

a

role

in

protein

function

Amino

acid

substitutions

involving

Serine

Threonine

and

Asparagine

should

also

be

checked

for

their

O-GlcNac

potential

and

threshold

Here

we

have

a

Threonine

to

Isoleucine

substitution

-LRB-

-RRB-

that

after

checking

with

YinOYang

-LRB-

-RRB-

showed

no

significant

threshold

changes

between

the

wildtype

and

the

mutant

allele

The

possible

effect

of

amino

acid

changes

in

proteins

can

also

be

assessed

using

similarity

scores

-LRB-

based

on

Grantham

table

-LSB-

-RSB-

-RRB-

in

which

a

value

above

for

an

amino

acid

substitution

indicates

a

higher

chance

of

impact

on

protein

function

Among

seven

novel

UVs

in

the

and

genes

found

in

the

present

study

only

in

has

a

similarity

score

above

whereas

and

in

have

the

lowest

score

-LRB-

Table

-RRB-

Table

amino

acid

properties

of

novel

unclassified

mutations

in

and

within

an

Indonesian

breast

cancer

populationGeneAmino

acid

changeChange

of

chargeChange

of

amino

acid

groupSimilarity

scorea

species

with

conserved

to

b

c

d

e

f

to

GlnPos

to

no

c

f

to

Ilepolar

to

non

c

to

GluNo

charge

to

b

c

to

LeuPolar

to

non

b

d

e

to

gabased

on

Grantham

table

-LSB-

Grantham

et

al.

-LSB-

-RSB-

a

score

above

indicates

significance

changesa

Macaca

mullata

b

Bos

taurus

c

Canis

familiaris

d

Rattus

rattus

e

Mus

musculus

f

Gallus

gallus

h

Monodelphis

domestica

Overall

we

propose

that

among

the

seven

novel

UVs

there

are

three

mutations

that

are

possibly

pathogenic

for

its

location

in

a

conserved

region

and

and

the

because

of

two

adjacent

acidic

amino

acid

being

formed

and

a

high

similarity

score

respectively

When

comparing

the

three

different

Indonesian

regions

the

percentages

of

breast

cancer

patients

with

pathogenic

mutations

was

significantly

higher

in

Denpasar

-LRB-

Bali

island

-RRB-

than

in

Jogjakarta

and

Jakarta

-LRB-

Java

island

-RRB-

-LRB-

-LRB-

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

-LRB-

P

chi-square

test

-RRB-

-RRB-

The

percentages

of

breast

cancer

patients

with

UV

mutations

in

Jakarta

Jogjakarta

and

Denpasar

were

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

-LRB-

n.s.

-RRB-

Although

the

number

of

patients

is

too

small

to

draw

firm

conclusions

these

data

may

point

to

geographic

differences

within

Indonesia

It

was

initially

suggested

that

the

and

genes

would

be

responsible

for

most

cases

of

inherited

breast

cancer

but

more

recent

studies

suggest

that

they

would

account

for

a

far

smaller

proportion

with

considerable

variation

among

different

populations

-LSB-

-RSB-

We

found

that

the

incidence

of

mutations

in

these

genes

varies

depending

on

the

diagnostic

group

In

this

sense

mutations

were

present

in

-LRB-

-RRB-

of

early

onset

patients

-LRB-

group

A

-RRB-

-LRB-

-RRB-

in

patients

with

bilateral

breast

cancer

-LRB-

group

D

-RRB-

and

-LRB-

-RRB-

of

patients

with

two

cases

of

breast

cancer

before

the

age

of

-LRB-

group

B

-RRB-

The

proportion

of

families

affected

by

mutations

depends

on

the

population

analyzed

and

on

the

criteria

used

to

select

the

patients

Family

history

of

breast

cancer

was

however

absent

or

not

suggestive

of

a

hereditary

predisposition

in

three-fourth

of

the

deleterious

mutations

carriers

and

in

more

than

of

UV

carriers

This

suggests

that

BRCA

screening

policies

based

on

family

history

only

would

miss

a

considerable

proportion

of

mutation

carriers

In

conclusion

a

relatively

high

percentage

of

early

onset

Indonesian

breast

cancer

patients

carry

a

germline

mutation

in

either

or

Several

novel

pathogenic

and

germline

mutations

have

been

found

as

well

as

a

variety

of

novel

unclassified

variant

mutations

that

may

therefore

be

specific

for

the

Indonesian

population

It

is

likely

that

some

of

the

unclassified

variant

mutations

may

have

a

functional

role

in

breast

cancer

development

which

deserves

to

be

explored

further

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