Ethnic differences in the effect of parity on breast cancer incidence in premenopausal women in singapore

ETH N I C
D IFF E RE N CE S
I N
T HE 
E FFE CT 
OF
P A RITY 
O N 
B REAS T

CA N C ER 
I NCI DE N CE
 I N
 PRE ME N OPA U S AL
WO ME N
IN
S INGA PO R E







YAP 
P EN G
LE N G
KA RE N

(MBBS(Singapore),
FRCS(Edinburgh),
FRCS(Glasgow),
FAMS(General
Surgery))









A
 THES IS 
S UB MI T TE D 
 FO R
T HE
DEG RE E
O F
MA STE R
O F
SC IE N CE







DE PA R TME NT 
O F
EP IDE MIOL OG Y
A ND
PU BL IC 
HE AL T H

NA TIO NA L
 U NIV ER SI TY
 OF 
S ING AP O RE 







2009

1





ACK NO WL E DG E ME N TS



This
project
and
thesis
would
not
have
come
to
fruition
if
not
for
the
contributions

and
assistance
received
from
the
following:

My
supervisor
Professor
Chia
Kee
Seng
for
the
invaluable
instruction
and


direction
of
the
project,
from
its
conceptualization
through
to
the
completion
of

this
thesis;


Helena
Verkooijen
and
Cheung
Kwok
Hang
who
have
been
instrumental
in

retrieving
and
sorting
the
data
from
the
registries;

Professor
Soo
Khee
Chee
and
Professor
London
Lucien
Ooi
who
inspired
me

towards
pursuing
this
course
in
the
first
place
and

Dr
Ann
Lee
for
guiding
me
through
the
rigors
of
laboratory
research.

In
addition,
I
must
not
fail
to
mention
my
understanding
husband
and
parents

who
took
turns
to
mind
the
little
ones
in
order
to
give
me
uninterrupted
time
to

work.


i







TA BLE 
O F 
CO NTE N TS

ACKNOWLEDGEMENTS ......................................................................................................... I

TABLE
OF
CONTENTS............................................................................................................ II

SUMMARY.............................................................................................................................V

A


INTRODUCTION .................................................................................................................V


B


OBJECTIVES ......................................................................................................................V


C


MATERIALS
AND
METHODS................................................................................................V


D


RESULTS ......................................................................................................................... VI


E


DISCUSSION .................................................................................................................... VI


LIST
OF
TABLES ................................................................................................................... VII

LIST
OF
FIGURES .................................................................................................................. IX

LIST
OF
PRESENTATIONS
AND
PUBLICATIONS
FROM
THIS
STUDY .................................. XI

MAIN
BODY
OF
THESIS........................................................................................................ 1

1



INTRODUCTION .......................................................................................................... 1


2



LITERATURE
REVIEW .................................................................................................. 2


2.1



BREAST
CANCER
WORLDWIDE:
DIFFERENCES
IN
INCIDENCE ............................................. 2


2.2



FACTORS
PREDISPOSING
TO
BREAST
CANCER ................................................................. 5


2.2.1
 
BIOLOGICAL
FACTORS .................................................................................................. 5

2.2.2
 
HORMONAL
FACTORS ................................................................................................ 14

2.2.3
 
ENVIRONMENTAL
FACTORS ........................................................................................ 19

2.3



ETHNIC
DIFFERENCES
IN
BREAST
CANCER
RISK
F ACTORS ............................................... 25


2.3.1
 ETHNIC
DIFFERENCES
IN
BREAST
CANCER
INCIDENCE ..................................................... 25

2.3.2
 ETHNIC
DIFFERENCES
IN
REPRODUCTIVE
RISK
FACTORS
FOR
BREAST
CANCER ................... 27

2.3.3
 ETHNIC
DIFFERENCES
IN
CLINICAL
FEATURES
OF
BREAST
CANCER .................................... 29

2.3.4
 ETHNIC
DIFFERENCES
IN
BREAST
CANCER
MORTALITY.................................................... 30

2.4



EPIDEMIOLOGY
OF
BREAST
CANCER
IN
SINGAPORE ....................................................... 32


2.4.1
 
SINGAPORE
POPULATION
DEMOGRAPHICS
AND
ETHNIC
DIVERSITY ................................. 32

2.4.2
 
INCIDENCE
OF
BREAST
CANCER
IN
SINGAPORE.............................................................. 32

2.4.3
 
TRENDS
IN
BREAST
CANCER
INCIDENCE ....................................................................... 32

2.4.4
 
ETHNIC
DIFFERENCES
IN
BREAST
CANCER
TRENDS ........................................................ 35

2.4.5
 
ETHNIC
DIFFERENCES
IN
AGE‐SPECIFIC
INCIDENCE ........................................................ 36

ii





2.4.6
 
FERTILITY
RATES ....................................................................................................... 37

2.5



CLINICAL
ASPECTS
OF
BREAST
CANCER ........................................................................ 41


2.5.1
 
CLINICAL
PRESENTATION ............................................................................................ 41


2.5.2
 
STAGING
OF
BREAST
CANCER ..................................................................................... 41

2.5.3
 
BREAST
CANCER
TREATMENT ..................................................................................... 41

3



OBJECTIVES
OF
STUDY ............................................................................................. 42


4



MATERIALS
AND
METHODS..................................................................................... 43


4.1



DATA
S OURCES ......................................................................................................... 43


4.1.1
 
THE
SINGAPORE
NATIONAL
REGISTRY
OF
BIRTHS
AND
DEATHS
(SNRBD) ....................... 43

4.1.2
 
THE
SINGAPORE
CANCER
REGISTRY
(SCR) ................................................................... 43

4.2



ETHICS
APPROVAL ..................................................................................................... 44


4.3



LINKAGE
OF
DATA ..................................................................................................... 44


4.4



STUDY
COHORT ........................................................................................................ 44


4.5



DEFINITIONS ............................................................................................................. 45


4.6



DATA
ANALYSIS ........................................................................................................ 45


5



RESULTS

.................................................................................................................... 47


5.1


THE
SINGAPORE
NATIONAL
REGISTRY
OF
BIRTHS
AND
DEATHS
(SNRBD)
1986‐2002 ..... 47


5.2


DESCRIPTION
OF
STUDY
POPULATION .......................................................................... 50


5.2.1
 
ETHNIC
DISTRIBUTION ............................................................................................... 50

5.2.2
 
PARITY ..................................................................................................................... 50

5.2.3
 
AGE
AT
FIRST
BIRTH .................................................................................................. 51

5.2.4
 

AGE
AT
LAST
BIRTH .................................................................................................. 52

5.2.5
 
FOLLOW‐UP ............................................................................................................. 53

5.2.6
 
BREAST
CANCERS ...................................................................................................... 54

5.2.7
 
AGE
AT
CANCER
DIAGNOSIS ....................................................................................... 54

5.2.8
 DURATION
BETWEEN
LAST
BIRTH
BEFORE
CANCER
AND
BREAST
CANCER
DIAGNOSIS ........ 54

5.2.9
 
DURATION
BETWEEN
FIRST
BIRTH
AND
CENSOR
DATE................................................... 55

5.2.10


5.3


MOTHERS
WHO
HAD
CHILDREN
AFTER
BREAST
CANCER ............................................. 56

ETHNIC
DIFFERENCES
IN
REPRODUCTIVE
RISK
FACTORS
FOR
BREAST
CANCER ................... 57


5.3.1
 
AGE
AT
FIRST
BIRTH
AND
BREAST
CANCER
RISK ............................................................ 57

5.3.2
 
AGE
AT
LAST
BIRTH
AND
BREAST
CANCER
RISK............................................................. 59

5.3.3
 
PARITY
AND
BREAST
CANCER
RISK .............................................................................. 59

5.3.4
 
EFFECT
OF
ETHNICITY
ON
BREAST
CANCER
RISK ............................................................ 59

5.3.5
 
EFFECT
OF
ETHNICITY
AND
PARITY
ON
BREAST
CANCER
RISK .......................................... 60

iii





6



DISCUSSION .............................................................................................................. 65


6.1



SUMMARY
OF
MAIN
F INDINGS ................................................................................... 65


6.2



WHAT
OTHER
STUDIES
HAVE
FOUND ........................................................................... 66


6.3



POSSIBLE
EXPLANATIONS
FOR
THE
F INDINGS ................................................................ 67


6.3.1
 
TRANSIENT
POST‐PREGNANCY
RISE
IN
BREAST
CANCER
RISK.......................................... 67

6.3.2
 
BREAST‐FEEDING
PRACTICES ...................................................................................... 67

6.3.3
 
BODY
MASS
INDEX .................................................................................................... 67

6.3.4
 
AGE
AT
FIRST
BIRTH .................................................................................................. 68

6.3.5
 
HORMONAL
RECEPTOR
SUBTYPE ................................................................................ 69

6.3.6
 
ALPHA

FETOPROTEIN ................................................................................................ 69

6.4



STRENGTHS
OF
S TUDY ............................................................................................... 70


6.5



LIMITATIONS
OF
STUDY.............................................................................................. 72


7



CONCLUSION ............................................................................................................ 73


8



BIBLIOGRAPHY.......................................................................................................... 74


APPENDICES ....................................................................................................................... 90

APPENDIX

A
 
DEFINITIONS
USED ....................................................................................... 90

APPENDIX

B
 
ABBREVIATIONS ........................................................................................... 91

APPENDIX
C
 
LIST
OF
VARIABLES
IN
DATASET ...................................................................... 92

APPENDIX
D
 
COMMANDS
USED
IN
STATA ........................................................................ 93

APPENDIX
E
 
ETHICS
APPROVAL ........................................................................................ 99

APPENDIX
F
 
PUBLICATION ............................................................................................. 101




iv







SUM M A RY



A


Introdu c tion


The
effect
of
risk
factors
for
breast
cancer
development
is
known
to
be
modified

by
ethnicity.
Differences
in
the
effect
of
multiparity
on
breast
cancer
risk
have

been
shown
in
to
exist
in
Caucasian,
African-American
and
Hispanic
women.

Studies
in
Asian
populations
are
lacking.
A
literature
review
on
the
subject
was

done.



B


Obje cti ve s


This
thesis
proposes
that
there
are
ethnic
differences
in
the
effect
of
multiparity

on
breast
cancer
incidence
in
pre-menopausal
women
in
the
three
major
ethnic

groups
in
Singapore.



C


Ma teri als
a nd
M et hod s


Through
the
Singapore
National
Registry
of
Births
and
Deaths,
women
who
had

a
first
childbirth
in
the
years1986-2002
were
linked
with
the
Singapore
Cancer

Registry
to
ascertain
if
they
had
breast
cancer.
The
study
dataset
comprised

228,419
mothers,
of
whom
523
had
breast
cancer.
Multivariate
Cox
analysis
was

used.
The
relationship
between
ethnicity,
parity
and
premenopausal
breast

cancer
risk
was
examined,
adjusted
for
age
at
first
and
last
childbirth.




v







D


Re sul t s


Our
results
show
that
the
effect
of
parity
on
breast
cancer
risk
is
modified
by

ethnicity.
The
risk
in
uniparous
Malay
women
was
higher
than
that
of
uniparous

Chinese
(hazard
ratio[HR]
1.91
relative
to
Chinese,
95%
confidence
interval
[CI]

1.17-3.13),
whereas
Indians
had
a
lower
risk
(HR
0.38,
95%
CI
0.12-1.19).
In

Chinese
and
Indian
women,
multiparity
had
no
effect
on
breast
cancer
risk.
In

contrast,
Malay
women
had
a
significant
risk
reduction
with
increasing
parity
(2

children:
HR
1.82
relative
to
uniparous
Chinese,
95%
CI
1.21-2.73；
≥3

children:
HR
1.16,
95%
CI
0.73-1.85).



E


Di scussi on


This
is
the
first
study
to
show
that
the
effect
of
multiparity
on
premenopausal

breast
cancer
risk
is
modified
by
ethnicity
in
three
Asian
ethnic
groups.
Further

studies
are
needed
with
detailed
prospective
collection
of
information
in
order
to

confirm
these
findings
and
explain
the
underlying
mechanisms
for
the
observed

differences.

vi







LIS T 
O F
 TABL ES

TABLE
1.

AGE-STANDARDIZED
INCIDENCE
RATES
AND
DEATH
RATES
FOR
BREAST
CANCER
IN

SELECTED
COUNTRIES ..................................................................................................................3


TABLE
2.
BREAST
CANCER
RISK
FACTORS. .......................................................................................6

TABLE
3.
AGE-ADJUSTED
BREAST
CANCER
INCIDENCE
RATES
IN
USA
BY
ETHNICITY................25

TABLE
4.
TOTAL
FERTILITY
RATES
IN
WOMEN
IN
SINGAPORE
1955-2007. ..................................37

TABLE
5.
NUMBER
OF
BIRTHS
IN
SINGAPORE
BY
CALENDAR
YEAR...............................................47

TABLE
6.
BIRTH
ORDER
OF
OLDEST
CHILD
REGISTERED
IN
THE
BIRTH
REGISTRY
IN
THE
PERIOD

1986-2002..................................................................................................................................48

TABLE
7.
PARITY
AND
ETHNICITY
OF
THE
228,419
MOTHERS
IN
THE
BIRTH
REGISTRY.............50

TABLE
8.
PARITY
STATUS
(UNIPAROUS
VS
MULTIPAROUS)
OF
THE
228,419
MOTHERS

ACCORDING
TO
ETHNICITY. ........................................................................................................51


TABLE
9.
AGE
AT
BIRTH
OF
FIRST
CHILD
ACCORDING
TO
ETHNICITY
OF
THE
228,328
WOMEN. 51

TABLE
10.
AGE
AT
BIRTH
OF
FIRST
CHILD
ACCORDING
TO
PARITY
OF
THE
228,328
WOMEN.....51

TABLE
11.
CATEGORIZING
AGE
AT
FIRST
BIRTH
BY
ETHNICITY
IN
THE
228,328
WOMEN............52

TABLE
12.
AGE
AT
BIRTH
OF
LAST
CHILD
AND
ETHNICITY
OF
THE
228,328
WOMEN. ..................52

TABLE
13.
AGE
AT
BIRTH
OF
THE
LAST
CHILD
ACCORDING
TO
PARITY
OF
THE
228,328
WOMEN.

......................................................................................................................................................52

TABLE
14.
AGE
AT
WHICH
CANCER
WAS
DIAGNOSED
IN
THE
523
WOMEN
WHO
DEVELOPED

BREAST
CANCER . ........................................................................................................................54


TABLE
15.
DURATION
BETWEEN
BIRTH
OF
FIRST
CHILD
AND
DATE
OF
CENSORING
IN
THE

228,369
WOMEN. .......................................................................................................................56

TABLE
16.
MODELLING
AGE
AT
FIRST
BIRTH
AND
BREAST
CANCER
RISK,
UNADJUSTED
AND

ADJUSTED
FOR
AGE
AT
LAST
BIRTH
AND
PARITY,
ACCORDING
TO
ETHNIC
GROUP . ..............58


TABLE
17.
BREAST
CANCER
RISK
WITH
ETHNIC
GROUP
INCLUDED
IN
THE
MODEL. .....................60

TABLE
18.
BREAST
CANCER
RISK,
PERSON-YEARS
AND
ADJUSTED
HAZARD
RATIOS,
STRATIFIED

BY
ETHNIC
GROUP
AND
PERIOD
OF
DIAGNOSIS. .......................................................................61


TABLE
19.
BREAST
CANCER
RISK,
PARITY
AND
ETHNICITY,
WITH
C HINESE
WOMEN
AS
THE

REFERENCE
GROUP....................................................................................................................62


vii





TABLE
20.
BREAST
CANCER
RISK,
PARITY
AND
ETHNICITY,
WITH
UNIPAROUS
CHINESE
WOMEN

AS
THE
REFERENCE
GROUP. ......................................................................................................64







viii






LIS T 
O F
 FIG U R ES

FIGURE
1.
AGE-ADJUSTED
BREAST
CANCER
INCIDENCE
RATES
FOR
SELECTED
COUNTRIES ...... 4

FIGURE
2.

AGE-SPECIFIC
BREAST
CANCER
INCIDENCE
RATES
IN
SELECTED
COUNTRIES ........... 7

FIGURE
3.
AGE-ADJUSTED
INCIDENCE
OF
BREAST
CANCER
ACCORDING
TO
ETHNICITY
IN
THE

USA,
BASED
ON
SEER
DATA
1975-2004 ..............................................................................26

FIGURE
4.
AGE-ADJUSTED
BREAST
CANCER
MORTALITY
RATES
FOR
SELECTED
COUNTRIES ...30

FIGURE
5.
AGE-ADJUSTED
BREAST
CANCER
MORTALITY
ACCORDING
TO
ETHNICITY
IN
USA

BASED
ON
SEER
DATA
1975-2004 .........................................................................................31


FIGURE
6.
AGE-STANDARDIZED
INCIDENCE
RATES
OF
FEMALE
BREAST
CANCER
IN
SINGAPORE

1968-2002 ..................................................................................................................................33

FIGURE
7.
AGE-SPECIFIC
INCIDENCE
OF
FEMALE
BREAST
CANCER
IN
SINGAPORE
1968-1992

BY
BIRTH
COHORT .......................................................................................................................34


FIGURE
8:
AGE-SPECIFIC
INCIDENCE
RATE
OF
BREAST
CANCER
IN
SINGAPORE
WOMEN
SEEN
IN

TIME
PERIODS
1993-1997
AND
1998-2002,
SHOWING
A
SHIFT
IN
THE
PEAK
INCIDENCE

AGE
GROUP ..................................................................................................................................34


FIGURE
9.
AGE-STANDARDIZED
INCIDENCE
RATES
OF
FEMALE
BREAST
CANCER
IN
SINGAPORE

FROM
1968-2002,
STRATIFIED
BY
ETHNIC
GROUP

.................................................................36


FIGURE
10.
AGE-SPECIFIC
FEMALE
BREAST
CANCER
INCIDENCE
RATES
IN
SINGAPORE
FROM

1968-2002,
STRATIFIED
BY
ETHNICITY ....................................................................................37

FIGURE
11.
TOTAL
FERTILITY
RATES
IN
WOMEN
IN
SINGAPORE
1957-2001 ..............................37

FIGURE
12.
TOTAL
FERTILITY
RATES
IN
WOMEN
IN
SINGAPORE
1968-2002,
STRATIFIED
BY

ETHNICITY ....................................................................................................................................38


FIGURE
13.
TOTAL
FERTILITY
RATE
(PER
WOMAN)
AND
AGE-STANDARDISED
INCIDENCE
RATE

OF
BREAST
CANCER
(PER
10,000
WOMEN
PER
YEAR)
IN
SINGAPORE,
BASED
ON
DATA
IN


TABLE
4
AND
SINGAPORE
C ANCER
R EGISTRY
DATA ..............................................................39

FIGURE
14.
SCATTERPLOTS
OF
CUMULATIVE
BREAST
CANCER
INCIDENCE
RATES
AND
TOTAL

FERTILITY
BY
ETHNICITY. ............................................................................................................40


FIGURE
15.
DESIGN
OF
STUDY
BASED
ON
INFORMATION
AVAILABLE
IN
THE
SINGAPORE

NATIONAL
REGISTRY
OF
BIRTHS
AND
DEATHS. ......................................................................44

FIGURE
16.
DISTRIBUTION
OF
DURATION
BETWEEN
BIRTH
OF
LAST
CHILD
AND
DEVELOPMENT

OF
BREAST
CANCER,
STRATIFIED
BY
ETHNIC
GROUP. .............................................................55


ix





FIGURE
17.
BREAST
CANCER
RISK,
PARITY
AND
ETHNICITY,
WITH
CHINESE
WOMEN
AS
THE

REFERENCE
GROUP....................................................................................................................63


FIGURE
18.
BREAST
CANCER
RISK,
PARITY
AND
ETHNICITY,
WITH
UNIPAROUS
CHINESE
WOMEN

AS
THE
REFERENCE
GROUP. ......................................................................................................64





x







LIS T 
O F
 P RE SE N TA TI O NS 
A ND 
P UB LICA TIO NS 
FR O M
T HIS 


STU DY



1.


Verkooijen
HM,
Yap
K,
Chia
KS.


Multiparity
and
the
Risk
of
Pre-menopausal
Breast
Cancer:
Different
Effects

Across
Ethnic
Groups
in
Singapore.
The
Lancet
Asia
Medical
Forum
2007.
21-22

April
2007



2.


Verkooijen
HM,
Yap
KP,
Bhalla
V,
Chow
KY,
Chia
KS.


Multiparity
and
the
risk
of
premenopausal
breast
cancer:
different
effects
across

ethnic
groups
in
Singapore.
Breast
Cancer
Res
Treat.
2009;
113(3):
553-8.


xi





xii





MA I N
 BO D Y
 OF
 T HE SIS



1





IN TR O D UC TIO N


Breast
cancer
incidence
in
Singapore
is
rising.
We
have
noticed
over
the
past
years

of
treating
breast
cancer
that
there
are
differences
amongst
the
ethnic
groups.
This

thesis
proposes
that
there
are
ethnic
differences
in
the
effect
of
parity
on
breast

cancer
incidence
in
pre-menopausal
women
in
Singapore.
An
extensive
literature

review
of
the
subject
sets
the
background
for
our
paper.



1







2





LI TE RA TU RE 
RE VIE W





Brea st 
 Ca ncer
World wid e:
Differe nc e s
in 
Incid en ce




2.1 


Breast
cancer
is
the
most
common
cancer
in
women
worldwide
(1).
According
to

World
Health
Organization
(WHO)
statistics,
it
is
the
most
common
cancer
worldwide

in
women
with
slightly
over
a
million
new
cases
of
breast
cancer
detected
each
year


(2).
There
are
approximately
548,000
deaths
from
breast
cancer
each
year
around

the
world,
making
it
the
fifth
leading
cause
of
cancer
deaths
after
cancers
of
the
lung

(1.4
million
deaths/year),
stomach
(866,000
deaths),
liver
(653,000
deaths),
and

colon
(677,000
deaths)
(1).




Breast
cancer
incidence
is
highest
in
the
developed
countries.
From
the
International

Agency
for
Research
on
Cancer
(IARC)
2002
estimates,
the
more
developed

countries
had
an
overall
world
age-standardized
rate
of
67.8
per
100,000/year
as

compared
to
a
rate
of
23.8
in
the
less
developed
countries
(3).
In
the
United
States

alone,
the
age-adjusted
incidence
rate
was
126.1
per
100,000
women
per
year
from

2001-2005
(4).
The
incidence
and
death
rate
estimates
of
several
countries
obtained

from
the
WHO
estimates
are
listed
in
Table
1
(5):



2








Countr y


Argentina


Br east
Canc er
 W orl dwi de

AgeAge- St andar di z ed

St andar di z ed

Deat h
R at e
( per

Inc i denc e
R at e

100, 000)

(per
 100, 000)


(y ear
 of
esti mat e)

(y ear
 of

esti mat e)

46
(2002)

25
(2005)


Australia


67
(2002)


18
(2005)


Bangladesh


25
(2002)


16
(2005)


Brazil


34
(2005)


18
(2005)


106
(2005)


21
(2005)


China


14
(2005)


8
(2005)


Denmark


77
(2002)


28
(2005)


France


72
(2002)


23
(2005)


India


25
(2005)


16
(2005)


Japan


38
(2002)


9
(2005)


Malaysia


38
(2002)


23
(2005)


Netherlands


81
(2002)


28
(2005)


Sweden


55
(2002)


18
(2005)


United
Kingdom


75
(2005)


26
(2005)


103
(2002)


19
(2005)


17
(2002)


8
(2005)


Canada


United
States

Zimbabwe




TABLE
1.

Age-standardized
incidence
rates
and
death
rates
for
breast
cancer
in

selected
countries.
(5)




Even
though
incidence
rates
differ
between
countries,
over
the
past
three
decades

there
has
been
a
consistent
increase
in
incidence
rates
worldwide
of
a
magnitude
of

30-40%
(6).
Althuis
et
al
(6)
illustrated
this
elegantly
in
Figure
1.

3












FIGURE
1.
Age-adjusted
breast
cancer
incidence
rates
for
selected
countries.
(6)




However,
after
year
2000,
a
slight
decrease
in
breast
cancer
incidence
has
been

observed,
which
will
be
described
further
in
section
2.3.1.



In
Singapore,
breast
cancer
is
the
most
common
incident
cancer
in
females.
In
the

period
1998-2002,
the
world
age-standardised
incidence
rate
was
54.9
per

100,000/year
(7).
Similar
to
trends
worldwide,
breast
cancer
incidence
in
Singapore


has
also
been
steadily
rising.
This
is
discussed
in
greater
detail
in
section
2.4.

4







2.2 





Fa ct or s
Predi sp osi ng 
to 
Br ea st
Can c er




Breast
cancer
is
a
multi-factorial
disease.
Table
2
summarizes
some
of
the
factors

that
influence
the
predisposition
to
breast
cancer,
either
acting
individually
or
in

concert
with
other
factors.



2.2 .1 
 


Biologi cal 
 Fa ctor s




Gender

Breast
cancer
is
100
times
more
common
in
women.
Breast
cancer
in
men

comprises
less
than
1%
of
all
breast
cancers.
In
Singapore,
there
were
5500
new

breast
cancer
cases
in
females
in
1998-2002
compared
with
only
23
in
males
during

the
same
period
(7).



Age


The
breast
cancer
age-specific
incidence
rate
rises
rapidly
a
decade
before

menopause.
After
menopause,
rates
plateau
in
most
populations,
as
shown
in
Figure

2
from
Bray
et
al
(8).


5







Risk
 Fact or 

Biological
Factors

Gender

Age

Genetics

Height

Birth
Weight

Birth
Order

Mammographic
Density

Premalignant
Pathology

Cancer
in
Other
Breast



 Hig h
Ris k
Gro u p


Rel ative
 Risk


Female

Elderly

Mutation
gene
carriers

Tall

≥4
kg


Lower
order

≥75%

Atypical
Hyperplasia

Present


100

>10

10

1.02-1.07

1.24

1.1

4.6

4-5

5

3


Menarche


Highest
quintile
of
plasma

oestradiol
levels

Early
menarche


Menopause


Late
menopause


Parity

Age
at
First
Childbirth

Breastfeeding


Nulliparous

Age
≥35

Women
who
do
not
breastfeed


Hormone
Replacement

Therapy

Oral
Contraceptives

Fertility
Treatment

Abortions


Current
Users


10%
risk
reduction
for
every
2

years
delay
in
menarche

17%
increase
in
risk
for
every
5

years
delay
in
menopause

1.35

1.5

4.3%
risk
reduction
for
every
12

months
of
breastfeeding

1.35


Current
Users

No
difference

No
difference


1.2

1

1







2


Alcohol

Multivitamin
Intake

Obesity

Soy
Intake

Ionizing
Radiation


Current
Smokers
who
are

BRCA1/BRCA2
carriers

No
difference

No
difference

BMI
>28
kg/m2

≤5
mg
isoflavones/day

Exposure


Physical
Activity


Reduced


Hormonal
Factors

Endogenous
Hormones


Environmental
Factors

Smoking


1


1

1.26

1.4

Varies
with
dose
and
age
of

exposure

1.2




TABLE
2.
Breast
cancer
risk
factors.
Relative
risks
are
derived
from
supporting

references
quoted
in
the
text.

6







FIGURE
2.

Age-specific
breast
cancer
incidence
rates
in
selected
countries.
(8)







In
Singapore,
based
on
1998-2002
data,
the
age-specific
incidence
rates
in
women

aged
50-54
are
almost
twice
that
of
women
aged
40-44
(7).



The
effect
of
risk
factors
on
breast
cancer
varies
with
age.
The
following
factors

reduced the risk of early onset breast cancer but increased the risk of later onset breast cancers
— nulliparity, obesity and oral contraceptive use
(9;
10;
11).
Similarly,
differences
were

also
noted
in
tumour
characteristics
(12;
13)
and
survival
(13)
between
age
groups.

Tumours
were
classified
as
high
risk
if
they
were
>2cm,
estrogen
receptor
negative

(ER-),
node
positive
and
high
grade.
These
high
risk
tumours
were
found
to
have
an


early
onset
and
were
associated
with
a
worse
actuarial
survival
and
a
peak
in
hazard

at
2
years
after
cancer
diagnosis,
whereas
later
onset
tumours
had
a
better
survival

and
did
not
exhibit
the
hazard
peak
(13).
This
qualitative
age-interaction
effect

suggests
that
breast
cancers
occurring
in
younger
and
older
women
may
be
different

entities
(12).



Genetics

7





Hereditary
breast
cancers
account
for
5-10%
of
all
incident
breast
cancers.
The
two

major
genes
implicated
in
hereditary
breast
cancer
are
the
tumour
suppressor
genes

BRCA1
and
BRCA2.
BRCA1
was
identified
in
1991
(14)
and
cloned
in
1994
(15).

This
was
followed
by
the
identification
of
BRCA2
in
1995
(16).
Mutations
in
these

genes
are
more
common
among
Ashkenazi
Jewish
women,
where
the
population

frequency
of
the
common
founder
mutations
is
estimated
to
be
2.5%
(17;
18).
In

carriers,
the
lifetime
risk
of
breast
cancer
was
estimated
to
be
as
high
as
85%
(19).

However,
some
studies
report
a
much
lower
risk
estimate
of
40%-56%
by
age
70

(20;
21).



Besides
the
BRCA
genes,
which
have
a
low
population
frequency
but
a
high

penetrance
in
carriers,
studies
are
beginning
to
detect
various
breast
cancer

susceptibility
genes
which
are
more
common
but
exert
a
smaller
effect
on
risk.
The

Breast
Cancer
Association
Consortium,
an
international
collaboration,
studied
16

putative
single
nucleotide
polymorphisms
(SNPs)
previously
reported
in
smaller

studies
to
affect
breast
cancer
risk
(22).
Eighteen
studies
were
pooled,
with
a
total
of

between
12,013
to
31,595
subjects
(cases
and
control)
for
each
SNP
studied.
Small

associations
with
breast
cancer
were
found
for
5
SNPs
(CASP8
 D302H,
IGFBP3
 −

202
 c
 >
a
,
PGR
 V660L,
SOD2
V16A,
and
TGFB1
 L10P).
Further
evaluation
of
4
of


these
SNPs
and
another
5
SNPs
(comprising
11,391–18,290 cases and
14,753–22,670
controls)
showed
significance
of
the
CASP8
 D302H
and
TGFB1
L10P
variants,

estimated
to
attribute
0.3%
and
0.2%
towards
familial
breast
cancer
risk
(23).



As
more
large-scaled
studies
are
done
in
this
field,
it
is
likely
that
other
SNPs
will
be

identified
in
future.



Height

Height
has
a
positive
association
with
breast
cancer
risk.
An
earlier
study
in
Norway

of
570,000
women
had
shown
that,
within
each
age
group,
the
risk
was
highest
in
the

tallest
women
(24).
In
a
large
pooled
analysis
of
7
studies
with
a
total
of
337,819

women
and
4,385
incident
invasive
breast
cancers,
height
was
found
to
have
a

8





positive
association
with
breast
cancer
(25).In
premenopausal
women,
a
relative
risk

of
1.02
was
observed
with
every
5
cm
height
increment;
in
post-menopausal
women

the
relative
risk
was
1.07.




The
age
at
which
maximum
height
is
reached
is
an
indicator
of
the
age
at
which
the

pubertal
growth
spurt
occurs.
Earlier
age
has
been
found
to
be
associated
with

increased
risk,
particularly
of
more
aggressive
tumour
types
(26)
and
of
ductallobular
carcinoma
but
not
ductal
or
lobular
carcinoma
(27).


9







Birth
weight


The
role
of
intrauterine
factors
in
the
aetiology
of
breast
cancer
was
suggested
by
the

observation
that
the
initially
low
breast
cancer
risk
in
Asian
migrants
gradually

increased
over
several
generations
to
become
at
par
with
the
majority
Caucasian

population
in
USA
(28).
Although
initial
studies
did
not
reveal
any
relationship

between
birth
weight
and
breast
cancer
risk
(29;
30),
these
studies
were
limited
by

small
sample
sizes.



A
large
case-control
study
nested
within
the
two
Nurses
Health
Studies
showed
an

increased
adjusted
odds
of
breast
cancer
in
women
whose
birth
weights
were
higher

(31).
Park
et
al
(32)
showed
in
a
meta-analysis
that
the
odds
of
breast
cancer
was

1.24
with
birth
weights
of
≥4000g
(95%
CI
1.04-1.48)
and
1.15
(95%
CI
1.04-1.26)

for
birth
weights
3500-3599g,
with
respect
to
the
reference
group
of
2500-2999g.



The
underlying
mechanisms
of
this
birth
weight-breast
cancer
association
are

currently
unclear.
A
possible
explanation
is
the
effect
of
intrauterine
exposures
to

factors
with
mammotrophic
and
growth
hormone-like
effects.



Birth
Order

In
 the
 meta-analysis
 of
 the
 relationship
 between
 birth
 order
 and
 breast
 cancer
 risk

(32),
 it
 was
 found
 that
 higher
 birth
 orders
 were
 associated
 with
 a
 reduced
 breast

cancer
 risk,
 although
 the
 relationship
 was
 only
 seen
 in
 higher
 birth
 orders
 or
 ≥5

(odds
 ratio
 [OR]
 0.88,
 95%
 CI
 0.75-1.01).
 However,
 additional
 evidence
 to
 support

this
is
lacking.

Mammographic
Density

Mammographic
density
is
a
reflection
of
the
amount
of
fibroglandular
tissue
in
the

breast,
which
is
radiodense.
A
small
study
found
that
ductal
carcinoma-in-situ
arose

in
pre-existing
areas
of
mammographically
dense
tissue
(33).
This
suggests
that

epithelial
proliferation
occurs
in
radiodense
regions
of
the
breast.



10






Over
the
past
30
years,
over
50
studies
have
been
performed
evaluating

mammographic
density
and
breast
cancer
risk
(34).
In
a
meta-analysis,
increased

mammographic
density
was
associated
with
increased
breast
cancer
risk
(35).
This

association
also
showed
a
dose-response
relationship.
When
compared
with
breast

density
of
<5%,
the
pooled
relative
risk
of
breast
cancer
was
1.78,
2.46,
3.02
and

4.59
with
densities
of
5-24%,
25-49%,
50-74%
and
≥75%
respectively,
after

adjusting
for
age
and
body
size
(total
cases:non-cases
3004:6468).



Mammographic
density
has
been
shown
to
correlate
with
known
risk
factors
for

breast
cancer,
including
menarche,
age
at
first
full-term
birth,
parity
and

premenopausal
status,
supporting
the
theory
that
these
factors
may
be
associated

with
one
another
in
breast
cancer
pathogenesis
(36).



Although
this
effect
of
mammographic
density
was
seen
across
different
ethnic

groups,
the
magnitude
of
risk
differed
with
ethnicity
(37).

Compared
to
whites,
the

association
was
stronger
in
Asian-Americans
and
weaker
in
African-Americans
(38).

The
weaker
association
seen
in
African-American
women
could
be
related
to
their

larger
breast
size,
as
the
relationship
between
mammographic
density
and
breast

cancer
risk
appears
to
be
weaker
in
women
with
larger
breasts
(39).



Premalignant
Pathology

The
relationship
between
benign
pathology
on
breast
biopsies
and
subsequent
risk

of
cancer
development
has
been
extensively
studied
by
Page
and
Dupont
(40;
41).

Lesions
were
classified
as
non-proliferative,
proliferative
without
atypical
hyperplasia

and
atypical
hyperplasia.
Women
with
proliferative
lesions
without
atypical

hyperplasia
had
1.5
to
2
times
the
risk
of
cancer
compared
to
the
general
population

(women
with
non-proliferative
lesions)
(42;
40).
The
risk
was
4-5
times
with
atypical


hyperplasia
(40;
41;
42).
This
risk
was
further
exacerbated
if
these
women
with

atypical
hyperplasia
had
a
family
history
of
breast
cancer in a first degree relative – the
risk
was
9.7
for
atypical
ductal
hyperplasia
(95%
CI
4.7-20)
and
8.4
(95%
CI
3.5-20)

(41).

11







Strategies
to
reduce
the
cancer
risk
in
women
with
atypical
hyperplasia
include

chemoprevention
and
prophylactic
surgery.
Tamoxifen
was
the
first
drug
proven
to

reduce
breast
cancer
risk
in
women
at
high
risk
(43;
44).
A
more
recent
trial
has

shown
that
raloxifene
is
as
effective
as
tamoxifen
for
chemoprevention
when
used
in

post-menopausal
women
(45).
However,
currently
there
is
no
data
as
to
whether

chemoprevention
improves
survival.


12