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
 
 ... 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.

... 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? ??... 
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