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Family history, hormone replacement therapy and breast cancer risk on Hispanic and non-Hispanic women, The New Mexico Women's Health Study
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Family history, hormone replacement therapy and breast cancer risk on Hispanic and non-Hispanic women, The New Mexico Women's Health Study
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FAMILY HISTORY, HORMONE REPLACEMENT
THERAPY AND BREAST CANCER RISK IN
HISPANIC AND NON-HISPANIC WOMEN,
THE NEW MEXICO WOMEN’S HEALTH STUDY
by
Rui Li
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)
April 2001
Copyright 2000 Rui Li
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UMI Number: 1406456
UMI
UMI Microform 1406456
Copyright 2001 by Bell & Howell Information and Learning Company.
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
Bell & Howell Information and Learning Company
300 North Zeeb Road
P.O. Box 1346
Ann Arbor, Ml 48106-1346
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UNIVERSITY OF SOUTHERN CALIFORNIA
The Graduate School
U niversity Park
LOS ANGELES, CALIFORNIA 90089-1695
This thesis, w ritten b y
• dui L !_ __________
U nder th e direction o f hff... Thesis
C om m ittee, and approved b y a ll its members,
has been p resen ted to and accepted b y The
Graduate School, in p a rtia l fu lfillm e n t o f
requirem ents fo r th e degree o f
41 cater &£ (t/'ente _ _ _ _ _
Dean o f Graduate Studies
D ate M ay II, 2001
THESIS CO M M ITTEE
Chairperson
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ACKNOWLEDGEMENTS
First, I would like to express my gratitude to my graduate advisor Dr. Frank D.
Gilliland and my colleague, Ms. Yu-fen Li, for their guidance, encouragement and
assistance in my research. Their insights and suggestions have helped greatly
increase my fund of knowledge about research in the field. I also would like to
thank my committee members, Dr. John M. Peters and Dr. Kiros T. Berhane for
their valuable time and helpful comments. Finally, special thanks goes to my
family in Beijing and my husband who have supported me and made it possible for
me to complete my graduate studies at USC.
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TABLE OF CONTENTS
ACKNOWLEDGEMENTS ............................... II
LIST OF TABLES ............... ....V
LIST OF ABBREVIATIONS ...... ..VI
ABSTRACT ....... VII
CHAPTER 1 INTRODUCTION .............. 1
1.1 D em ographic Risk Fa c t o r s .......................................................................................... 3
1.2 Repr o d u c tiv e Ris k Fa c t o r s.......................................................................................... 5
1.2.1 Age at menarche............................................................................................ 5
1.2.2 Pregnancy and age at first full-term births................................................. 6
1.2.3 Lactation......................................................................................................... 6
1.2.4 Abortions........................................................................................................ 7
1.2.5 Age at menopause...........................................................................................7
1.3 Lifestyle Ris k Fa c t o r s .................................. 8
1.3.1 Smoking.......................................................................................................... 8
1.3.2 Alcohol............................................................................................................ 8
1.3.3 Physical activity............................................................................................. 9
1.3.4 Body weight..................................................................................................10
1.4 Genetic S u sc e p t ib il it y...................................................................................................10
1.5 Po st m e n o pa u sa l H o r m o ne U s e .................................................................................11
CHAPTER 2 FAMILY HISTORY AND BREAST CANCER RISK.... ....13
2.1 M ateria ls a n d M e t h o d s ................................................................................................ 16
2.1.1 Identification o f cases and controls............................................................17
2.1.2 Data collection.............................................................................................17
2.1.3 Statistical analysis....................................................................................... 18
2.2 R e s u l t s ........................................................................................................... 20
2.3 D is c u s s io n ......................... 26
iii
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CHAPTER 3 HORMONE REPLACEMENT THERAPY AND BREAST
CANCER.......................................................................... 30
3.1 M ateria ls a n d M e t h o d s...............................................................................................32
3.1.1 Identification o f case subjects....................................................................33
3.1.2 Identification o f controls........................................................... 34
3.1.3 Data collection................ 34
3.1.4 Statistical analysis............................... 36
3.2 Re s u l t s ........................ 37
3.3 D is c u s s io n ............................................. 46
CHAPTER 4 CONCLUSION.................. 51
4.1 Etiology of B r ea st Ca n c e r D e v elo pm en t.. ..................... 53
4.2 Pr ev en tio n S trategies fo r H eritable Risk of B r e a st C a n c e r ............. 55
4.3 H orm o ne R eplac em en t Th e r a py a n d O th er O p t io n s..................... 56
4.4 Fu tu r e D ir e c t io n s................................... 57
BIBLIOGRAPHY.... ...... .................................5 8
iv
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LIST OF TABLES
T a b l e 2.1 D istr ibu t io n, o d d s ratios (OR) a n d 95% c o n fid en c e in terv a ls
(Cl) FOR SELECTED DEMOGRAPHIC CHARACTERISTICS AND BREAST CANCER RISK
FACTORS, NMWHS, 1992-1994*.............................................. 21
Ta b l e 2.2 U n iv a r ia t e O d d s R atio s (O R s) a n d m u l tiv a r ia t e a d ju ste d O R s
.. AND 95% CONFIDENCE INTERVAL (95% Cl) OF BREAST CANCER IN RELATION TO
FIRST- OR SECOND-DEGREE FAMILY HISTORY (FH) OF BREAST CANCER,
N M W H S, 1 9 9 2 -1 9 9 4 ............................................................................. .................................22
Ta b l e 2.3 M u t u a l l y a d ju ste d O d d s Ra t io s (O R s) a n d 95% co nfidence
INTERVAL (95% Cl) OF BREAST CANCER IN RELATION TO FAMILY HISTORY (FH)
OF BREAST CANCER STRATIFIED BY AGE GROUPS OR MENOPAUSAL STATUS,
NMWHS, 1992-1994................ .24
T a b l e 3.1 D istr ibu t io n, o d d s ratios (O R) a n d 95% c o n fid en c e in terv a ls
(Cl) FOR SELECTED DEMOGRAPHIC CHARACTERISTICS AND POSTMENOPAUSAL
BREAST CANCER RISK FACTORS, NMWHS, 1992-1994*...................... 38
Ta b l e 3.2 D istr ibu t io n of to tal estr o g en u se , estr o g en u se a l o n e,
COMBINED ESTROGEN AND PROGESTERONE USE FOR HISPANIC AND NON-
H isp a n ic w h ite s , N M W H S, 1 9 9 2 -1 9 9 4 ........................................... 41
Ta b l e 3.3 M u lt iv a r ia te Od d s ratios (O R s) a n d 95% c o n fid en c e in terv a l
(95% Cl) OF BREAST CANCER IN RELATION TO TOTAL USE OF ESTROGEN, USE OF
ESTROGEN ALONE AND COMBINED USE OF ESTROGEN AND PROGESTERONE,
NMWHS, 1 9 9 2 -1 9 9 4 * ............................................................. 44
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LIST OF ABBREVIATIONS
95% Cl 95% Confidence Interval
BMI Body-mass Index
CASH Study Cancer And Steroid Hormone Study
CHRT Combined Estrogen-progesterone Replacement Therapy
ERT Estrogen Replacement Therapy
FH Family History
FTB Full-term Birth
HRT Hormone Replacement Therapy
IGF-1 Insulin-like Growth Factor 1
MET Metabolic Equivalents
NMTR New Mexico Tumor Registry
NMWHS New Mexico Women’s Health Study
oc Oral Contraceptive
OR Odds Ratios
SEER Program Surveillance, Epidemiology and End Results Program
SIR Standardized Incidence Ratios
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Rui Li Frank D. Gilliland
ABSTRACT
FAMILY HISTORY, HORMONE REPLACEMENT THERAPY AND
BREAST CANCER RISK IN HISPANIC AND NON-HISPANIC WOMEN,
THE NEW MEXICO WOMEN’S HEALTH STUDY
To date, epidemiological studies have reported inconsistent findings about the
relationship between family history and breast cancer risk in Hispanic women; and
little information is available to assess postmenopausal breast cancer risk
associated with hormone replacement therapy among this minority population. To
investigate the effects of positive FH and HRT use on breast cancer risk among
Hispanic women, we examined data from the New Mexico Women’s Health Study.
We found an increased risk in women with a history of breast cancer in first-degree
relatives and second-degree relatives. Hispanics had higher risk estimates for a
positive family history than non-Hispanic women. With respect to HRT use, we
found an increased risk associated with long-term users of estrogen. Hispanic
postmenopausal women appeared to be at a significantly greater risk than non-
Hispanic whites.
vii
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CHAPTER 1
INTRODUCTION
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Breast cancer is the most common cancer among women in the US, accounting for
almost 30% of all newly diagnosed cancers (Parker et al., 1997). Additionally,
breast cancer is the second leading cause of cancer death in American women,
following lung cancer, and the leading cause of death among women aged 40 to 55
years (Parker et al., 1997).
Risk factors associated with breast cancer have been widely examined in non-
Hispanic white women. Little is available among minority populations in US. The
Hispanic population is rapidly growing and estimated to exceed 20 million by the
year 2030 (Ramirez et al., 1995). There are pronounced temporal trends in breast
cancer occurrence among Hispanic women, with consistent increases in the
incidence (56% over 19 years) and the mortality (nearly 86% over 30 years)
(Eidson et al., 1994). Thus, an understanding of the etiologic factors of breast
cancer among Hispanic group is important for decision-making of medical
management of this disease in this minority population in US.
New Mexico Women Health Study (NMWHS) provided us opportunities to
examine the risk factors for breast cancer in both Hispanic and non-Hispanic
women. There are two central objectives in this thesis: 1) To determine whether
there is ethnic-specific difference in the association between family history of
2
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breast cancer and risk of this disease in Hispanic and non-Hispanic white women;
2) To investigate whether there is an increased risk associated with Hormone
replacement therapy in Hispanic and non-Hispanic white women. In the following,
simple statistics, established or potential risk factors of breast cancer are first
introduced in Chapter 1. In Chapter 2 and Chapter 3, the relationship between
positive family history, hormone replacement therapy and breast cancer risk are
described respectively in detail. Furthermore, the results and conclusions drawn
from them are also discussed. Finally, possible genetic and environmental causes of
breast cancer are summarized and potential prevention strategies are discussed in
Chapter 4.
1.1 Demographic Risk Factors
The number of new cases of and deaths from breast cancer has increased sharply
over the past 25 years. Froml970 to 1997, breast cancer cases were increased by
nearly 161% and deaths increased by nearly 50% (Parker et al., 1997; Silverberg
and Grant, 1970). These changes are in large part due to an increase in the size of
the female population, in particular the population of older women (Sondik, 1994).
Breast cancer is extremely rare among women younger than age 2Q and is
uncommon among women younger than age 30. Incidence increases sharply after
age 30, however, and become substantial before age 50. During 1991 to 1995,
3
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the incidence of breast cancer among American women aged 30 to 34 years was 25
per 100,000, increased to 200 per 100,000 among women age 45 to 49 years and
raised to 463 per 100,000 among women aged 70 to 74 years (Statistics, 1998). The
rate of increase in breast cancer incidence continues throughout life but slows down
between ages 45 and 50 years (Pike et al., 1993). This finding strongly suggests
that the involvement of reproductive hormones in breast cancer etiology, given the
fact that non-hormone-dependent cancers do not exhibit this change in slope of the
incidence curve around the time of menopause.
Furthermore, breast cancer incidence varies among racial and ethnic groups in the
US. In comparison with non-Hispanic whites, lower incidence rates have been
reported for Blacks, Asian, American Indians, and Hispanics (Kelsey and Hom-
Ross, 1993). A consistent pattern was present for both incidence and mortality
rates; American Indians had the lowest rates and non-Hispanic whites the highest,
with Hispanics having intermediates rates (Kelsey and Hom-Ross, 1993). Unlike
most other common cancers, breast cancer incidence is higher among women of
upper rather than lower social class. This association is largely explained by the
known reproductive risk factors. Women in lower socioeconomic strata are more
likely to have more children and to have them at younger age than women in higher
socioeconomic strata (Heck and Pamuk, 1997).
4
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1.2 Reproductive Risk Factors
It is well known that hormones influence risk and prognosis of breast cancer.
Estrogen induces some beast epithelial cell proliferation (Pike et al., 1993).
Proliferating cell populations are more susceptible to carcinogenic effects
(Butterworth, 1991), and further result in an increase in cancer risk. Thus, breast
cancer risk would be predicted to be higher during periods of estrogen exposure, as
in the premenopausal period, or in women receiving hormonal replacement therapy,
as in postmenopausal women. Epidemiological research has clearly identified
important reproductive risk factors, which include early age at menarche, late age at
natural menopause, late age at full-term birth and nulliparity.
1.2.1 Age at menarche
Early age at menarche has been demonstrated as a risk factor for breast cancer in
many case-control studies. An approximately 15% decrease in breast cancer risk
results from each year that menarche is delayed (Pike et al., 1983). Women with
early menarche and rapid establishment menarche cycles had an almost fourfold
increased risk of breast cancer when compared with women with late menarche and
long duration of irregular cycles (Henderson et al., 1985). However, the findings of
NMWHS indicated age at menarche was not significantly associated with risk of
breast cancer in both Hispanic and non-Hispanic women (Gilliland et al., 1998a).
5
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1.2.2 Pregnancy and age at first full-term births
In the majority of epidemiological studies, a younger age at first-full-term birth
predicts lower lifetime risk of breast cancer. Women who have a late first full-term
birth (after age 30) have a greater breast cancer risk than nulliparous women.
Furthermore, nulliparous women have a greater breast cancer risk than parous
women (before age 30) (Kelsey et al., 1993). In NMWHS, older age at first full-
term birth appeared to be a stronger risk factor in Hispanic women (OR for age >26
years at FTB = 2.26, 95% Cl, 1.17-4.38, compared to age <19 years at FTB), but
not significant in non-Hispanic women (Gilliland et al., 1998a).
1.2.3 Lactation
Epidemiological studies relating breast cancer risk to breast-feeding patterns have
not drawn clear conclusion. The overall evidence from case control and cohort
studies supports a reduction in risk with longer duration of breast-feeding, but the
findings have varied substantially in the level of risk reduction (Michels et al.,
1996; Russo and Russo, 1995). From NMWHS, the effect of lactation varied by
menopause status as well as ethnicity. Among Hispanic women, no overall
association was found between breast-feeding and breast cancer risk except for
women who had lactated for more than 12 months. A protective association has
also been found in non-Hispanic white women (Gilliland et al., 1998a).
6
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1.2.4 Abortions
In early pregnancy, the number of undifferentiated cells increases as rapid growth
of the breast epithelium occurs. If the pregnancy continues, these cells differentiate
and the number of cells susceptible to malignancy decreases. The interruption of
the differentiation of breast cells as a result of spontaneous and induced abortions
had been hypothesized to increase a women’s risk of developing breast cancer
(Krieger, 1989). This hypothesis appears to be supported by case control studies
and meta-analyses (Brind et al.^ 1996). In NMWHS, an increased risk associated
with an induced abortion after a first birth was shown for all premenopausal women
or for postmenopausal Hispanic women (Gilliland et al., 1998a).
1.2.5 Age at menopause
The rate of increase in the age-specific incidence rate of breast cancer slows
markedly at the time of menopause. It has been estimated that women who
experience natural menopause before age 45 have only one-half the breast cancer
risk of those whose menopause occurs after age 55 (Trichopoulos et al., 1972). The
reduction in risk of breast cancer with early menopause is probably due to the
cessation of breast cell division with the termination of menstrual cycles. However,
there were no clear indications of the effect of age at menopause on breast cancer
risk in NMWHS (Gilliland et al., 1998a).
7
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1.3 Lifestyle Risk Factors
In addition to reproductive risk factors described previously, epidemiological
studies have also identified a number of lifestyle factors that may influence breast
cancer risk.
1.3.1 Smoking
Smoking has been reported both to increase and decrease risk of breast cancer. The
decrease has been suggested to be due to the reduced serum and urinary estrogen
found in smokers (Michnovicz et al., 1988). Studies showing an increased risk
attribute this effect to the numerous carcinogens in cigarette smoke (Ambrosone et
al., 1995). The association of smoking and breast cancer in New Mexico women
has not been investigated and might be examined in the future.
1.3.2 Alcohol
Although the association between alcohol consumption and breast cancer risk has
been controversial, substantial evidence has accumulated to support the existence
of a positive association. A recent meta-analysis indicated that consumption of 3
drinks per day increased risk by about 50 percent relative to nondrinkers (Smith-
Wamer et al., 1998). Increase in plasma oestrone and oestradiol induced by alcohol
may be responsible for this increase. In NMWHS, the effect of alcohol intake was
8
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inconsistent. A reduced risk was indicated for low and moderate drinkers among
non-Hispanic women. But there was also a suggestion of an increased risk for
strong drinkers among postmenopausal women in both ethnic groups (Baumgartner
KB, unpublished data).
1.3.3 Physical activity
Regular physical activity has been hypothesized to prevent breast cancer, largely by
reducing circulating levels of sex hormones. The mechanisms by which physical
activity reduces exposure to hormones vary by period of life. Despite the evidence
that higher levels of physical activity are associated with lower levels of circulating
ovarian hormones, epidemiological studies relating physical activity to risk of
breast cancer show inconsistent results (Bernstein et al., 1994). These
inconsistencies are likely to be attributed to methodological differences in physical
activity assessment. Studies have differed in the ages at which physical activity was
assessed; methods for measuring intensity, frequency, and duration of physical
activity. In NMWHS, a strong protective effect of physical activity has been
suggested in both Hispanic and non-Hispanic women. About 30% of reduction in
breast cancer risk was associated with high-energy expenditure during leisure time
physical activity (Gilliland FD, Li YF et al., unpublished data, 2000).
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1.3.4 Body weight
Most evidence shows that body weight (BMI, calculated as weight in kilograms
divided by the square of height in meters, to account for variation in height) during
the postmenopausal years increases beast cancer risk, but obesity during the
premenopausal years actually reduces risk (Hunter and Willett, 1993). This inverse
relationship can be explained in terms of the differential effects of pre- and
postmenopausal obesity on endogenous hormone levels. Using the data from
NMWHS, for premenopausal women, there was little or no increased risk
associated with increased weight; but for postmenopausal women, a 14 kg
increment in weight change since age 18 resulted in a significant increase in breast
cancer risk (OR =2.27, 95% Cl, 1.09-4.73). The risk was more apparent in non-
Hispanic white women. Among Hispanic women, an increased risk of breast
cancer, though not significant, was consistently associated with any level of weight
change more than 4kg since age 18 (Wenten M and Gilliland FD, unpublished data,
2000).
1.4 Genetic Susceptibility
A family history of breast cancer increases the likelihood of breast cancer
development. This may be attributable to genetic and environmental similarities
among family members. Overall, about 10% of breast cancer is attributable to
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family history, and about half of this is attributable to dominantly inherited
susceptibility genes (Easton et al., 1993a; Ford and Easton, 1995; Greene, 1997;
Hulka and Stark, 1995). In general, breast cancer risk is two or three times higher
for women with an affected first-degree relative, and less than twice as high with an
affected second-degree relative. Risks are further increased if two first-degree
relatives are affected, or if the relative was diagnosed of cancer before age 40-45
(Pharoah et al., 1997). The investigation of the association between family history
and breast cancer risk using data from NMWHS are extensively described in
Chapter 2.
1.5 Postmenopausal Hormone Use
A substantial body of experimental, clinical, and epidemiological evidence
indicates that hormones play a major role in the etiology of breast cancer
(Henderson et al., 1988). The known risk factors for breast cancer can be
understood as measures of the cumulative exposure of the breast to estrogen and,
perhaps, progesterone. There is evidence that long-term use of exogenous
estrogens, given as hormone replacement therapy to postmenopausal women,
increases the risk of breast cancer (1997). Furthermore, the addition of
progesterone to estrogen treatment has become increasingly common, because it
minimizes or eliminates the increased risk of endometrial cancer associated with
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the estrogen use. The effect of combined estrogen and progesterone hormone
replacement therapy on breast cancer risk has been the subject of numerous
epidemiological studies. However, data concerning long-term effect of such
combined replacement therapy are limited and inconclusive. We examined the data
from NMWHS to determine the effect of estrogen use (ERT) or combined
estrogen-progesterone use (CHRT) on breast cancer risk in both Hispanic and non-
Hispanic white women. More details are discussed in Chapter 3.
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CHAPTER 2
FAMILY HISTORY AND BREAST CANCER RISK
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It is well recognized that a family history of breast cancer is associated with an
increased risk for the disease. About 10% of breast cancers are attributable to
family history (Easton et al., 1993a; Ford and Easton, 1995; Greene, 1997; Hulka
and Stark, 1995). The precise magnitude of breast cancer risk associated with
family history depends on a number of factors including the nature of the family
history (such as number and type of affected relatives, and age of onset of breast
cancer in the relatives) and the age at diagnosis of the case patient. A recent meta
analysis has shown that having a first-degree relative with breast cancer
approximately doubles the risk of this disease. The risk is further elevated if both
the mother and sister have had breast cancer or when the mother or sister was
diagnosed at a young age (Pharoah et al., 1997).
The impact of family history on breast cancer risk may be due to the fact that
relatives tend to have similar genetic susceptibility or are exposed to the same
environmental risk factors. Two dominantly inherited genes, BRCA1 and BRCA2,
have been identified and contribute to early onset breast cancer (Ford et al., 1998;
Miki et al., 1994; Wooster et al., 1995). Moreover, some studies have suggested
that the type or proportion of mutations in BRCA1 or BRCA2 differ by ethnic
groups (Sellers et al., 1999). Such mutations may account for more than 10% of
breast cancer risk with family history among Ashkenazi Jews (Warner et al., 1999).
14
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But in other populations, these mutations only account for less than 3% of early
onset cases (Peto et al., 1999). Additionally, some studies found that a large
fraction of families with fewer cases of breast cancer was due to mutations in other
genes (Eeles et al., 1994; Schubert et al., 1997; Serova et al., 1997). Based on the
emerging evidence, it is clear that inheritance of polymorphic or mutated alleles at
different loci may strongly influence breast cancer risks; however, their
contribution to ethnic variation in breast cancer risk is yet to be determined. Until
the role of a potentially large number of polymorphic or mutated alleles has been
clarified, family history of breast cancer will continue to be a useful surrogate
measure of the contribution of genetic factors to breast cancer occurrence.
Although familial breast cancer has been extensively studied in a few ethnic
groups, little information is available for Hispanic women, a large and growing
population in the US. The few reported studies present inconsistent findings about
the effect of family history on breast cancer risk in Hispanic women (Bondy et al.,
1992; Buchanan etal., 1985; Mayberry and Branch, 1994). First, Buchanan et al
reported higher incidence of familial breast cancer among Mexican Americans in
Laredo, Texas (Buchanan et al., 1985). Second, the findings of Bondy et al
suggested a lower familial risk of breast cancer in Hispanics than in whites and
blacks (Bondy et al., 1992). Third, the Cancer and Steroid Hormone (CASH) study
1 5
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indicated an increased risk among Hispanic women with breast cancer in their first-
degree relative (Mayberry and Branch, 1994). Further data on this issue are
important for genetic counseling and clinical management of the breast cancer
families in this minority population. The New Mexico Women’s Health Study
(NMWHS) provided the opportunity to evaluate the relation between positive
family history and breast cancer risk in both Hispanic and non-Hispanic women.
The primary focus of this report is an examination of patterns of familial risk
among Hispanic women. We investigated whether Hispanic women with a family
history of breast cancer are at excess risk of breast cancer and compared the risk
estimates between Hispanic and non-Hispanic women using the data collected from
this population-based case-control study.
2.1 Materials and Methods
The New Mexico Women's Health Study is a statewide population-based case-
control study ofbreast cancer in Hispanic and non-Hispanic white women. Women
newly diagnosed with an invasive or in situ breast carcinoma during the period of
January 1, 1992 through December 31, 1994 who were residents of the state and
between 30-74 years of age at diagnosis were eligible for the study.
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2.1.1 Identification o f cases and controls
The general design of this investigation has been previously described (Gilliland et
ah, 1998a). Women with new primary breast cancer were ascertained by the New
Mexico Tumor Registry (NMTR), a population-based tumor registry and a member
of the Surveillance, Epidemiology and End Results (SEER) Program of the
National Cancer Institute (Hankey et al., 1999). All Hispanic cases were eligible
for the study. Approximately 33% of non-Hispanic white cases were randomly
selected to match on the age groups and geographic distribution of Hispanic cases
ascertained by the NMTR in the three-year period from 1988 through 1990. A total
of 491 eligible Hispanic breast cancer cases was ascertained. The stratified random
selection of non-Hispanic white women resulted in ascertainment of 493 cases.
Population-based controls (frequency-matched for ethnicity, the three age groups
(30-39,40-64, 65-74 years), and the seven health planning districts) were selected
by a modified random-digit dialing method (Waksberg, 1978).
2.1.2 Data collection
In-person interviews were conducted at a location of the participant's choice.
Written informed consent was obtained at the onset of the interview. All
questionnaires were translated into Spanish and interviews were conducted in
Spanish or English according to the participant's preference.
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Eligible women were classified into three risk groups based on their responses to
family history of breast cancer. "First-degree relative with breast cancer" was
defined as having a mother, daughters or sisters diagnosed with breast cancer.
There were 193 (12.4%) women who were classified into this category. "Second-
degree relative with breast cancer" was defined as having grandmothers or aunts
affected with breast cancer. There were 213 (13.7%) women who were classified
into this category. "Positive family history of breast cancer" was defined as having
either first- or second-degree family member with breast cancer. There were 360
(23.1%) women who were classified into this group.
2.1.3 Statistical analysis
Conditional logistic regression which conditioned on the frequency-matched
variables (age groups, geographic district, and ethnicity) was used to compute odds
ratios and 95 % Cl's (SAS Institute Inc, 1996). We selected potential confounding
variables based on review of the literature, univariate analyses, and change of the
effect estimates by 10% or more in multivariate analyses. The odds ratios for
positive family history with breast cancer were adjusted for known or suggested
risk factors for breast cancer, including age within age strata and the following
covariates: parity (nulliparous, 1, 2, 3, and >4 births), age at first full-term birth
(nulliparous, 18,19-20,21-22, 23-26 and >27 years), age at menarche (<13,13,
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and >14 years), education (<12, 12, 13-15 and >16 years), cumulative months of
lactation (nulliparous, parous but never breastfed, 1-12 and >12 months), physical
activity estimated by MET values (0-24, 25-49 and >50 METs/week), gain of body-
mass index (BMI) since age 18 (<1.32, 1.32-2.92, 2.92-5.31, and >5.31 kg/m2 ),
estrogen use alone (never used, <48 and >48 months). Analyses were also
conducted separately to compare the ORs according to two age groups (50 or >50
years) and menopausal status. Menopausal status was classified as premenopausal,
postmenopausal (natural or surgical) and unknown menopausal as described in a
previous report (Gilliland et al., 1998a). To assess differences in risk for Hispanics
and non-Hispanic whites, analyses were stratified by ethnicity with models
conditioned on age groups and geographic districts.
We excluded from the analyses the subjects with missing or unavailable data on
age at first full-term birth (n=5), education (n=4), cumulative months of lactation
(n=5), age at menarche (n=6), physical activity (n=5), gain of body-mass index
(BMI) since age 18 (n=27), estrogen use (n=9). Thus, the final model comprised
696 cases and 821 controls.
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2.2 Results
In this study, a total of 712 breast cancer cases and 844 frequency-matched
population-based controls were interviewed. Family background of breast cancer
appeared relatively common as approximately 27% of cases and 20% of controls
identified as having at least one first- or second-degree relative with breast cancer.
Selected characteristics of cases and controls stratified by ethnicity are provided in
Table 2.1. Compared to non-Hispanic white women, Hispanic women were
younger at their first full-term birth, had less education, a higher parity, less
frequent use of estrogen, and greater gain in body weight since the age of 18. In
addition, Hispanics cases reported a lower level of total physical activity than
controls. Patterns of breast cancer risk differed by ethnicity. Parity, education, and
change in body mass index were associated with breast cancer among Hispanic but
not among non-Hispanic women. Total physical activity was a protective factor for
non-Hispanic white and Hispanic women.
A family history of breast cancer was more common in cases than controls (Table
2.2). Fifteen percentage of case patients (103) and 10.7% of control subjects (90)
had at least one affected first-degree relatives with breast cancer, and 16.2% (115)
versus 11.6% (98) had at least one affected second-degree relatives.
20
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Table 2.1 Distribution, odds ratios (OR) and 95% confidence intervals (Cl) for
selected demographic characteristics and breast cancer risk factors, NMWHS,
1992-1994*
Hispanic Non-Hispanic
Risk Factor Cases Controls Cases Controls
(n=332) (n=388) OR 95% Cl (n=380) (n=456) OR 95% Cl
Education (years)
12- 104 86 1.00 24 29 1.00
12 130 150 0.69 0.46-1.01 102 111 1.13 0.61-2.09
13-15 61 88 0.50 0.31-0.80 107 123 1.09 0.59-2.02
16+ 35 64 0.41 0.24-0.70 146 192 0.95 0.52-1.74
A ge (years) at menarche
<13 133 170 1.00 185 211 1.00
13 101 109 1.23 0.85-1.76 111 140 0.90 0.65-1.25
14+ 95 108 1.14 0.78-1.65 84 103 0.87 0.61-1.25
A ge (years) at first full-term birth
18- 71 89 0.65 0.36-1.17 43 67 0.77 0.45-1.31
19-20 71 94 0.66 0.37-1.19 58 73 0.89 0.54-1.47
21-22 50 64 0.68 0.37-1.26 59 64 1.01 0.61-1.68
23-26 . 62 68 0.74 0.40-1.36 82 94 1.03 0.65-1.65
27+ 39 42 0.80 0.41-1.56 76 84 1.20 0.74-1.93
nulliparous 38 30 1.00 60 73 1.00
Number o f full-term births
nulliparous 38 30 1.00 60 73 1.00
1 29 35 0.68 0.33-1.38 63 58 1.43 0.86-2.38
2 66 98 0.54 0.30-0.96 128 138 ‘ 1.18 0.76-1.82
3 80 72 0.98 0.54-1.77 66 101 0.71 0.44-1.15
4+ 119 153 0.69 0.39-1.21 63 86 0.75 0.46-1.24
Cumulative months o f lactation
nulliparous 38 30 1.00 60 73 1.00
parous, never 133 145 0.77 0.44-1.34 110 125 1.04 0.66-1.62
parous, 1-12 109 128 0.72 0.41-1.26 167 157 1.29 0.85-1.96
parous, 12+ 52 82 0.53 0.29-0.97 43 99 0.55 0.33-0.92
Estrogen use (months)
never used 220 225 1.00 179 243 1.00
48- 64 87 0.74 0.50-1.10 85 98 0.94 0.65-1.37
48+ 48 76 0.66 0.42-1.03 116 115 1.00 0.68-1.45
2 1
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Table 2.1 (con tinued)
Risk Factor
Hispanic Non-Hispanic
Cases Controls
(n=332) (n=388) OR 95% Cl
Cases Controls
(n=380) (n=456) OR 95% Cl
Total physical activity
(METS/week)
0-24 100 63 1.00 99 96 1.00
25-49 116 114 0.69 0.45-1.05 110 138 0.79 0.54-1.16
50+ 115 210 0.35 0.23-0.52 169 221 0.77 0.54-1.10
Gain of body mass index (kg/mJ )
1.32- 38 72 1.00 124 146 1.00
1.32-2.92 77 86 1.77 1.06-2.96 97 126 0.88 0.61-1.27
2.92-5.31 78 107 1.37 0.83-2.26 85 99 0.91 0.62-1.34
5.31+ 127 116 2.20 1.35-3.58 71 80 0.96 0.63-1.44
* Numbers may not sum to total for all covariates because o f missing data.
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Women with a family history of breast cancer had a significant increase in breast
cancer risk in all women, Hispanics and non-Hispanic white women. For both
Hispanic and non-Hispanic women, an elevated, though not statistically significant,
risk of breast cancer was observed among those with at least one affected first-
degree relative. Hispanic women who had a second-degree relative with breast
cancer were two-fold more likely to be diagnosed with breast cancer than those
without family history of breast cancer in second-degree relative. We next
compared the ORs of breast cancer with positive family history in women within
younger and older age groups (Table 2.3). A trend toward lower risk in the older
age group was observed in both Hispanic and non-Hispanic women. But the
differences were not statistically significant. The effects of a family history of
breast cancer were larger among premenopausal than postmenopausal women
(Table 2.3).
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Table 2.2 Univariate Odds Ratios (ORs) and multivariate adjusted ORs and 95% confidence interval
(95% Cl) of breast cancer in relation to first- or second-degree family history (FH) of breast cancer,
NMWHS, 1992-1994
A ll Hispanic non-Hispanic
R isk Factor case control
(n=712) (n=844)
N N OR 95%CI
case control
(n=332) (n=388)
N N OR 95%CI
case control
(n=380) (n=456)
N N OR 95%CI
first-degree relatives with breast cancer
N o 609 754 LOO 292 352 1.00 317 402 1.00
Yes 103 90 1.36 1.00-1.86 40 36 1.30 0.80-2.12 63 54 1.46 0.98-2.18
adjusted OR and 95% Cl* 1.32 0.96-1.82 1.41 0.84-2.36 1.35 0.89-2.06
second-degree relatives with breast:cancer
N o 597 746 1.00 289 353 1.00 308 393 1.00
Y es 115 98 1.54 1.14-2.07 43 35 1.63 1.00-2.65 72 63 1.50 1.02-2.19
adjusted OR and 95% Cl* 1.59 1.17-2.16 1.99 1.18-3.36 1.45 0.97-2.15
positive family history with breast cancer**
N o 522 674 1.00 257 320 1.00 265 354 1.00
Yes 190 170 1.45 1.14-1.85 75 68 1.41 0.97-2.05 115 112 1.51 1.10-2.07
adjusted OR and 95% Cl* 1.48 1.15-1.90 1.65 1.11-2.48 1.42 1.02-1.99
* Conditional logistic regression models matched for age-group, and health planning district and adjusted for age at first
full-term birth, parity, cumulative months o f lactation, education, estrogen use, physical activity, change in body mass index
** Reported positive family history o f breast cancer in first- or second-degree relatives
K >
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Table 2.3 Mutually adjusted Odds Ratios (ORs) and 95% confidence interval (95% Cl) of breast cancer in
relation to family history (FH) of breast cancer stratified by age groups or menopausal status, NMWHS,
1992-1994
Age___________________ M enopausal Status*
Risk Factor < 5 0
OR** 95% Cl
>50
OR** 95% Cl
Premenopausal
OR** 95% Cl
Postmenopausal
OR** 95% Cl
AM
No. n=661 n=895 n=554 n=765
positive family history with breast
N o 1.00
cancer ***
1.00 1.00 1.00
Y es 1.65 1.11-2.45 1.57 1.12-2.21 1.96 1.26-3.06 1.56 1.08-2.25
Hispanic
N o. n=326 n=394 n=268 n=324
positive family history with breast
N o 1.00
cancer ***
1.00 1.00 1.00
Yes 1.82 0.98-3.36 1.55 0.88-2.75 2.20 1.07-4.51 2.08 1.09-3.97
non-Hispanic
No. n=335 n=501 n=286 n=441
positive family history with breast cancer ***
N o 1.00 1.00 1.00 1.00
Yes 1.72 0.99-3.01 1.54 0.99-2.40 2.11 1.11-3.88 1.44 0.90-2.31
* The sum does not add up to the total because o f some missing values or unavailable information in menopausal status.
** Conditional logistic regression models matched for age-group, and health planning district and adjusted (when applicable)
for age at first full-term birth, parity, cumulative months o f lactation, education, estrogen use, physical activity, change in body
mass index
*** Reported positive family history o f breast cancer in first- or second-degree relatives
K >
2.3 Discussion
In this statewide population-based study, we observed an increased risk of breast
cancer in both Hispanic and non-Hispanic white women with a positive family
history of breast cancer. The association of family history with breast cancer was
more evident in premenopausal women. There were no clear indications that the
risk estimates were different for Hispanic and non-Hispanic women. Our results are
broadly consistent with the extensive body of evidence that breast cancer risk
increases in women with a family history of breast cancer (Andrieu et al., 1993;
Byrne et al., 1991; Colditz et ah, 1993; Eerola et al., 2000; Egan et al., 1998;
Ghadirian et al., 1998; Hirose et al., 1997; Lippert et al., 1999; Lynch et al., 1988;
Magnusson et al., 1998; Roseman et al., 1990; Sattin et al., 1985; Slattery and
Kerber, 1993).
Studies investigating ethnic variation in the risk associated with a family history of
breast cancer among Hispanic and non-Hispanic whites have been inconsistent. In a
study of Mexican-American women in Laredo, Texas, the risk of familial breast
cancer was reported to be higher in Hispanics than other ethnic groups (Buchanan
et al., 1985). In contrast, Bondy et al found that the standardized incidence ratios
(SIR) for familial breast cancer appeared to be much lower among Hispanic
patients than Whites and Blacks (Bondy et a l, 1992). The findings of a CASH
26
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study suggested Hispanic women with breast cancer in first-degree relative were
nearly twice as likely to be diagnosed as breast cancer compared to women with no
family history (Mayberry and Branch, 1994). Our findings support the hypothesis
Hispanic women with a family history of breast cancer are at increased risk of
breast cancer.
Family history can be related to genetic or environmental factors. Both may
contribute to the observed elevated risk. Our analysis also revealed difference in
risk associated with family history that seemed to be more marked between pre-
and postmenopausal women among non-Hispanic whites than among Hispanics.
This raises the possibility that these risk patterns may be attributed to genetic
variation among different populations. Two dominant genes that contribute to the
association of family history with breast cancer have been widely studied are
BRCA1 and BRCA2. Mutations in the identified susceptibility genes BRCA1 and
BRCA2 are rare in the general population (Ford and Easton, 1995) and may be
responsible for the early-onset of breast cancer or high-risk breast cancer families
(Peto et al., 1999). The extent to which the familial risks estimated in our study can
be explained by these genes remains unclear. Sequencing analysis ofBRCAl and
BRCA2 mutations are required to address it. In a study of 53 young Hispanic
women with a family history of breast cancer, Gillespie and Griffith found no
27
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classical truncation mutations in BRCA1, suggesting that BRCA1 is not an
important determinant of familial risks in this population. The role of BRCA2 and
other susceptibility genes, have not been examined in this population (Gillespie DL
and Griffith JK, unpublished data, 2000).
Strengths of this study include a population-based design, large sample size, and
detailed information on potential risk factors for breast cancer. But the retrospective
design raises concerns of recall bias of family history among cases and controls.
Cases of breast cancer may be more likely to remember a positive family history
than control subjects. Some studies have considered reports in first-degree relatives
to be more reliable than those in second-degree relatives (Love et al., 1985; Parent
et al., 1995). Therefore, the effect of family history in second-degree relative on
breast cancer risk may be inflated. We lack data to directly assess the magnitude of
this potential bias. We had no data regarding age at diagnosis of the relatives with
breast cancer, so we were unable to assess the risk of breast cancer in relation to the
women with early onset in a relative.
In conclusion, an increased risk associated with positive family history of the
disease was found in both Hispanic and non-Hispanic women. The risk estimates
were not significantly different between these two ethnic groups. This implies that
28
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Hispanic women with positive family history of breast cancer should also be urged
to adhere to recommendations for breast cancer surveillance through more frequent
clinical breast examinations.
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CHAPTER 3
HORMONE REPLACEMENT THERAPY AND BREAST
CANCER
30
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The use of estrogen and estrogen-progesterone combinations for hormone
replacement therapy (HRT) is becoming increasingly common, mainly for the
alleviation of menopausal symptoms (Couzi et a l, 1995) and prevention of
osteoporosis (Gambrell, 1991; Glowacki, 1991; Lufkin and Ory, 1989;
Thomeycroft, 1989). Although evidence for efficacy has yet to be clearly
established, HRT is also used for long-term prevention of coronary heart disease
(King, 1996; Stampfer and Colditz, 1991; Umland et al., 1999). Women and their
physicians need information concerning the risks associated with HRT use as well
as the substantial benefits of HRT use for informed decision-making. There is
concern that HRT, either with estrogens alone or when combined with
progesterone, may have adverse effects on breast cancer risk. In a large
collaborative meta-analysis of the effect of HRT on breast cancer risk, it was
concluded that risks increased with duration of use (1997). Furthermore, two recent
studies suggested that combined estrogen-progesterone treatment was associated
with greater increase in breast cancer risk than estrogen alone (Persson et al., 1999;
Schairer et al., 2000).
The Hispanic population in the U.S. is rapidly growing and is expected to become
the largest minority population by the year 2030 (Ramirez et al., 1995). Although
breast cancer is the most common cancer and a leading cause of cancer mortality
31
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among Hispanic women, and the relationship between HRT and breast cancer has
been investigated extensively, little information on the adverse effects of HRT
among Hispanic women is available (Becker et al., 1993; Eidson et al., 1994;
Miller et al., 1996; Trapido et al., 1995).
The New Mexico Women’s Health Study (NMWHS), a population-based case
control study, offered the opportunity to investigate the effect of HRT on breast
cancer risk in both Hispanic and non-Hispanic white women. We examined data on
HRT use among Hispanic and non-Hispanic white postmenopausal participants
from this study and estimated the relative risk associated with duration of use of
estrogen and progesterone.
3.1 Materials and Methods
The New Mexico Women's Health Study is a statewide population-based case-
control study o f breast cancer in Hispanic and non-Hispanic white women. Women
newly diagnosed with an invasive or in situ breast carcinoma during the period
January 1, 1992 through December 31, 1994 who were residents of the state and
between 30-74 years of age at diagnosis were eligible for the study. This study was
restricted to postmenopausal women (natural or surgical) or women older than 54
years with unknown menopausal status.
32
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3.1.1 Identification o f case subjects
Women with new primary breast cancer were ascertained by the New Mexico
Tumor Registry (NMTR), a population-based tumor registry and a member of the
Surveillance, Epidemiology and End Results (SEER) Program of the National
Cancer Institute (Hankey et al., 1999). All Hispanic cases were eligible for the
study. Because the overall expected number of breast cancer cases for the study
period was approximately three times higher for non-Hispanic whites than for
Hispanics, we randomly selected approximately 33% of non-Hispanic white cases
while including all Hispanic cases to maximize our power to examine ethnic
differences in risk with the available sample size. The sampling strata for non-
Hispanic white cases were age group (30-39, 40-64, 65-74 years) and geographic
region defined by seven state health-planning districts. The sampling fraction for
non-Hispanic whites in each of these 21 strata was chosen to give a distribution
similar to the age and geographic distribution of Hispanic cases ascertained by the
NMTR in the three-year period 1988 through 1990. A total of 491 eligible Hispanic
breast cancer cases was ascertained. The stratified random selection of non-
Hispanic white women resulted in ascertainment of 493 cases. Of the cases that
completed interviews, 149 Hispanics and 217 non-Hispanic whites were
postmenopausal and therefore eligible for the analysis.
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3.1.2 Identification o f controls
Controls were ascertained using random-digit dialing with frequency matching on
ethnicity, the three age groups, and the seven health planning districts. We used a
modified approach to the Waksberg random-digit dialing method (Waksberg, 1978)
that has been described previously (Gilliland et al., 1998a). There were a total of
1,039 eligible controls ascertained from approximately 3,400 respondents who
completed the telephone-screening interview including 511 Hispanic and 528 non-
Hispanic white women. Of those eligible controls, 178 Hispanic and 225 non-
Hispanic white postmenopausal women were available for the analysis.
3.1.3 Data collection
In-person interviews were conducted at a location of the participant's choice.
Written informed consent was obtained at the onset of the interview. Information
was collected on the following items: demographic characteristics, reproductive
and menstrual history, use of oral contraceptives (OC) and exogenous hormones,
family history of breast disease, personal history of breast disease covering all
surgeries, medical and screening history, radiation, body size, cigarette smoking,
history of alcohol consumption, dietary intake, education, income, physical
activity, pesticide and herbicide exposure, and acculturation factors. All
questionnaires were translated into Spanish and interviews were conducted in
Spanish or English according to the participant's preference.
34
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Menopausal status was classified as premenopausal, natural postmenopausal,
surgical postmenopausal and unknown menopausal status. The classification
criteria of menopausal status have already been described in a previous report
(Gilliland et al., 1998a). Only postmenopausal women were included in the
analysis. Women with unknown menopausal status were also considered, if they
had reached the age of natural menopause of 90% of the participants (54 years).
The women with missing menopausal status were excluded. Thus, the final study
group consisted of 366 cases and 403 controls.
The main effects of different hormone treatments were considered separately on the
risk of breast cancer. Hormone replacement therapy was assessed by cumulative
number of months of estrogen use or estrogen plus progesterone use. Use of
estrogen alone was classified as estrogen replacement therapy (ERT). Simultaneous
use of estrogen and progesterone was defined as combined hormone replacement
therapy (CHRT). Total use of estrogen was also used to examine the overall effects
of hormone replacement therapy on the risk of breast cancer in both Hispanic and
non-Hispanic groups. Duration of estrogen use was categorized as never used, less
than 17 months, 17 to 60 months, 60 to 140 months, and longer than 140 months.
Use of progesterone was categorized as never used any hormone, or as use less than
12 months, 12-41 months, 41 to 72 months and longer than 72 months.
35
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The odds ratios of hormone use were adjusted for known or suggested risk factors
for breast cancer, including age within age strata and the following covariates:
parity (nulliparous, 1, 2, 3, and 4 births), age at first full-term birth (nulliparous,
18,19-20,21-22, 23-26 and 27 years), age at menarche (<13,13, and 14 years),
education (<12, 12, 13-15 and 16 years), income status (<10k, 10-20k, 20-3Ok,
30-40k, and >40k), cumulative months of lactation (nulliparous, parous but never
breastfed, 1-12 and >12 months), smoking coded as yes or no, physical activity
estimated by MET values (0-24, 25-49 and 50 METs/week), difference of body-
mass index (BMI) between usual BMI and BMI at age 18 (<1.37, 1.37-3.13, 3.13-
5.67, and >5.67 kg/m2 ).
3.1.4 Statistical analysis
Conditional logistic regression which conditioned on the frequency-matched
variables (age groups, geographic district, and ethnicity) was used to compute odds
ratios and 95 % Cl's. Multivariate odds ratios from conditional logistic regression
models (SAS Institute Inc, 1996) were used to estimate the individual effects of
total use of estrogen, use of estrogen alone, or combined use of estrogen plus
progesterone adjusted for reproductive and non-reproductive factors (Breslow and
Day, 1980). We selected potential confounding variables based on review of the
literature, univariate analyses, and change of the effect estimates by 10% or more in
36
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multivariate analyses. To assess differences in risk for Hispanics and non-Hispanic
whites, analyses were stratified by ethnicity with models conditioned on age groups
and geographic districts. Tests for trend with duration of use of hormone
replacement were computed by assigning consecutive median values to levels of
the duration categories (excluding never-users). The likelihood-ratio test,
comparing models with and without interaction terms, was used to test for
interactions.
Estrogen use was unknown for one women. Progesterone use was not available for
one woman. Women who had missing data for income (n=43), education (n=5), age
at menarche (n=4), age at first full-term birth (n=2), cumulative months of lactation
(n=3), and physical activity (n=2) were also excluded from all models that included
these factors. The final model included 340 cases and 376 controls; and 137 cases
and 169 controls for Hispanic group and 203 cases and 207 controls for non-
Hispanic group.
3.2 Results
Selected demographic characteristics of cases and controls stratified by ethnicity
are presented in Table 3.1. For both ethnic groups, earlier age at first full-term
births, greater gain in body weight since the age of 18, and more frequent smoking
37
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Table 3.1 Distribution, odds ratios (OR) and 95% confidence intervals (GI) for
selected demographic characteristics and postmenopausal breast cancer risk factors,
NMWHS, 1992-1994*
H i s p a n i c __________________ Non-Hispanic
Risk Factor Cases Controls Cases Controls
(n=149) (n=178) OR 95% Cl
p «
(n=217) (n=225) OR 95% Cl P**
Education (years)
12- 70 50 1.00 23 20 1.00
12 47 75 0.45 0.26-0.77 <0.01 63 64 0.71 0.34-1.45 0.29
13-15 18 28 0.48 0.23-1.01 56 57 0.80 0.39-1.66
16+ 13 25 0.36 0.16-0.80 73 82 0.65 0.32-1.31
Income (dollars)
<10k 43 34 1.00 17 14 1.00
10k-20k 45 43 0.85 0.45-1.62 0.02 32 38 0.68 0.29-1.62 0.28
20k-30k 15 27 0.43 0.19-0.96 47 40 0.92 0.40-2.13
30k-40k 15 24 0.57 0.25-1.29 31 40 0.60 0.25-1.41
40+ 20 43 0.36 0.17-0.76 73 85 0.64 0.29-1.41
Age (years) at menarche
<13 52 74 1.00 105 100 1.00
13 46 48 1.35 0.77-2.36 0.09 61 75 0.82 0.53-1.28 0.31
14+ 49 55 1.22 0.71-2.11 51 49 0.91 0.56-1.49
A ge (years) at first full-term births
18- 32 41 0.52 0.23-1.17 25 35 0.80 0.39-1.63
19-20 26 33 0.64 0.27-1.49 0.08 29 41 0.82 0.41-1.62 0.09
21-22 20 32 0.46 0.19-1.10 32 39 0.92 0.46-1.80
23-26 30 38 0.61 0.27-1.41 50 42 1.36 0.72-2.59
27+ 19 18 0.86 0.33-2.23 46 32 1.73 0.89-3.38
Nulliparous 22 16 1.00 34 35 1.00
Number o f full-term births
Nulliparous 22 16 1.00 34 35 1.00
1 5 11 0.32 0.09-1.14 <0.01 33 24 1.62 0.79-3.32 0.09
2 16 37 0.28 0.11-0.70 64 54 1.40 0.76-2.57
3 32 24 1.06 0.45-2.52 40 56 0.80 0.42-1.50
4+ 74 90 0.64 0.30-1.36 46 56 0.93 0.49-1.75
Cumulative months o f lactation
Nulliparous 22 16 1.00 34 35 1.00
parous, never 50 65 0.55 0.26-1.18 0.08 64 66 1.13 0.62-2.05 0.05
parous, 1-12 46 58 0.62 0.29-1.36 98 86 1.39 0.79-2.47
parous, 12+ 31 38 0.60 0.26-1.38 21 36 0.63 0.31-1.30
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Table 3.1 (continued)
Hispanic Non-H ispanic
Risk Factor Cases Controls
(n=149) (n=178) OR 95% Cl P M
Cases Controls
(n=217) (n=225) OR 95% Cl P "
Cigarette smoking
N o 86 92 1.00 111 101 1.00
Y es 63 86 0.71 0.45-1.11 0.02 106 124 0.74 0.50-1.08 0.08
Total physical activity (METS/week)
0-24 51 36 1.00 62 43 1.00
25-49 52 57 0.68 0.38-1.22 0.02 56 69 0.58 0.34-0.98 0.05
50+ 46 85 0.39 0.22-0.69 98 112 0.61 0.37-0.99
Gain o f body mass index (kg/m2 )
1.37- 28 38 1.00 66 71 1.00
1.37-3.13 26 39 1.10 0.53-2.29 0.02 56 64 0.87 0.53-1.44 0.42
3.13-5.67 36 51 1.08 0.55-2.14 57 53 1.05 0.63-1.76
5.67+ 59 50 2.01 1.03-3.93 38 37 1.07 0.60-1.90
* Numbers may not sum to total for all covariates because o f missing data.
* * p-value from Chi-Square tests
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history were more common among cases than controls. Hispanic women, compared
with non-Hispanic women, were older at their menarche, had a higher parity, lower
income, and less education. In addition, Hispanics reported a low level of total
physical activity more frequently than non-Hispanic whites.
Age-adjusted odds ratios for postmenopausal breast cancer risk factors are also
shown in Table 3.1. Patterns of risk differed by ethnicity. Parity, education, income
status, and change in BMI were associated with breast cancer among Hispanics but
not among non-Hispanic women. Total physical activity was a protective factor for
non-Hispanic whites as well as Hispanics.
We next examined the patterns of use for various types of hormone therapy (Table
3.2). The prevalence and duration of hormone use were higher in non-Hispanic
white than Hispanic women. Overall, 51.0% (76) of breast cancer cases and 62.9%
(112) of controls among Hispanic women versus 70.5% (153) and 75.1% (169) of
non-Hispanic whites had ever used HRT. Thirty-four percent of all participants
never used hormones, 36.7% used estrogen alone (ERT), and 29.5% used combined
estrogen-progesterone (CHRT, i.e., estrogen and progesterone taken
simultaneously). Among women who had ever used HRT, the median duration was
54 months in Hispanic versus 71 months in non-Hispanic whites. A total duration
40
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Table 3.2 Distribution of total estrogen use , estrogen use alone, combined
estrogen and progesterone use for Hispanic and non-Hispanic whites,
NMWHS, 1992-1994
Hispanic Non-Hispanic
Risk Factor Cases Controls Cases Controls
(n=T49) (n-178) (n=217) (n=225)
Total estrogen use in ERT + CHRT (months)
Median Mean Median Mean Median Mean Median Mean
49 92.5 59 85.8 70 106.89 72 101.2
N % N % N % N %
17- 27 18.1% 39 21.9% 32 14.8% 38 16.9%
17-60 14 9.4% 24 13.5% 40 18.4% 43 19.1%
60-140 16 10.7% 25 14.0% 35 16.1% 41 18.2%
140+ 19 12.8% 24 13.5% 46 21.2% 47 20.9%
never 73 49.0% 65 37.1% 64 29.5% 56 24.9%
Estrogen use alone in ERT (months)
Median Mean Median Mean Median Mean Median Mean
63 102.3 55.5 86.0 96 134.3 72 106.9
N % N % N % N %
17- 18 14.8% 25 18.1% 15 11.6% 25 16.6%
17-60 7 5.7% 15 10.9% 13 10.1% 18 11.9%
60-140 9 7.4% 19 13.8% 9 7.0% 26 17.2%
140+ 15 12.3% 14 10.1% 28 21.7% 26 17.2%
never 73 59.8% 65 47.1% 64 49.6% 56 37.1%
Estrogen use in CHRT* (months)
Median Mean Median Mean Median Mean Median Mean
41 75.5 59 85.5 67 86.8 59.5 93.9
N % N % N % N %
17- 9 9.0% 14 13.3% 17 11.2% 13 10.0%
17-100 11 11.0% 13 12.4% 40 26.3% 33 25.4%
100+ 7 7.0% 12 11.4% 31 20.4% 28 21.5%
never 73 73.0% 65 62.9% 64 42.1% 56 43.1%
Progesterone use in CHRT (months)
Median Mean Median Mean Median Mean Median Mean
18 33.1 24 43.0 48 62.8 43.5 53.5
N % N % N % N %
12- 11 11.0% 17 17.1% 22 14.5% 17 13.1%
12-60 11 11.0% 13 12.4% 34 22.4% 34 26.2%
60+ 5 5.0% 9 8.6% 32 21.1% 23 17.7%
never 73 73.0% 65 61.9% 64 42.1% 56 43.1%
* ERT: estrogen replacement therapy
** CHRT: combined hormone replacement therapy
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of estrogen use longer than 140 months was reported by 13% of Hispanics and 21%
of non-Hispanic whites, respectively (Table 3.2). Consistent with the more recent
introduction of CHRT, short-term HRT users were more likely to have taken
combined therapy (median duration -56.6 months for estrogen use in CHRT;
median duration =33.4 months for progesterone use in CHRT) than long-term users
(median duration=71.6 months for estrogen use in ERT).
To investigate the effect of HRT use on breast cancer risk, we examined risks in
relation to increasing duration of ERT and CHRT use. The association between
breast cancer risk and months of use of any form of HRT is shown in Table 3.3.
After adjustment for selected nonreproductive and reproductive factors, a marked
elevation in risk among Hispanic women were observed. Both total estrogen use
(ERT + CHRT) and estrogen use alone (ERT) were statistically significant for long
term users (OR for >140 months of total estrogen use=2.70, 95%CI 1.03-7.08; OR
for >140 months of estrogen use alone=5.53, 95%CI 1.47-20.87 compared with
women on total estrogen and estrogen alone for < 17 months). Non-Hispanic white
women also showed an increased risk associated with a duration > 140 months, but
there was no gradient in trend by number of months. However, the risks were not
significantly different within two ethnic groups (P= 0.76). Additionally, the ORs
for long-term users of any single or combined use of HRT were smaller and were
not statistically significant (Table 3.3).
42
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After adjustment for progesterone use, we found no marked alterations in risk
estimates for ERT use (OR for >140 months of ERT in Hispanics=2.98, 95% Cl
1.06-8.38). Estrogen use, with or without progesterone, was associated with breast-
cancer risk among Hispanic women, and a gradient in risk associated with duration
of use (p<0.05 for trend). We found no significant evidence of a risk increase for
the intake of progesterone as part of CHRT; however, the duration of CHRT use
was substantially less than duration of ERT use (Table 3 .3).
Finally, in order to assess the impact of age at menopause, a potential confounder,
on the effects of risk estimates for HRT use, we restricted the analysis to those
women with a known age at menopause and adjusted for this factor in the analysis.
The results showed that risk estimates for breast cancer were slightly higher,
though less precise and followed the same pattern of increased risk for breast
cancer with duration of HRT use (data not shown). We were unable to assess the
effect of duration of progesterone use on breast cancer risk, because too few
women with a known age at menopause had used progesterone.
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Table 3.3 Multivariate Odds ratios (ORs) and 95% confidence interval
(95% Cl) of breast cancer in relation to total use of estrogen, use of
estrogen alone and combined use of estrogen and progesterone, NMWHS,
1992-1994 *
Risk Factor All Hispanic N on-H ispanic
OR 95% Cl OR 95% Cl OR 95% Cl
Total estrogen use in ERT** + CHRT*** (months)
17- 1.00 1.00 1.00
17-60 1.31 0.75-2.29 0.99 0.37-2.64 1.56 0.73-3.30
60-140 1.06 0.60-1.85 1.24 0.48-3.22 1.09 0.51-2.34
140+ 1.75 1.02-3.03 2.70 1.03-7.08 1.70 0.82-3.56
non-users o f HRT 1.60 0.99-2.58 1.73 0.84-3.58 1.82 0.89-3.70
Trend p=Q.Q6 p=0.03 p=0.27
Estrogen use alone in ERT (months)
17- 1.00 1.00 1.00
17-60 1.05 0.46-2.39 0.97 0.25-3.72 1.31 0.40-4.32
60-140 0.83 0.37-1.87 1.80 0.50-6.57 0.74 0.22-2.52
140+ 2.57 1.25-5.28 5.53 1.47-20.87 2.65 0.95-7.34
non-users o f HRT 1.93 1.06-3.50 2.39 0.94-6.06 2.73 1.06-7.04
Trend p<0.01 p<0.01 p=0.03
Estrogen use in CHRT (months)
17- 1,00 1.00 1.00
17-100 1.50 0.68-3.32 0.95 0.22-4.00 1.60 0.54-4.76
100+ 1.35 0.59-3.11 1.76 0.35-8.82 1.16 0.37-3.69
non-users o f HRT 1.46 0.71-3.00 1.54 0.48-4.92 1.13 0.38-3.34
Trend p=0.68 p=0.48 p=0.83
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Table 3.3 (continued)
Risk Factor All Hispanic Non-Hispanic
___________________________ OR 95% Cl OR 95% Cl OR 95% Cl
Progesterone use in CHRT (months)
12- 1.00 1.00 1.00
12-60 1.06 0.51-2.21 1.26 0.33-4.92 0.95 0.35-2.55
60+ 1.39 0.62-3.11 1.94 0.37-10.17 1.19 0.41-3.46
non-users o f HRT 1.28 0.66-2.48 1.79 0.58-5.56 0.91 0.35-2.39
Trend p=0.40 p=0.44 p=0.69
Estrogen use adjusted for progesterone use(months) ****
17- 1.00 1.00 1.00
17-60 1.33 0.71-2.49 1.07 0.35-3.27 1.57 0.68-3.62
60-140 1.03 0.54-1.96 1.41 0.48-4.11 0.95 0.39-2.29
140+ 1.80 0.99-3.25 2.98 1.06-8.38 1.69 0.76-3.75
non-users o f HRT 1.20 0.63-2.25 1.41 0.51-3.93 1.16 0.46-2.92
Trend p=Q.Q5 p=0.03 p -0 .2 4
Conditional logistic regression models matched for age-group, and health
planning district and adjusted for covariates: age at first full-term birth, age at
menarche, number of full-term births, education, income, duration of breast fed,
smoking status, and physical activity, gain of body mass index (137 cases and
169 controls in Hispanic women; 203 cases and 207 controls in non-Hispanic
women).
** ERT: estrogen replacement therapy
*** CHRT: combined hormone replacement therapy
**** Adjusted simultaneously for ERT and CHRT use
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3.3 Discussion
We found significantly increased breast cancer risk among long-term ERT users.
Postmenopausal Hispanic women had substantially larger risks from long-term
ERT use than did non-Hispanic white women. Hispanic women who used
estrogens without progesterone longer than 140 months were estimated to have a
nearly five times greater risk for breast cancer than those who used estrogens for
less than 17 months. There was little suggestion of increased risk associated with
CHRT use in either Hispanic or non-Hispanic white women.
The effect of HRT on breast cancer risk has been assessed in numerous studies and
the evidence has been summarized in a recent meta-analysis (1997). Our findings
about the relationship between ERT and breast cancer in Hispanic and non-
Hispanic white women are compatible with the conclusions of this meta-analysis
based on more than 90% of the world's epidemiological data. This meta-analysis
found that longer duration of HRT use was associated with increased breast cancer
risk. Although the link between HRT and breast cancer is supported by
observational data, the risk associated with HRT use remains controversial because
studies continue to show inconsistent findings. Recent studies reported no
significant increased risk in association with use of estrogen alone (Newcomb et
al., 1995; Persson et ah, 1999; Schuurman et al., 1995; Stanford et al., 1995).
46
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The Women's Health Initiative should provide additional information to clarify the
relationships between ERT and breast cancer risk. Our data support variation in the
effects of ERT on breast cancer risk, comparing Hispanic and non-Hispanic white
postmenopausal women. No comparable studies are available for Hispanic women,
but the relationship between HRT and breast cancer risk has been examined among
black and white women in a recent case-control study from North Carolina
(Moorman et al., 2000). The ethnic-specific analysis revealed no important
differences between black and white women. The explanation for the differences in
risk between Hispanic and Non-Hispanic white women is unclear.
Our findings support the conclusion that long-term ERT use is associated with
increased risk, especially among Hispanic women. Whether added progesterone
enhances the risk of breast cancer among ERT users is an important issue. Studies
findings are inconsistent for the risk associated with HRT using estrogens
combined with progesterone (Bonnier et al., 1995; Colditz et al., 1995; Newcomb
et al., 1995; Persson et al., 1997; Persson et al., 1992; Schairer et al., 1994;
Stanford et al., 1995). We found little evidence that added progesterone increases
the risk of breast cancer beyond that of ERT alone. However, our findings are
limited because women in our study did not use CHRT for as long a period as they
used ERT. We lacked data on the pattern of CHRT use.
47
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The biological mechanisms underlying the effect of endogenous and exogenous
hormones on breast cancer risk are complex. Steroid and metabolic peptide
hormones are likely to play critical roles in breast carcinogenesis for Hispanic and
non-Hispanic white women (Bernstein and Ross, 1993; Stoll, 1999). Breast cancer
risk is greatly increased among women who have higher cumulative exposure to
estrogens and other steroid hormones (Bernstein and Ross, 1993). Metabolic
hormones, particularly insulin and insulin-like growth factor (IGF-1), may act
synergistically with steroid hormones in stimulating breast cell proliferation,
serving as carcinogenic promoters of carcinogenesis (Giovannucci, 1999; Perks and
Holly, 2000; Stoll, 1999; Yee and Lee, 2000).
Differences in the joint patterns of cumulative hormone exposure may account for a
portion of the observed variation in the risk estimates of breast cancer between
these two ethnic groups. Hispanic women have higher prevalence rates of impaired
glucose tolerance and hyperinsulinemia. Based on the synergistic effects of insulin
and estrogens on breast cell proliferation (Peyrat et al., 1988; Stewart et al., 1990),
the addition of estrogens from long-term ERT use might be associated with a
greater increment in risk among Hispanic than non-Hispanic white women.
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There are several potential limitations associated with our findings. Recall bias may
be present for the reporting of hormone use. Non-differential misclassification is
likely to dilute the magnitude of the relationship between HRT and breast cancer
risk, and could account for our non-significant findings among non-Hispanic white
women. Although the data were collected in the early 1990s when concerns about
HRT use and breast cancer were not as widely appreciated as today, differential
recall bias is a possibility. Third, control subjects were selected by random-digit
dialing methods that may introduce differences between cases and controls because
telephone coverage varies by socioeconomic variables and other health-related
factors in New Mexico (Gilliland et al., 1998b). To reduce this possibility, we
selected controls from strata defined by age, ethnicity, and geographic region to
ensure a distribution similar to that of the cases. Fourth, our risk estimates could be
confounded by other risk factors for breast cancer. Information on covariates was
not available for all subjects. However, since the estimates have been adjusted for
the most important risk factors including reproductive factors and physical activity,
such bias appears unlikely to account for the complex pattern of results observed.
Finally, characteristics that differentiate HRT users from non-users were not well
documented. To reduce the effect of this potential bias, we compared risks in short
term and long-term users.
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In summary, this study provides evidence that postmenopausal ERT was positively
associated with higher risks of breast cancer among Hispanic women, and that there
was also a dose-response relationship associated with increased duration of use.
Although there is significant variability in the range of menopausal estrogen use
(McNagny et al., 1997), there has been a steady rise in usage patterns over the past
decade (Wysowski et al., 1995). Thus, the increasing prevalence of ERT may result
in an increase in breast cancer occurrence among this growing ethnic population.
Moreover, our findings also highlight the importance of the inclusion of multi
ethnic populations in epidemiological studies, especially currently growing
minority populations, which may provide insight into ethnic differences in the
distribution and significance of risk factors. Further studies are needed to identify
biological, behavioral, psychosocial, and cultural factors that result in this increased
breast cancer risk associated with ERT in Hispanics.
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CHAPTER 4
CONCLUSION
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Breast cancer is the second most common cancer among women in the world. We
have shown ethnic differences in breast cancer risk associated with HRT use and
positive FH of this disease. The data ofNMWHS suggest the need for etiological
investigations among Hispanic women in order to provide useful information in
further efforts to control breast cancer in this rapidly growing minority population.
The aim of primary prevention is to eliminate or modify established risk factors for
breast cancer; secondary prevention is the diagnosis and treatment of early cancers.
Prevention of breast cancer is difficult because many associated factors are
endogenous and thus difficult to modify (e.g. age at menarche). On the other hand,
some established risk factors are easy to manipulate. As discussed in Chapter 1,
early or multiple pregnancies, accumulative lactation for more than 12 months,
regular physical exercise, limiting high-level alcohol consumption, avoidance of
obesity in postmenopausal women may all have a protective effect and should be
considered by women at high risk of breast cancer.
The measures the women may wish to consider to reduce breast cancer risk are
dependent upon the underlying risks of developing the disease. This chapter begins
with a summary of possible mechanisms of breast cancer development based on
epidemiological risk factors mentioned in previous chapters. At present, few
52
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methods exist for breast cancer screening or prevention for those with an inherited
susceptibility to breast cancer. The likelihood of benefit is increased by targeting
high-risk populations for prevention. Genetic consulting for high-risk women is
discussed in this chapter. Finally, long-term benefits, effect on breast cancer risk of
hormone replacement therapy and other options are also outlined in the following
paragraphs.
4.1 Etiology of Breast Cancer Development
The cause of breast cancer cannot be explained by a single agent. Rather, the
occurrence of breast cancer is a result of the accumulation of damage over many
years within breast cells. Two types of molecular mechanisms produce cancer:
mutations of DNA and induction of cell proliferation. Mutations occur within
critical genes that are responsible for regulating cell growth, death, differentiation,
and chromosomal replication (Weinberg, 1989). Mutations either activate or
inactivate the affected genes. On the other hand, proliferation exhibits its tumor-
forming effects by promoting cell division.
Furthermore, these genetic changes are induced by either internal or external
factors. Internal causes of breast cancer include a variety of extracellular factors
associated with breast cancer such as estrogen. The extent of estrogen exposure
53
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over a woman’s life is a significant risk factor for breast cancer (Kelsey and
Bernstein, 1996). For example, early menarche, late menopause, and nulliparity are
all associated with an increased risk of breast cancer. This is likely to be due to the
proliferative response of breast epithelial cells to estrogen via the estrogen receptor
(Nandi et al., 1995). Another internal cause of breast cancer is the inheritance of a
mutated gene that increases an individual’s risk of acquiring breast cancer (Szabo
and King, 1995). In this case, every cell in the body has an identical genetic
alteration that substantially increases an individual’s risk of breast cancer over a
lifetime. However, this genetic predisposition is not deterministic; approximately
20% of carriers never develop breast cancer (Easton et al., 1993b). Therefore, the
development of cancer in predisposed individuals may require environmental
stimuli as well.
External causes include many types of environmental exposures such as smoking
carcinogens and ionizing radiation. After menopause, a major external exposure is
the use of exogenous hormones. The increased risk of breast cancer among long
term postmenopausal estrogen use is presumably due to their estrogenic effects
(Chapter 3). In one word, many details of breast carcinogenesis are incomplete, and
other contributing factors probably need to be documented with further research.
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4.2 Prevention Strategies for Heritable Risk of Breast Cancer
Knowledge about genes that predispose to the development of breast cancer has
been explored in recent years. Although information about the number and
frequency of these genes remains unclear, and the probability that carriers will
develop breast cancer is incompletely defined, risk assessment can still be provided
for some families, in which an aggregation of multiple affected individuals or
individuals with early-onset breast cancer suggests a heritable predisposition to
breast cancer, and may contribute to decisions about medical care for the patient
and her family members. For example, molecular analysis of genes predisposing to
breast cancer is an option that may provide further risk modification for high-risk
families or individuals.
Genetic testing should be carried out within the framework of a recommended
genetic counseling protocol to assure informed and autonomous patient decision
making. Moreover, Studies on genetic and environmental cancer risk modifiers,
genotype-phenotype correlations, and the impact of cancer screening and
prevention options will provide insight into the features and management of high-
risk individuals.
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4.3 Hormone Replacement Therapy and Other Options
Estrogen replacement therapy (ERT) in postmenopausal women has a number of
potential beneficial effects. The effects of estrogen used alone and in combination
with progesterone on cardiovascular disease, cancer risk, and osteoporosis are
currently being evaluated in the Women’s Health Initiative.
Because family history and estrogen exposure are the two major known risk factors
for development of breast cancer, there is a concern about providing estrogen
replacement therapy to women who are at an increased risk (e.g. positive FH of
breast cancer). NMWHS and other epidemiological studies have shown that
estrogen use for less than 5 years is not associated with increased risk of
developing breast cancer. Hence, short-term replacement therapy for relief of
postmenopausal symptoms could be considered taking for most postmenopausal
women.
When deciding about long-term use of hormone replacement therapy, the potential
benefits on coronary heart disease and osteoporosis and the effect on breast cancer
risk should be weighed. Most women at high risk of osteoporosis will benefit from
hormone replacement therapy. Likewise, most women at high risk of coronary
heart disease, including those with first-degree relatives with breast cancer, will
56
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also benefit (Col et al., 1997; Grady et al., 1992). However, the risks of estrogen
replacement are unlikely to outweigh the benefits for most women who have two or
more first-degree relatives with breast cancer BRCA1/BRCA2 mutation carriers
(Col et al., 1997). In this case, other treatment options should be considered to
reduce the risk of cardiovascular disease and osteoporosis. These include the
selective estrogen-receptor modulators Tamoxifen (Decensi et al., 1998; Grey et
al., 1995).
4.4 Future Directions
Breast cancer remains the most common cancer and the second most common
cause of cancer death in women in the US. The incidence of breast cancer has been
increasing in both Hispanic and non-Hispanic white women (Eidson et al., 1994).
Available evidence provides a basis for a number of strategies that can reduce risk
of breast cancer, although some of these represent complex decision-making.
However, to date, well-established risk factors account for only approximately 40%
of breast cancers in the US (Madigan et al., 1995). Additional research to identify
modifiable risk factors for breast cancer, as well as to elucidate underlying biologic
mechanisms, will help in devising preventive strategies.
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Family history, hormone replacement therapy and breast cancer risk on Hispanic and non-Hispanic women, The New Mexico Women's Health Study
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