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EPIDEMIOLOGY
Reproductive factors and the risk of breast cancer in old age:a Norwegian cohort study
Julie Horn • Bjørn Olav Asvold • Signe Opdahl •
Steinar Tretli • Lars J. Vatten
Received: 3 January 2013 / Accepted: 8 April 2013 / Published online: 19 April 2013
� Springer Science+Business Media New York 2013
Abstract Reproductive factors, including early age at
menarche, late age at first birth, low parity, and late age at
menopause, are associated with increased risk of breast
cancer, but it is not clear to which degree the associations
persist into old age. Altogether 58,426 Norwegian women
born between 1886 and 1928 were followed up for breast
cancer incidence from 1961 to 2008. Associations of
reproductive factors with breast cancer risk were analyzed
separately for the age intervals 55–69 and 70 years and
older, using Cox regression. The associations were of
similar strength in the two age strata. At 70 years and later,
hazard ratios (HR) for the following comparisons were
found: late (C17 years) versus early (\13 years) age at
menarche [HR 0.79, 95 % confidence interval (CI): 0.62,
1.01, P for trend \0.001]; late (C35 years) versus early
(\20 years) age at first birth (HR 1.54, 95 % CI: 1.13, 2.11,
P for trend \0.001); high (C5) versus low (1) parity (HR
0.68, 95 % CI: 0.54, 0.86, P for trend = 0.001) and late
(50–54 years) versus early (\45 years) age at menopause
(HR 1.44, 95 % CI: 1.10, 1.90, P for trend = 0.002). These
findings suggest that reproductive events may have life-
long effects on breast cancer risk.
Keywords Age factors � Breast cancer � Menarche �Age at first birth � Parity � Menopause
Introduction
Early age at menarche, late age at first birth, low parity, and
late age at menopause are established factors associated with
increased risk for breast cancer [1]. Nonetheless, the
underlying mechanisms are not well understood, and it is not
known to which degree these associations extend to old age,
suggesting a life-long influence on the incidence of breast
cancer. It has been hypothesized that pregnancy, despite
being associated with a transient increase in breast cancer
risk during the first years following a delivery [1], may cause
permanent morphological changes in breast tissue that pro-
vide a lasting protection against breast cancer, and that the
protection is strengthened by increasing number of preg-
nancies [2]. On the other hand, timing of menarche and age at
menopause may reflect biological traits that determine the
cumulative exposure to menstrual factors, and the total
number of regular menstrual periods may play a role for
breast cancer risk apart from the influence of factors related
to pregnancy [3]. Whereas a late age at menopause has been
considered an important risk factor in elderly women [4–6],
it is not clear to which degree events in the distant past,
including age at menarche and age at first birth, have life-
long effects on the risk. The results of some observational
studies suggest that associations of some of these repro-
ductive factors may be attenuated in old age [4, 7–9], but only
a few studies have addressed this issue in detail, and the
results have not been consistent.
J. Horn (&) � B. O. Asvold � S. Opdahl � S. Tretli � L. J. Vatten
Department of Public Health, Norwegian University of Science
and Technology, Trondheim, Norway
e-mail: [email protected]
J. Horn
Department of Gynecology and Obstetrics, Levanger Hospital,
Health Trust Nord-Trøndelag, Levanger, Norway
B. O. Asvold
Department of Endocrinology, St. Olavs Hospital, Trondheim
University Hospital, Trondheim, Norway
S. Tretli
Cancer Registry of Norway, Institute of Population-based Cancer
Research, Oslo, Norway
123
Breast Cancer Res Treat (2013) 139:237–243
DOI 10.1007/s10549-013-2531-0
In the 1980s, Kvale et al. assessed reproductive factors
in relation to breast cancer risk in a cohort of more than
63,000 Norwegian women born between 1886 and 1928
[10–12], including 1,565 incident breast cancer cases
diagnosed from 1961 to 1980. The results confirmed that
early age at menarche, late age at first birth, low parity, and
late age at menopause are associated with increased risk,
however, the analyses had limited statistical power to
assess risk factors at old age. In the present study, we
followed Kvale’s cohort for an additional 28 years (until
2008) and assessed whether established associations of
reproductive factors with breast cancer risk persist into old
age.
Methods
Study population and follow-up
Between 1956 and 1959, all women living in three Nor-
wegian counties (Vestfold, Nord-Trøndelag, and Aust-
Agder) who were born between 1886 and 1928 (at
28–73 years of age), were invited to participate in a clinical
breast cancer screening. The original study has been
described in detail by Kvale et al. [10–12]. In brief, the
women had a clinical breast examination conducted by
physicians (not including a mammography), and informa-
tion on history of breast disease and reproductive history
was collected during a structured interview, including
questions related to age at menarche, age at first birth,
number of full-term pregnancies, and age at menopause.
Information about place of residence, marital status, and
occupation (own or husband’s) was collected from the
local population register.
With the aid of the unique 11-digit identity number that
was allocated to every Norwegian citizen in 1960, the
study participants were linked to incidence data at the
Cancer Registry of Norway and to data on vital status at
Statistics Norway. The Cancer Registry of Norway was
established in 1951 and the reporting of cancer diagnoses
from physicians and hospitals is compulsory. The popula-
tion registry at Statistics Norway provides complete and
updated information about vital status and date of
emigration.
Among the women who were invited to the screening,
84,981 were eligible for follow-up, since they were still
alive on January 1, 1961, at the start of follow-up. A total
of 63,041 (74.2 %) of these women had attended the breast
screening and had been interviewed.
Among the 63,041 participants, we excluded 759
(1.2 %) women with a history of breast cancer before the
age of 55 years. We also excluded 933 (1.5 %) women
who died or emigrated before 55 years of age, and 2,923
(4.6 %) women with missing information on parity or age
at menarche. Thus, 58,426 women were included in the
analyses. The analyses of age at first birth and number of
births were restricted to 45,374 women with known age at
first birth, and the analysis of age at menopause included
20,398 participants with known natural menopause at the
time of the breast survey.
Participants were followed from January 1, 1961, or
from the age of 55 years, whichever occurred last. They
contributed person-time until the date of a first breast
cancer diagnosis, until date of death or emigration, or until
December 31, 2008, whichever occurred first.
Statistical analysis
We used Cox proportional hazards regression to estimate
hazard ratios of breast cancer by categories of age at
menarche, age at first birth, parity, and age at menopause.
We assessed the association of each reproductive factor
separately, with adjustment for age (using age as the time
scale) and birth cohort (in 5-year categories). In a second
step, we also adjusted for reproductive events occurring
before the exposure under study. The two analytic
approaches yielded nearly identical estimates, and in the
results section, we describe the results from the second
step. In a separate analysis, the association of each repro-
ductive factor was adjusted for marital status (ever/never
married), women’s or husband’s occupation (professional/
private enterprise, manual work, domestic or other work),
county and place of residence (urban/rural) as proxies for
socioeconomic status, and for all other reproductive fac-
tors, but these adjustments did not materially influence the
estimates (data not shown). P values for trend across
exposure categories were calculated by treating the median
values within the categories as a continuous variable.
We estimated separate hazard ratios for the age intervals
55–69 years and 70 years and older. Participants contrib-
uted person time to one or both age intervals, depending on
their age at start and end of follow-up. To test if the
association between a reproductive factor, treated as a
categorical variable, and breast cancer risk differed by age
interval, we estimated the association in two different
models. The first model assumed a constant hazard ratio,
while the second model included time-dependent covari-
ates that allowed hazard ratios to differ between the two
age intervals. The difference between the models was
assessed by likelihood ratio tests, yielding a p value for
interaction. The proportional hazard assumption was met in
all analyses, as evaluated by log minus log plots and
Schoenfeld residuals. All analyses were performed using
STATA for Windows (Version 12.1� StataCorp LP,
1985–2011).
238 Breast Cancer Res Treat (2013) 139:237–243
123
The study was approved by the regional committee for
medical research ethics and by the Norwegian Data
Inspectorate.
Results
Characteristics of the participants at baseline and charac-
teristics of breast cancer cases by age at diagnosis are
summarized in Table 1. Among the 58,426 women inclu-
ded in the analyses, 49,155 women died and 52 emigrated
during follow-up. There were 691,607 person-years of
follow-up in the younger (55–69 years) and 714,052 per-
son-years in the older age interval (70 years and older). A
total of 1,077 women were diagnosed with invasive breast
cancer in the younger age interval (median age at diag-
nosis, 64 years), and 1,822 were diagnosed in the older age
interval (median age at diagnosis, 78 years).
Hazard ratios (HR) for the associations of reproductive
factors with breast cancer risk in the two age intervals
(55–69 years and 70 years and older) are shown in
Table 2. At the age of 70 years and older, there was an
inverse association of age at menarche with breast cancer
risk (P for trend\0.001) that appeared to be stronger than
for the age interval 55–69 years (P for trend = 0.13).
However, the test for interaction between the age intervals
did not suggest that the difference was statistically signif-
icant (P for interaction = 0.67).
Age at first birth was positively associated with the risk
of breast cancer in both age intervals (P for trend\0.001).
Compared to women who gave their first birth before the
age of 20, the hazard ratio during the 55–69 year age
interval was 1.69 (95 % confidence interval (CI): 1.09,
2.64) for women who were 35 years or older at first birth,
and 1.54 (95 % CI: 1.13, 2.11) at 70 years and older.
Compared to parous women, nulliparous women were at
increased risk of breast cancer both at 55–69 years (HR
1.34; 95 % CI: 1.16, 1.55) and at 70 years and above (HR
1.31; 95 % CI: 1.17, 1.46). Among parous women, parity
was inversely associated with risk, both in the 55–69 year
interval and at 70 years and later (P for trend = 0.001).
Compared to women with 1 child, having 5 or more chil-
dren was associated with a risk reduction of 41 % in the
age interval 55–69 years (HR 0.59; 95 % CI: 0.42, 0.83)
and 32 % for women 70 years and above (HR 0.68; 95 %
CI: 0.54, 0.86).
Age at menopause was positively associated with breast
cancer risk both at 55–69 years of age (P for trend = 0.09)
and at 70 years and above (P for trend = 0.002). In the
younger age interval (55–69 years), menopause between
50–54 years of age was associated with 38 % higher risk
(HR 1.38; 95 % CI: 0.87, 2.19) compared to menopause
before 45 years. The corresponding increase in risk in the
older age interval (70 years and above) was 44 % (HR
1.44; 95 % CI: 1.10, 1.90).
Discussion
In this cohort study of 58,426 women, with breast cancer
follow-up into old age, we assessed whether reproductive
factors that are associated with breast cancer risk in middle
age, are also associated with risk in old age. During more
than 1.4 million person-years of follow-up, 2,899 women
developed breast cancer, and our findings show equally
strong associations for age at menarche, age at first birth,
parity, and age at menopause after 70 years of age as
between 55 and 69 years of age.
Strengths of this study include the population-based
prospective design with long-term follow-up and the large
number of incident breast cancers. Also, the high atten-
dance of eligible women and the high comparability at
baseline between women who participated and women who
declined to participate [10] strengthen the validity of the
findings. The reporting of new breast cancers to the Cancer
Registry of Norway is mandatory and regulated by law, and
the registration is considered to be nearly complete [13,
14].
The historical feature of the study is another interesting
aspect, since the participants are too old to have entered
any organized mammography screening program, and most
of the women are too old to have been given hormone
treatment around menopause. Thus, the Norwegian Mam-
mography Screening Program was gradually introduced
from 1996 [15], and only 7 % of the women in the cohort
were in the eligible age group. Similarly, hormone treat-
ment around menopause was not prevalent in Norway
before the 1990s [16, 17], and therefore, the study popu-
lation has largely been unaffected by modern interventions
that influence breast cancer incidence.
It is a weakness of the study that information on family
history of breast cancer was not available, and that baseline
measurements of body mass index were not conducted. In
relation to the information that was collected, some women
were still at childbearing age, and for these women number
of births may be misclassified. However, the consequence
of this potential misclassification is that the women would
be grouped in a lower parity category, which most likely
would have attenuated the estimated associations.
There are few other studies of reproductive factors and
breast cancer risk in old women, and results have not been
consistent [4, 6–9, 18]. However, other researchers have
also reported negative associations of age at menarche
[3, 6, 8, 9] and parity [4], and positive associations of age at
first birth [7, 18] and menopause [3, 4, 6, 18] in women
65 years and older. In some studies, age at menarche, age
Breast Cancer Res Treat (2013) 139:237–243 239
123
at first birth or parity were not associated with breast cancer
risk in old age, and the authors’ interpretation was that
effects of reproductive factors may be attenuated with
advancing age [4, 7, 9]. However, in those studies, the lack
of association with breast cancer risk in old age may be
explained by low statistical power. Compared to previous
studies, the larger population and the longer follow-up
allowed us to assess more reliably the associations of
reproductive factors with breast cancer risk in old age.
Similar to most other studies, we could not distinguish
between tumor types, as indicated by hormone receptor
status or other subtypes. There is evidence that the distri-
bution of hormone receptor status of breast tumors may
change over the life span, and that among elderly women,
the proportion of estrogen and progesterone receptor
positive tumor types may be higher than in middle age
[19]. We cannot exclude that a similar tendency could be
present in our study. It has also been suggested that the
effect of various risk factors may vary by estrogen and
progesterone receptor status, and that reproductive factors
typically show stronger associations with hormone receptor
positive than with hormone receptor negative tumors
[20–22]. Therefore, an analysis of reproductive factors with
separate breast cancer subtypes could be useful, and pro-
vide a more differentiated assessment of breast cancer risk
in older women.
Russo et al. [23] have suggested that pregnancies,
especially an early first pregnancy, may lead to permanent
morphological changes that make the breast tissue more
resistant to carcinogenic events. Our results suggest that
effects of reproductive factors persist into old age, and
Russo et al’s suggestion that early age at first birth and
parity provide a permanent protective effect against breast
cancer seems to be compatible with our findings.
Age at menarche and age at menopause determine a
woman’s reproductive period, including the number of
ovulatory cycles, and may be an indicator of the cumula-
tive estrogen exposure during reproductive age [1, 24].
Table 1 Baseline characteristics of the study population (58,426 Norwegian women followed up from 1961 to 2008) and breast cancer cases by
age at diagnosis
Baseline characteristics Participants at risk
(n = 58,426)
Breast cancer cases 55–69 years
(n = 1,077)
Breast cancer cases C 70 years
(n = 1,822)
Year of birth, median (IQR) 1911 (1902–1920) 1915 (1908–1921) 1911 (1902–1919)
Place of residence (%)
Urban 21.3 24.2 21.7
Rural 78.7 75.8 78.3
Occupation, own or husband’s (%)
Professional, clerical 27.8 32.2 30.4
Farming, fishing, industrial 42.8 38.7 41.1
Domestic, others 29.4 29.1 28.5
Marital status (%)a
Never married 10.7 12.9 12.7
Ever married 89.3 87.1 87.3
Age at menarche (years), mean (SD) 14.2 (1.4) 14.1 (1.3) 14.1 (1.4)
Age at first birth (years), mean (SD)b 26.3 (4.9) 26.8 (4.9) 27.1 (5.3)
Nulliparous (%) 18.5 21.7 22.1
Number of children among parous women (%)b
1 21.2 26.5 23.1
2 33.1 36.9 35.3
3 22.2 22.4 22.0
4 11.8 8.5 11.1
C5 11.7 5.7 8.4
Age at menopause (years), mean (SD)c 48.1 (4.5) 48.3 (4.2) 48.8 (4.1)
Age at diagnosis (years), median (IQR) 64 (60–67) 78 (74–84)
Year at diagnosis, median (IQR) 1978 (1970–1985) 1991 (1982–1998)
IQR inter quartile range, SD standard deviationa Among women with known marital status (n = 58,191)b Among women with known age at first birth (n = 45,374)c Among women with known age at menopause (n = 20,398)
240 Breast Cancer Res Treat (2013) 139:237–243
123
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Breast Cancer Res Treat (2013) 139:237–243 241
123
Therefore, the increased breast cancer risk associated with
early age at menarche and late age at menopause that we
found among elderly women may be attributed to effects
that could be mediated by endocrine exposures during
reproductive age.
Furthermore, age at menarche and age at menopause
may also affect breast cancer risk in some degree through
other biological traits. It has been suggested that estrogen
concentrations in postmenopausal women may be posi-
tively associated with breast cancer risk [24, 25]. However,
in a meta-analysis of 13 studies, Key et al. [26] reported
only a weak association of age at menarche and the level of
postmenopausal estrogens. Similarly, the association
between age at menopause and estrogen levels was atten-
uated after adjustment for time since menopause [27, 28].
Therefore, these results appear to weaken the possibility
that associations of age at menarche and age at menopause
in elderly women are mediated by postmenopausal estro-
gen concentrations.
In conclusion, our results provide evidence that the
associations of early age at menarche, late age at first birth,
low parity, and late age at menopause with breast cancer
risk persist into old age. The findings suggest that repro-
ductive events may have life-long effects on breast cancer
risk and support the hypothesis that pregnancy reduces
breast cancer risk through permanent changes in breast
tissue.
Acknowledgments This study was funded by the Norwegian Can-
cer Society.
Conflict of interest The authors declare that they have no conflict
of interest.
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factors and breast cancer risk among older women. Breast Cancer
Res Treat 102(3):365–374. doi:10.1007/s10549-006-9343-4Ta
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242 Breast Cancer Res Treat (2013) 139:237–243
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