TUGAS INDIVIDU

MATA KULIAH : ASUHAN KEPERAWATAN MATERNITAS

JURNAL MATERNITAS
FAMILY HISTORY AND THE RISK OF BREAST
CANCER: A SYSTEMATIC REVIEW AND META-
ANALYSIS

OLEH
NIRSAM
NIM : 201401117

PRODI S1 KEPERAWATAN
STIKes WIDYA NUSANTARA
PALU
2016
Int. J. Cancer: 71, 800–809 (1997)
r 1997 Wiley-Liss, Inc.
FAMILY HISTORY AND THE RISK OF BREAST CANCER:
A SYSTEMATIC REVIEW AND META-ANALYSIS
Paul D.P. PHAROAH1,2,*, Nicholas E. DAY1, Stephen DUFFY1, Douglas F. EASTON1 and Bruce A.J. PONDER2
1Institute of Public Health, Robinson Way, Cambridge, UK
2CRC Human Cancer Genetics Group, Addenbrooke’s Hospital, Cambridge, UK
An increased risk of breast cancer in women with a family
history of breast cancer has been demonstrated by many
studies using a variety of study designs. However, the extent
of this risk varies according to the nature of the family history
(type of relative affected, age at which relative developed
breast cancer and number of relatives affected) and may also
vary according to age of the individual. The aim of our study
was to identify all the published studies which have quantified
the risk of breast cancer associated with a family history of
the disease, and to summarise the evidence from these
studies, with particular emphasis on age-specific risks accord-
ing to subject and relative age. Seventy-four published studies
were identified. The pooled estimate of relative risk (RR)
associated with various family histories was as follows: any
relative, RR 5 1.9 (95% CI, 1.7–2.0); a first-degree relative,
RR 5 2.1 (CI 5 2.0, 2.2); mother, RR 5 2.0 (CI 5 1.8, 2.1);
sister, RR 5 2.3 (CI 5 2.1, 2.4); daughter, RR 5 1.8 (CI 5 1.6,
2.0); mother and sister, RR 5 3.6 (CI 5 2.5, 5.0); and a
second-degree relative, RR 5 1.5 (CI 5 1.4, 1.6). Risks were
increased in subjects under age 50 and when the relative had
been diagnosed before age 50. Int. J. Cancer 71:800–809, 1997.
r 1997 Wiley-Liss, Inc.
A familial component to breast cancer has been recognised for
many years. Indeed, Paul Broca (1866) described a family with
multiple cases of breast cancer over 130 years ago. Since then, a
large number of epidemiological studies have been carried out to
attempt to quantify the risks of breast cancer associated with a
positive family history, and nearly all of these have found elevated
relative risks to female relatives of breast cancer patients. However,
the extent of this risk varies according to the nature of the family
history (type of relative affected, age at which the relative
developed breast cancer and number of relatives affected) and may
also vary according to the age of the individual (Kelsey and
Gammon, 1990; Goldgar et al., 1996).
Recent rapid increases in our understanding of the genetic basis
of breast cancer have created a resurgent interest in identifying
those at increased risk because of family history. There is thus a
need for age-specific risks to be quantified more precisely to enable
appropriate counselling to be provided for at-risk women and to
determine the most appropriate treatment for those at risk. Al-
though reviews of family history and risk of breast cancer have
been published, there has been no systematic review which has
identified all the relevant studies. The purpose of our study was to
identify all the published studies which have quantified the risk of
breast cancer associated with a family history of the disease, and to
summarise the evidence from these studies, with particular empha-
sis on the age-specific risks according to subject and relative age.
This analysis should prove useful in clarifying directions for future
research.
METHODS
Search methods
Published studies were identified using the Medline (National
Library of Medicine, Washington, DC) databases for 1966–present
using the terms ‘‘breast neoplasms’’ and ‘‘family’’. In order to
identify studies in which family history-associated risk was not a
primary aim, but in which family history had been recorded, a
search on the terms ‘‘breast neoplasms’’ and ‘‘cohort’’ or ‘‘case-
control’’ was also performed. Studies identified in this way were
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
then read to abstract any reported family history data. The
computer-aided searches were complemented by hand-searching
the references of all studies identified. This method was also used
to identify the studies reported before 1966.
Design of the meta-analysis
The results of the studies are presented as relative risks (RR):
equivalent to the odds ratio estimate from a case-control study, and
the observed/expected ratio in a retrospective cohort design. Most
studies reported only the crude risk estimate, but 14 studies
reported both crude risk and risk adjusted for other risk factors in a
multivariate analysis (Bain et al., 1980; Brinton et al., 1995; Byrne
et al., 1991; Calle et al., 1993; Carter et al., 1989; Chen et al., 1994;
Colditz et al., 1993; Gomes et al., 1995; Harris et al., 1990;
Helmrich et al., 1983; Parazzini et al., 1992; Rookus et al., 1994;
Toti et al., 1986; UK National Case-Control Study Group, 1989).
For this analysis, the adjusted values have been used. In addition,
12 studies report only adjusted relative risks (Clavel et al., 1991;
Jick et al., 1989; Le et al., 1984; Lee H.P. et al., 1992; Luporsi,
1988; Negri et al., personal communication; Richardson et al.,
1991; Rohan et al., 1988; Sattin et al., 1985; Siskind et al., 1989;
White et al., 1994; Zaridze and Andrieu et al., 1995). 95%
confidence intervals (CI) described are either those published, or
have been estimated from available published data. Where insuffi-
cient data were given to calculate a confidence interval, only the
point estimate of RR is given. Pooled estimates of risk were
obtained by calculating a weighted average of the log relative risk
estimates (Breslow and Day, 1980). Studies were weighted accord-
ing to the inverse of the variance of the log relative risk, which was
estimated from the confidence interval by the formula:
study variance (v1) 5 [ln (upper 95% confidence limit)
2 ln (lower 95% confidence limit)]2/(3.92)2.
For the few studies where no confidence interval was given or
could be estimated and the relative risk was reported as significant
(Adami et al., 1981; Burns et al., 1981; Nomura et al., 1986), the
variance was calculated based on the assumption that the lower
95% confidence limit was 1.0. If the risk was reported as not
significant, a nominal weight of 5 was assigned (Bucalossi et al.,
1954; Murphy and Abbey, 1959; Ross et al., 1980; Schildkraut
et al., 1990; Smithers et al., 1952). Confidence intervals for the
summary estimate of log RR were calculated using the formula
95% CI ln (RR) 5 ln (RR) 6 1.96 3 SE ln (RR),
where SE ln (RR) 5 1/Œowi .
In order to calculate summary age-specific estimates, published
age-specific risks were grouped. Two age-group categories were
Contract grant sponsor: Cancer Research Campaign.
*Correspondence to: Institute of Public Health, Robinson Way, Cam-
bridge CB2 2SR, UK. Fax: 144 1223 330330.
E-mail: pp10001@medschl.cam.ac.uk
Received 18 December 1996; revised 24 January 1997
 FAMILY HISTORY AND BREAST CANCER RISK 801

used for both subject and relative age: under 50 years and 50 years
and over. However, some studies reported age-specific risks using
different age categories. For these, 2 categories were used with an
age cutoff as near to 50 as possible. For example, if a cutoff of 45
was published, the 45 and over age group would be categorised in
the 50 and over group for the summary estimates. Similarly, for
studies using a cutoff at 55 years, the under 55 year group would be
categorised in the under 50 year group for the purposes of obtaining
summary estimates. Where a cutoff based on menopausal status
was used, the pre- and peri-menopausal groups were included in
the under 50 group, and the post-menopausal group in the 501
group.
RESULTS
Fifty-two case control studies were identified. These are sum-
marised in Table I. Twenty-seven of the case-control studies used
controls selected from the general population, 22 used hospital
controls and the remaining 3 had both population and hospital
controls.
Twenty-two cohort studies were identified and are summarised
in Table II. Two types of design have been used, i.e., the
retrospective cohort and the prospective cohort. Many of the early
studies utilised the retrospective cohort design, in which breast
cancer incidence or mortality in relatives of breast cancer probands
was retrospectively ascertained. The observed number of cases/
deaths was then compared with the number expected if population
age-specific incidences were applied to the cohort of relatives. Four
studies used a prospective design in which family history of breast
cancer was ascertained in a cohort of women initially free of breast
cancer. Breast cancer incidence or mortality was then compared in
women in different family history categories. Two studies utilised a
nested case-control design in which incident breast cancer cases in

TABLE I – SUMMARY OF CASE CONTROL STUDIES

Study Controls1 Place Date Age group Cases Controls

Adami et al. (1981) P Sweden 1973–1974 Not given 1,330 1,330

Ambrosone et al. (1995) P New York 1986–1991 40–85 523 649
Bain et al. (1980) P USA 1976 30–55 1,092 10,620
Brignone et al. (1987) H Italy 1974–1983 Mean 55 853 853
Brinton et al. (1995) P USA 1990–1992 20–55 2,203 2,571
Brownson et al. (1988) P USA 1979–1986 Median 63 456 1,693
Burns et al. (1981) H Canada 1971–1975 30–79 1,232 602
Byrne et al. (1991) P USA 1973–1980 Over 35 3,351 3,583
Chen et al. (1994) P Iowa 1985 55–69 251 234
Clavel et al. (1991) H, P France 1981–1984 20–56 495 785
Gomes et al. (1995) H Brazil 1978–1987 25–75 300 600
Harris et al. (1990) H USA 1979–1981 ,30–701 401 519
Helmrich et al. (1983) H USA, Canada, Israel 1976–1980 ,70 1,185 3,227
Holzel et al. (1986) H Germany 1986 ,40–701 177 183
Jick et al. (1989) P USA 1978–1983 Median 43 127 174
Le et al. (1984) H France 1981–1984 22–46 265 265
Lee N.C. et al. (1987) P Costa Rica 1984 25–58 171 826
Lee H.P. et al. (1992) H Singapore 1984–1988 24–88 200 420
Luporsi (1988) H France 1983–1987 24–83 406 812
Marubini et al. (1989) H Milan 1982–1985 30–65 214 215
McPherson et al. (1987) H UK 1980–1987 16–64 1,125 1,125
Meirik et al. (1986) P Sweden, Norway 1984–1985 ,45 422 722
Mettlin et al. (1990) H USA 1982–1987 25–98 779 1,558
Morabia et al. (1993) H, P Baltimore 1973–1975 18–59 131 371
Negri, personal communication H N. Italy 1991–1994 ,75 2,569 2,588
Newcomb et al. (1994) P USA 1989–1991 ,75 6,888 9,529
Ngelangel et al. (1994) P Philippines 1988–1991 20–76 283 283
Nomura et al. (1986) P Hawaii 1975–1986 45–74 341 344
Olsson et al. (1989) P Sweden 1979–1985 ,47 174 459
Paffenbarger et al. (1980) H San Francisco 1970–1977 Not given 1,868 3,391
Parazzini et al. (1992) H Italy 1980–1983 23–74 3,415 2,916
Paul et al. (1990) P New Zealand 1983–1987 25–54 891 1,864
Primic-Zakelj et al. (1995) P Slovenia 1988–1990 25–54 624 624
Richardson et al. (1991) H France 1983–1987 26–66 450 603
Rohan et al. (1988) H Australia 1982–1984 20–74 451 451
Rookus et al. (1994) P Netherlands 1986–1989 20–54 918 918
Roseman et al. (1990) P Chicago 1968–1989 30–651 2,712 3,316
Ross et al. (1980) P USA 1971–1977 50–74 138 138
Rossing et al. (1996) P USA 1988–1990 50–64 537 545
Sattin et al. (1985) P USA 1980–1982 20–54 4,735 4,688
Schildkraut et al. (1990) H, P USA 1977–1978 ,60 158 1,464
Siskind et al. (1989) P Australia 1981–1985 Not given 459 1,091
Slattery and Kerber (1993) P USA 1966–1989 ,40–791 4,083 4,083
Tao et al. (1988) Ps China 1980–1984 ,70 497 497
Toti et al. (1986) H Italy 1980–1983 25–75 1,556 1,504
UK National (1989) P UK 1982–1985 ,36 755 755
White et al. (1994) P Seattle 1983–1990 21–45 747 961
WHO (1990) H Multinational 1979–1984 ,55 2,116 13,072
Wynder et al. (1978) H USA 1969–1975 .30 785 2,231
Yang et al. (1992) P Canada 1988–1989 Post-menopausal 699 685
Yuan et al. (1988) P California 1984–1985 20–69 534 534
Zaridze (Andrieu et al., 1995) H Russia 1992–1994 23–82 262 577
1P, population; H, hospital.
802 PHAROAH ET AL.

TABLE II – SUMMARY OF COHORT STUDIES

Study Cohort type1 Place Age group2 Date Cohort size3

Alexander et al. (1987) P Scotland 50–65 1981 186

Anderson V.E. et al. (1950) R USA Not specified 1958 544
Anderson K.E. et al. (1992) R UK ,36 1982–1985 740
Bucalossi et al. (1954) R Italy Not specified 1954 230
Calle et al. (1993) P USA .30 1982–1993 604,412
Carter et al. (1989) P USA 25–74 1971–1975 7,4265
Colditz et al. (1993) P USA 30–55 1976–1988 117,998
Hiatt et al. (1984) P4 USA Median 51 1974 119
Houlston et al. (1992) R UK ,45–551 Not specified 254
Jacobsen (1946) R USA 20–84 1946 200
Macklin (1959) R UK Not specified 1959 295
Morgan et al. (1974) R Canada 601 1974 1,701
Murphy and Abbey (1959) R USA Not specified 1959 200
Passey et al. (1952) R USA Not specified 1952 585
Penrose et al. (1948) R UK 20–84 1948 510
Peto et al. (1996) R UK ,60 1954–1981 3,295
Sellers et al. (1993) P USA 55–69 1985 35,815
Smithers et al. (1952) R USA Not specified 1952 556
Teare et al. (1994) R UK ,40–601 1984–1986 402
Tulinius et al. (1982) R Iceland Not specified 1982 499
Wassink (1935) R The Netherlands Not specified 1931 660
Woolf (1955) R USA Not specified 1955 216
1R, retrospective; P, prospective.–2Age of index cases for retrospective studies and age at entry into cohort for prospective studies.–3Number of
index cases in retrospective studies and person years follow-up in prospective studies except: 4Nested case control design (cohort size 5 number
of cases); 5Number of women in cohort with 10-year median follow-up.

a prospective cohort were matched to controls free of breast cancer
from the same cohort.
History of breast cancer in any relative
Twenty-six studies report the risk of breast cancer associated
with having a history of breast cancer in any relative (unspecified)
(Adami et al., 1981; Burns et al., 1981; Byrne et al., 1991; La
Vecchia et al., 1987; Clavel et al., 1991; Harris et al., 1990; Holzel
et al., 1986; Le et al., 1984; Lee N.C. et al., 1987; Luporsi, 1988;
Marubini et al., 1989; McPherson et al., 1987; Morabia et al.,
1993; Newcomb et al., 1994; Ngelangel et al., 1994; Olsson et al.,
1989; Primic-Zakelj et al., 1995; Richardson et al., 1991; Roseman
et al., 1990; Rossing et al., 1996; Sattin et al., 1985; Schildkraut et
al., 1990; Toti et al., 1986; WHO Collaborative Study of Neoplasia
and Steroid Hormones, 1990; Yang et al., 1992; Andrieu et al.,
1995). These are summarised in Figure 1, which shows that all but
one study found a positive association, with relative risks ranging
from 0.9–3.6. The pooled relative risk estimate was 1.9 (CI 5 1.7,
2.0).
Age-specific effects were described in four studies. McPherson
et al. (1987) found that the risk was higher if the relative had been
diagnosed under age 45, RR 5 2.2, compared to a relative risk of
1.6, if the relative had been diagnosed aged 45 or over. The other
three studies report risks according to the age of the subject.
Roseman et al. (1990) found the risk to women under 30 was
slightly higher than for older women, Brignone et al. (1987) found
the risk in pre- and post-menopausal women to be similar and
Clavel et al. (1991)/Andrieu et al. (1993) found little difference in
risk in women under 40 compared to those over 50.
History of breast cancer in a first-degree relative
The results of the 38 studies (Adami et al., 1981; Ambrosone et
al., 1995; Anderson K.E. et al., 1992; Bain et al., 1980; Brinton et
al., 1995; Bucalossi et al., 1954; Byrne et al., 1991; Calle et al.,
1993; Carter et al., 1989; Chen et al., 1994; Colditz et al., 1993;
Gomes et al., 1995; Helmrich et al., 1983; Houlston et al., 1992;
Meirik et al., 1986; Mettlin et al., 1990; Negri et al., 1988; Nomura
et al., 1986; Paul et al., 1990; Peto et al., 1996; Rohan et al., 1988;
Rookus et al., 1994; Roseman et al., 1990; Ross et al., 1980; Sattin
et al., 1985; Parazzini et al., 1992; Sellers et al., 1993; Siskind et
al., 1989; Slattery and Kerber, 1993; Teare et al., 1994; Toti et al.,
1986; Tao et al., 1988; UK National Case-Control Study Group,
1989; Wassink, 1935; White et al., 1994; Yuan et al., 1988; Hiatt et
al., 1984; Brownson et al., 1988) which have quantified the risk of
breast cancer in women with a history of breast cancer in at least
one first-degree relative are given in Figure 2. This shows that the
relative risk estimates ranged from 1.2–8.8, though in most studies
the relative risk was between 2 and 3. The pooled relative risk
estimate was 2.1 (CI 5 2.0, 2.2). The risk estimates varied
according to the study design: the pooled risk estimates for the
prospective cohort studies was 1.6 (CI 5 1.4, 1.9) compared to 2.2
(CI 5 2.1, 2.3) for the retrospective study designs. The pooled risk
estimate for the case-control studies with population controls was
2.2 (CI 5 2.1, 2.3) compared to 2.5 (CI 5 2.2, 2.7) for the
case-control studies using hospital controls.
Five studies reported risks according to age at diagnosis of the
relative. Four of these showed the risk of breast cancer to be
slightly higher for women whose relatives were diagnosed at a
younger age (Mettlin et al., 1990; Byrne et al., 1991; Sattin et al.,
1985; Houlston et al., 1992), and one study found age at diagnosis
of the relative to have no effect (Toti et al., 1986).
Eleven studies reported risks according to age of the subject
(Mettlin et al., 1990; Calle et al., 1993; Adami et al., 1981;
Ambrosone et al., 1995; Byrne et al., 1991; Meirik et al., 1986;
Sattin et al., 1985; Parazzini et al., 1992; Roseman et al., 1990;
Anderson K.E. et al., 1992; Houlston et al., 1992), with conflicting
results. Three studies showed an increase in risk in older women
(Mettlin et al., 1990; Ambrosone et al., 1995; Parazzini et al.,
1992), 5 studies showed an increased risk in younger women (Calle
et al., 1993; Adami et al., 1981; Meirik et al., 1986; Sattin et al.,
1985; Roseman et al., 1990) and 3 studies showed no effect of
subject age on risk (Byrne et al., 1991; K.E. Anderson et al., 1992;
Houlston et al., 1992).
Four studies reported possible interactions between age of the
proband and age of the relative at diagnosis. These all reported that
the subgroup of women with the highest risk are young women
whose relative was also young at the time of diagnosis (Mettlin et
al., 1990; Calle et al., 1993; Houlston et al., 1992; Peto et al.,
1996). One of these studies had found the overall risk to be higher
in older women (Mettlin et al., 1990).
 FAMILY HISTORY AND BREAST CANCER RISK
FIGURE 1 – Risk of breast cancer in women with a history of breast
cancer in any relative. k, case control study with hospital controls; j,
case control study with population controls; s, case control study with
hospital and population controls; q, prospective cohort study; p,
retrospective cohort study; 0 , weighted average.
History of breast cancer in the mother
The risk of breast cancer in women whose mother had breast
cancer has been reported in 18 studies (Parazzini et al., 1992;
Adami et al., 1981; Albert and Child, 1977; Bain et al., 1980;
Byrne et al., 1991; Calle et al., 1993; Carter et al., 1989; Clavel et
al., 1991; Colditz et al., 1993; Lee H.P. et al., 1992; Morgan et al.,
1974; Negri, personal communication; Sattin et al., 1985; Slattery
and Kerber, 1993; Toti et al., 1986; Tulinius et al., 1982; Jick et al.,
1989; Wynder et al., 1978). The results of these studies are
summarised in Figure 3. All of these found an elevated risk with
relative risks ranging from 1.3–8.2, though the relative risk was not
always significantly different from unity. The estimate of relative
risk obtained from combining all studies was 2.0 (CI 5 1.8, 2.1).
Five studies reported the effect of age at diagnosis in an affected
mother on risk to her daughter. In 2 of these, age was found to have
803
no effect (Byrne et al., 1991; Colditz et al., 1993), but in the other 3
the risk was found to be higher if the mother developed cancer at an
early age. Chen et al. (1994) found a relative risk of 4.4 if the
mother was affected before age 50 years compared to a relative risk
of 1.2 if the mother was aged 50 years or over at diagnosis; Tulinius
et al. (1982) found a relative risk of 2.7 for women whose mother
was under age 45 years at diagnosis compared with a RR of 1.1 for
women whose mothers were diagnosed aged 55–64 years; and
Andrieu et al. (1993)/Clavel et al. (1991) found a relative risk of
2.3 if the mother was affected before age 50 years compared to a
relative risk of 1.1 if the mother was aged 50 years or over at
diagnosis.
Eight studies reported the effect of age of the subject on risk in
women whose mother had breast cancer. In 5 of these, age was
found to have no effect (Andrieu et al., 1993; Clavel et al., 1991;
Byrne et al., 1991; Colditz et al., 1993; Paffenbarger et al., 1980;
Tulinius et al., 1982), and in 3 the risks were higher in younger
women (Bain et al., 1980; Calle et al., 1993; Jick et al., 1989). Bain
et al. (1980) found a higher risk only in the youngest age group, i.e.,
RR of 3.1 in women aged 30–39 compared to 1.9 in those aged
50–55.
Two studies described the effect of an interaction between
subject and relative age (Andrieu et al., 1993/Clavel et al., 1991;
Colditz et al., 1993). In both these studies, the risk was highest in
young women whose mother was also affected at a young age.
History of breast cancer in a sister
The estimates from 22 studies of risk to women who have a sister
with breast cancer (Adami et al., 1981; Albert and Child, 1977;
Alexander et al., 1987; Anderson V.E. et al., 1950; Bain et al.,
1980; Byrne et al., 1991; Calle et al., 1993; Carter et al., 1989;
Clavel et al., 1991; Jacobsen, 1946; Lee H.P. et al., 1992; Macklin,
1959; Murphy and Abbey, 1959; Negri, personal communication;
Parazzini et al., 1992; Penrose et al., 1948; Peto et al., 1996; Sattin
et al., 1985; Slattery and Kerber, 1993; Toti et al., 1986; Tulinius et
al., 1982; Woolf, 1955) are shown in Figure 4. Most studies
estimate a risk of between 2 and 3, though one older study reported
a reduced risk (Murphy and Abbey, 1959). The pooled estimate of
risk was 2.3 (CI 5 2.1, 2.4).
A higher risk of breast cancer when the sister was diagnosed at a
young age was found in 2 studies. Tulinius et al. (1982) found a
slightly higher risk (RR 5 3.3) if the sister was affected before age
45 compared to the risk (RR 5 2.8) to women whose sister had
been diagnosed aged 45 or over. Similarly, Byrne et al. (1991)
found a higher risk if the sister had been diagnosed aged less than
50 (RR 5 3.3) compared to a relative risk of 1.9 for women whose
sister had been diagnosed at a later age. One study found no effect
of sister age on risk (Chen et al., 1994).
The risk associated with having a sister with breast cancer was
found to be higher in 5 of 6 studies that reported results stratified by
subject age. Four of these found the risks to be particularly high in
the youngest age group, with risk falling rapidly with age (Bain et
al., 1980; Byrne et al., 1991; Calle et al., 1993; Paffenbarger et al.,
1980). One study found the risk decreasing steadily with age
(Tulinius et al., 1982), and another found risks to be similar for all
subject ages (Andrieu et al., 1993/Clavel et al., 1991).
History of breast cancer in a daughter
Nine studies reported the risk of breast cancer in women whose
daughter had had the disease (V.E. Anderson et al., 1950; Macklin,
1959; Murphy and Abbey, 1959; Jacobsen, 1946; Passey et al.,
1952; Penrose et al., 1948; Peto et al., 1996; Smithers et al., 1952;
Woolf, 1955). These were all retrospective cohort studies that
traced the mothers of women with breast cancer, and are sum-
marised in Figure 5. All but one of these studies (V.E. Anderson et
al., 1950) showed an elevated risk, with estimates ranging from
0.3–5.6. The pooled relative risk estimate was 1.8 (CI 5 1.6, 2.0).
One study reported on the effect of relative and subject age on
risk (Peto et al., 1996). In this study the risk associated with a
804 PHAROAH ET AL.

FIGURE 2 – Risk of breast cancer in women with a history of breast cancer in a first-degree relative. See legend to Figure 1 for explanation of
symbols.
 FAMILY HISTORY AND BREAST CANCER RISK
FIGURE 3 – Risk of breast cancer in women with a history of breast
cancer in the mother. See legend to Figure 1 for explanation of
symbols.
daughter history was found to be higher when subject was under
age 50 years and daughter was diagnosed before age 50.
History of breast cancer in mother and sister
The effect of having two affected first-degree relatives was
reported by 5 studies (Adami et al., 1981; Bain et al., 1980; Colditz
et al., 1993; Negri, personal communication; Sattin et al., 1985),
with a range of risk estimates from 2.5–13.6. The pooled risk
estimate was 3.6 (CI 5 2.5, 5.0).
History of breast cancer in a second-degree relative
Figure 6 shows the results from 10 studies that reported on the
risk conferred by a family history of breast cancer in a second-
degree relative (Adami et al., 1980, 1981; Teare et al., 1994; White
et al., 1994; Siskind et al., 1989; Paul et al., 1990; Rookus et al.,
1994; Sattin et al., 1985; Roseman et al., 1990; Toti et al., 1986;
Mettlin et al., 1990). These were generally lower than the risk
associated with having an affected first-degree relative, with risk
estimates ranging from 1.2–1.9. The summary risk estimate was 1.5
(CI 5 1.4, 1.6).
805
FIGURE 4 – Risk of breast cancer in women with a history of breast
cancer in a sister. See legend to Figure 1 for explanation of symbols.
Two studies found a constant age-specific risk for women with a
history of breast cancer in a second-degree relative (Mettlin et al.,
1990; Roseman et al., 1990).
Summary estimates of age-specific risk
As described above, those studies that reported on the effect of
age at diagnosis of the relative suggest a general trend for the risk to
be higher if the relative had been diagnosed at younger age, though
this effect has not been shown in all studies for all types of family
history categories. A similar trend is apparent for age of the subject.
However, a more consistent pattern begins to emerge from the
summary estimates of age-specific risk. These are shown in Table
III. For all classes of family history except a positive maternal
history, risk is greater in younger subjects, and when the relative
was affected before age 50, with the greatest risk in women under
age 50 who have a relative with early-onset breast cancer. The only
exceptions to this were the risks to women who have a mother
diagnosed with breast cancer aged 50 or more. In this group the risk
806 PHAROAH ET AL.
FIGURE 5 – Risk of breast cancer in women with a history of breast
cancer in a daughter. See legend to Figure 1 for explanation of symbols.
in women aged less than 50 were found to be lower then the risks to
older women. However, these risks are based on only 2 studies and
the confidence intervals are wide.
DISCUSSION
We identified 74 studies between 1935–1995 reporting the
relationship between family history and breast cancer. Four major
study designs were used, i.e., the retrospective cohort, the prospec-
tive cohort and case-control studies using either hospital or
population controls. In addition, various categories of family
history were investigated, encompassing both types of relative
affected, (i.e., mother or sister) and the age of the affected relative.
Our study has attempted to be as inclusive as possible, and we
have avoided introducing any subjective biases of our own such as
study quality. This does, however, introduce the potential for bias
by repetition of data due to overlap of study populations. We have
thus taken great care to include only one data set from studies
FIGURE 6 – Risk of breast cancer in women with a history of breast
cancer in a second-degree relative. See legend to Figure 1 for
explanation of symbols.
where the overlap from study populations was large, or where one
publication superseded another as a more recent report of an
ongoing study: as in reports from the Breast Cancer Detection
Demonstration Project (Brinton et al., 1982; Byrne et al., 1991),
studies from Sweden (Adami et al., 1980, 1981) and studies from
northern Italy (La Vecchia et al., 1987; Parazzini et al., 1992).
We found consistent results for the various study designs across
different family history types, despite the potential for different
kinds of bias that may apply. This consistency may in part be the
result of publication bias. However, the results of several early
studies of inheritance and cancer were interpreted as evidence that
inheritance plays no part in the development of cancer (Lane-
Claypon, 1926), and subsequent site-specific studies were carried
out to confirm or refute these findings (Wassink, 1935; Penrose et
al., 1948; Anderson V.E. et al., 1950; Woolf, 1955). It would thus
seem likely that any early studies which confirmed these findings
for site-specific cancers would have been published, but we failed
 FAMILY HISTORY AND BREAST CANCER RISK 807
TABLE III – POOLED ESTIMATES OF RISK (95% CI) BY AGE OF SUBJECT et al., 1992; Gomes et al., 1995; Harris et al., 1990; Helmrich et al.,
AND AGE OF AFFECTED RELATIVE
1983; Rookus et al., 1994; Toti et al., 1986; UK National
Family history Subject age Case-Control Study Group, 1989; Calle et al., 1993; Carter et al.,
category ,50 years $50 years All ages 1989; Colditz et al., 1993), and in all of these the unadjusted
relative risk was similar to the adjusted relative risk.
Any first-degree
relative The risk associated with a positive mother history tended to be
,50 years 3.3 (2.8, 3.9)1 1.8 (1.6, 2.0)1 2.3 (2.2, 2.5)2 less than the risk associated with a positive sister history, though
$50 years 1.8 (1.5, 2.2)1 1.7 (1.5, 2.0)1 1.8 (1.6, 2.0)2 the difference fails to reach statistical significance. This could be
All ages 2.4 (2.2, 2.7)3 1.9 (1.8, 2.0)3 2.1 (2.0, 2.2) the result of differential bias in the risk estimates, in that recall of
Mother maternal history is likely to be less complete than for sister history,
,50 years 2.5 (1.6, 3.8)4 1.7 (1.1, 2.6)4 2.0 (1.7, 2.4)5 though this effect would probably be small. There is also some bias
$50 years 1.6 (1.1, 2.3)4 1.7 (1.2, 2.4)4 1.7 (1.5, 2.0)5 induced by the confounding effects of parity; parous women are at
All ages 2.2 (1.9, 2.6)6 1.8 (1.6, 2.1)6 2.0 (1.8, 2.1)
Sister lower risk of breast cancer compared to nulliparous women (Kelsey
,50 years 3.3 (2.1, 4.5)7 1.8 (1.2, 2.4)7 2.7 (2.4, 3.2)8 and Gammon, 1990). Mothers are by definition parous, whereas
$50 years 3.0 (1.4, 4.6)7 1.9 (1.1, 2.7)7 2.0 (1.7, 2.4)8 sisters may be nulliparous, and this will explain some of the
All ages 3.0 (2.5, 3.5)9 2.0 (1.8, 2.3)9 2.3 (2.1, 2.4) difference risk. Easton et al. (1996) estimated that the risk to
Second-degree mothers or daughters of cases is reduced by a factor of about 0.8 as
relative a result of this effect. This would, for example, increase the true
All ages 1.7 (1.4, 2.0)10 1.6 (1.3, 2.0)10 1.5 (1.4, 1.6) relative risk to a woman under 50 with a mother affected before the
1(Calle et al., 1993; Houlston et al., 1992; Mettlin et al., 1990; Sattin age of 50 from 2.5 to 2.8. This compares with a relative risk of 3.3
et al., 1985; Peto et al., 1996).–2(Byrne et al., 1991; Calle et al., 1993; for the same woman with a sister history of breast cancer before age
Houlston et al., 1992; Mettlin et al., 1990; Sattin et al., 1985; Peto et 50. The remaining difference could be caused by other environmen-
al., 1996; Toti et al., 1986).–3(Calle et al., 1993; Houlston et al., 1992; tal factors that predispose to breast cancer, which are more likely to
Mettlin et al., 1990; Sattin et al., 1985; Parazzini et al., 1992; Peto et be shared by sisters, or by an unidentified genetic predisposition to
al., 1996; Adami et al., 1981; Ambrosone et al., 1995; Anderson K.E. et cancer which behaves in a recessive manner.
al., 1992; Byrne et al., 1991; Meirik et al., 1986; Roseman et al.,
1990).–4(Colditz et al., 1993; Andrieu et al., 1993/Clavel et al., It is now known that a high proportion of high-risk breast cancer
1991).–5(Byrne et al., 1991; Chen et al., 1994; Colditz et al., 1993; families are due to either of the genes BRCA1 (Miki et al., 1994) or
Tulinius et al., 1982; Andrieu et al., 1993/Clavel et al., 1991).–6(Bain et BRCA2 (Wooster et al., 1995). However, the extent to which the
al., 1980; Byrne et al., 1991; Calle et al., 1993; Colditz et al., 1993; familial risks estimated in our report can be explained by these
Paffenbarger et al., 1980; Tulinius et al., 1982; Jick et al., 1989; genes remains unclear, and population-based studies of BRCA1 and
Andrieu et al., 1993/Clavel et al., 1991).–7(Peto et al., 1996).–8(Byrne BRCA2 mutations are required to address this point. In particular, it
et al., 1991; Chen et al., 1994; Tulinius et al., 1982; Peto et al., seems unlikely that the excess familial risk seen above age 50 is due to
1996).–9(Bain et al., 1980; Byrne et al., 1991; Calle et al., 1993;
Paffenbarger et al., 1980; Tulinius et al., 1982; Peto et al., 1996).– these genes, which confer a risk of 20–30% between ages 50–70. This is
10(Mettlin et al., 1990; Roseman et al., 1990). only 6–9 times the population risk. Assuming a carrier frequency of 1 in
500 for BRCA1 and BRCA2 mutations, the familial relative risk in this
age group would be predicted to be around 1.05, much lower than the
to identify any such study. Further evidence for the lack of 1.7 estimated in our report. Thus other genes, perhaps with more
publication bias comes from the plots of relative risk by study. If common alterations, conferring lower risks, are likely to be important in
publication bias is operating, one would expect that, of published explaining familial breast cancer at higher ages.
studies, the larger ones report the smaller effects, as small positive Although the risk of breast cancer associated with a family
trials are more likely to be published than negative ones (Egger and history is higher in younger women, some studies suggest that the
Smith, 1995). This can be examined using the funnel plot (a modifica- risk is particularly high in women under 40 and then falls off
tion of Fig. 1) in which the effect size is plotted against sample size. If rapidly to a background level of elevated risk. The recent increase
this is done, the plot resembles an inverted funnel, with the results of the in our understanding of the genetic basis of breast cancer has
smaller studies being more widely scattered than those of the larger created a renewed interest in how those at increased risk because of
studies, as would be expected if there is no publication bias. family history can be identified, and how those risks might be
A second potentially important form of bias in the case-control modified. There is thus a need for age-specific risks to be more
and some of the retrospective cohort studies is recall bias. Because precisely quantified to enable appropriate counselling to be pro-
women with breast cancer are more likely to remember a positive vided for at-risk women and for use in determining treatment for
family history than control subjects, these study designs are likely those at risk. Our report has provided estimates for broad categories
to overestimate the effect size. This bias is avoided by prospective of age and family history, but meta-analysis based on individual
studies, and indeed there the risk estimates from the four prospec- data will be required to provide more precise age-specific risks.
tive cohorts are less than those for the other types of study.
However, this difference may also be partly accounted for by age
differences in the study populations.
ACKNOWLEDGEMENTS
Confounding by other risk factors for breast cancer (e.g., age at
menarche, parity, age at first birth, age at menopause) may also bias We thank Miss A. Matthews for help in obtaining copies of
results. However, 14 studies reported crude risk estimates and risk publications referred to in this study. B.A.J.P. is a Gibb Fellow of
estimates after adjustment for other risk factors (Bain et al., 1980; the Cancer Research Campaign (CRC), and P.D.P.P. and D.F.E. are
Brinton et al., 1995; Byrne et al., 1991; Chen et al., 1994; Parazzini supported by the CRC.

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