Journal Publication

Family History Score as a Predictor of Breast Cancer Mortality: Prospective data from the Cancer Prevention Study II, United States, 1982-1991
print version

by Quanhe Yang, Muin Khoury, Carmen Rodriguez, Eugenia E. Calle, Lilith M. Tatham, and W. Dana Flanders

	Abstract
	Materials and Methods
	Results
	References
	Discussion
	Tables

Abstract

A consistent predictor of a woman's risk for breast cancer is a family history of the
disease. Most studies of family history and breast cancer have used the number of affected
relatives in the family to calculate relative risk, but have not considered the heterogeneity of the
familial risk for breast cancer in a systematic way. Using data from a large prospective mortality
study of US adults, the authors compared simple classification of family history of breast cancer
(Yes/ No) to the method of using a family history score (FHS), which takes into account the
effects of family structure, age, and birth-cohort as predictors of breast cancer mortality. After 9
years of follow-up 1,428 cases of fatal breast cancer were observed among 453,073 women with
complete information on number and age of siblings and family history. Using the FHS, about
one third of women with a positive family history of breast cancer were at no higher risk for
breast cancer mortality than those without a family history of the disease. As a quantitative
measure of relative risk for each family, the FHS gave a better fit to the data, and it provided an
incremental improvement of predictive accuracy of developing fatal breast cancer. FHS also can
be used as a categorical variable to stratify families, allowing researchers to focus on which risk
groups would benefit from conducting further genetic analysis and to test the effects of genetic
factors, environmental exposure and gene-environment interactions on the etiology of
development of breast cancer.

Studies have consistently shown that women with a positive family history of breast
cancer in a first-degree relative have a higher risk of developing breast cancer than women
without a family history of the disease (1-7). The increased risk is further elevated if two first-degree
relatives have the disease (1, 8-11). Highest risk is experienced by those whose relatives
developed breast cancer early in their lives (2, 8, 9, 12), but risk may be elevated even if the
relative was affected when she was more than 70 years of age (3). Some reports have suggested a
steady decrease in the association between a positive family history and the risk for breast cancer
with increasing age (6, 12), whereas others found no variation in risk across age groups (13-16).
Other studies have argued that, for most women with a family history of breast cancer,
particularly those in whose mothers breast cancer was diagnosed when they were older, the
excess risk is not large (3, 13, 14). Several studies have shown that there is clear evidence for the
role of three genes (BRCA1, BRCA2, and p53) as the etiologic basis for the greatly increased risk
for breast cancer observed in some families (17-21).

Clearly, studies of family history and breast cancer indicate a high degree of heterogeneity
of familial risk for breast cancer. Breast cancer is likely to be multifactorial, involving genetic
factors, environmental exposure, and the gene-environment interaction. Many studies of family
history and breast cancer define exposure as the number of affected first-degree or second-degree
relatives (coded as 0, 1, or 2 or more), sometimes stratified by the relative's age at onset of the
disease. This method of using family-history information does not take into account the possible
effects of family structure, age, or racial differences among families with a positive family history
in assessing familial risk for breast cancer. It also fails to consider systematically the
heterogeneity of the familial risk for breast cancer, which may vary considerably among families.

In this study, we compare the method of using simple categories of observed numbers of cases of breast cancer in a family (0, 1, 2, or more) with using a quantitative family history score (FHS) method to predict breast cancer mortality. We also examine the power of different methods of defining a positive family history of breast cancer in predicting fatal breast cancer. The study uses data from a large prospective mortality study, the Cancer Prevention Study II (CPS-II), United States, 1982-1991. Although FHS had been used to study other chronic diseases (22-24), there is no prospective study, to our knowledge, which used FHS as a predictor of fatal breast cancer.

Materials and Methods

^{Cancer Prevention Study II}

Women in this study were selected from the 676,526 female participants of the Cancer
Prevention Study II, a prospective mortality study of about 1.2 million American men and
women begun by the American Cancer Society in 1982. Participants were identified and enrolled
by more than 77,000 American Cancer Society volunteers in all 50 States, the District of
Columbia, and Puerto Rico (25). In 1982, participants completed a confidential questionnaire that
included personal identifiers; demographic characteristics; personal and family history of breast
cancer and other diseases; and various behavioral, environmental, occupational, and dietary
exposures. The median age of female study participants in 1982 was 56 years; 75 percent of the
women were from 45 to 70 years of age, and none was younger than 30 years old.

Every 2 years, from 1982 through 1988, volunteers made personal inquiries to determine
whether or not study participants were living and to record the date and place of all deaths.
Automated linkage using the National Death Index (NDI) was used to extend follow-up through
December 31, 1991 (26) and to identify women who had died among the 13,219 women lost to
follow-up between 1982 and 1988. Mortality follow-up was completed through December 31,
1991; at that time 615,009 women (90.9 percent) were still living, 59,439 (8.8 percent) had died,
and for 2,078 (0.3 percent), follow-up stopped in September 1988 because of insufficient data for
NDI linkage.

Population for analysis

From the initial group of 676,526 participants, we excluded from the analysis 3,275
women (12 breast cancer deaths) with incomplete information on race, 56,861 women (3,048
breast cancer deaths) who had prevalent cancer (except nonmelanoma skin cancer) at study entry
in 1982, and 163,317 women (581 breast cancer deaths) with incomplete family history
information. After nine years of follow-up, 1,428 eligible cases of fatal breast cancer were
observed among 453,073 women. We treated these women as 453,073 families and assumed that
no two women were from the same family. Among 1,428 eligible cases, 170 (11.9%) had family
history of breast cancer. We used only mother's and sisters' information for the analysis and
excluded all males from the family in order to calculate FHS.

Data on family history of cancer

Information about history of cancer in the parents and siblings (up to six siblings) was
elicited on the 1982 questionnaire. This information included whether the parents and siblings
were still living; the age and sex of siblings and if deceased, their age at death; and whether a
diagnosis of cancer had been made in family members, the type of cancer, and the age at which
the diagnosis was made.

Derivation of family history score

Breast cancer risk among families was measured using a statistic that describes deviations
from expected risk for each family, and which takes into account family structure and the risk
covariates of family members (age, sex, race, and birth-cohort) (22, 27, 28). We calculated
standardized statistic for the ith family as follows:

where Oij is the observed breast cancer status for jth member in family I (0 or 1), and Eij is the expected risk for breast cancer for the jth member in family I. Ti is the family history score for
family I.

The expected risk for breast cancer for each person in a family was obtained by
multiplying age, race, and time-specific U. S. cancer-incidence rates from the Surveillance,
Epidemiology, and End Results (SEER) program by age, race, and birth cohort-specific person-years
at risk. Person-years at risk were accumulated until age at interview or age at death for
people without breast cancer or age when a diagnosis of breast cancer was made for people with
breast cancer. We estimated the cumulative incidence (risk) for breast cancer and the risk of a
person developing breast cancer by a specific age as follows (29):

where k is the age group, ID is the incidence density in the kth age group, and t is the age
interval. For people aged 65 years and older in 1982, we used 1973 SEER breast cancer-incidence
rates, and for people younger than 65 years of age at interview, we used 1982 SEER breast
cancer-incidence rates. The calculation of the expected occurrence of breast cancer takes into
account age, race, and birth-cohort differences in breast cancer incidence.

A negative value of FHS indicates that a family contains fewer women with breast cancer
than would be expected, and a positive value of FHS indicates that a family contains more
women with breast cancer cases than expected. The magnitude of the negative value of FHS was
mainly determined by the family size and average age of the family members. The larger families
with an older average age among family members without family history of breast cancer had a
larger negative FHS because the expected value of breast cancer for those families was high
(formula 1). Similarly, the smaller families with younger average age and with family history of
breast cancer had larger positive value of FHS. In CPS-II data set, all families with negative FHS
had no family history of breast cancer. The relative risks of developing fatal breast cancer among
families with a negative FHS was calculated by classifying FHS into 10 groups. This analysis
showed no trend and risks remained stable among these groups (results not shown). In the
present study, therefore, we set the FHS for the families with negative FHS equal to zero since
the main purpose of the study was to compare different methods of defining positive family
history of breast cancer to predict future cases of breast cancer mortality (22, 23).

There are primarily two methods used to calculate FHS; each version is based on a
comparison of the observed number of cases in a family with the expected number during the
observation period, taking into account some covariates of family (22, 27). We presented our
results using the method of calculating FHS developed by Chakroborty et al. (27). Williams et al.
(22) proposed a slightly different method to calculate FHS which used a correction term in the
formula to approximate the normal distribution. The usage of correction term set the FHS of all
families with expected values <0.5 to zero. Williams et al. (22) compared these two methods and
concluded that their outcomes were similar. For our analysis, both methods gave similar rankings
of positive FHS with different magnitudes of the score. Regardless of which method we used, the
results (the relative risk for breast cancer obtained by FHS) remained unchanged.

Statistical analysis

To assess the association between a family history of breast cancer and fatal breast
cancer, we used two different approaches. First, we classified families by the observed number of
cases of breast cancer in first degree relatives as follows: no family history of breast cancer, one
first-degree relative with cancer, and two or more first-degree relatives with breast cancer (only
0.4 percent of families with a positive family history of breast cancer had three or more first-degree
relatives with breast cancer). Second, we classified all families by FHS into four groups:
zero FHS, and three equal groups (33 percent each group) with a low, medium, or high FHS
among families with positive FHS. We compared the relative risk of developing breast cancer as
measured by these two different methods of measuring family history. We used the proportional
hazards model to calculate hazard ratios (30) while adjusting for the effects of multiple risk
factors, (menopausal status; age at menarche; age when first living child was born; history of
breast cysts; oral contraceptive use; other estrogen use; body-mass index; diethystilbestrol
(DES); education; religion; race; alcohol use; smoking status; and among postmenopausal
women, the age at which periods stopped) and were stratified on the basis of age at enrollment.

Because the estimates of the adjusted relative risks (odds ratios) obtained by logistic
regression were virtually identical to those obtained by proportional hazard model, we used
logistic regression to examine the goodness-of-fit and the accuracy of different methods of
defining a family history of breast cancer in predicting the development of fatal breast cancer.
Cox and Snell (31) and Nagelkerke (32) proposed a generalized coefficient of determination (R²)
and an adjusted generalized coefficient of determination (R²__adj) to give an objective measure of
how well each model fits the data. The R² and R²__adj are analogous in interpretation to R² in linear
regression analysis (32). The receiver operating characteristic (ROC) curve displays graphically
the discriminatory ability of a logistic model. The ROC curve rises quickly with high predictive
accuracy. Thus, the area under the curve (C statistic) approaches one for a model with higher
predictive accuracy (33). The value of C statistics range from 0 to 1.

Results

As of 1982, 32,937 (7.3 percent) women reported that breast cancer had been diagnosed
in either their mothers or sisters. Figure 1 shows the frequency distribution of breast cancer FHS
across all families. The FHS ranged from a minimum of 0 to a maximum of 46.2. The distribution
of positive FHS was skewed to the right with a mean FHS of 5.2 (standard deviation 2.2). To
examine the relationship between the observed number of relatives with breast cancer in the
families and the FHS, we tabulated the observed number of relatives with breast cancer in each of
four FHS categories: zero, low (lower 1/ 3 of positive FHSs), medium (middle 1/ 3 of positive
FHSs), and high (highest 1/ 3 of positive FHSs)( Table 1). As expected, all families without a
family history of breast cancer had a zero FHS. Among families with a family history of breast
cancer, the higher FHSs were associated with an increased number of relatives who had breast
cancer. The kappa statistics of ? = 0.65 (se = 0.0015) and z = 430 indicate that there is a good
degree of agreement between the two approaches of classifying family history of breast cancer
(34).

The families in which more women had more breast cancer tended to be larger (more
sisters) and older on average than those families in which fewer women had breast cancer, and a
larger proportion of the families were white (Table 2). The average expected number of breast
cancer cases calculated by cancer incidence rates was also higher for the families with a positive
history of breast cancer than for the families without a history of breast cancer (Table 2). On the
other hand, the families with higher positive FHSs tended to be smaller (there were fewer sisters
in the families) and on average, younger, and a larger proportion of the families were from other
racial groups. Among families with positive FHSs, FHSs were negatively correlated with
expected number of breast cancer cases (Table 2).

Table 3 compares the effects of using different methods of defining a positive family
history on the relative hazard for breast cancer mortality by age groups (we derived the adjusted
relative hazard by using a proportional hazard model and controlling for other covariates). Using
the usual definition of "any affected mother or sisters" resulted in calculated risks which were
positively associated with a positive family history of breast cancer, with the magnitude of the
relative hazard increasing with the age of the participants. Using FHS, about one third of the
families with a positive family history (lower 1/ 3 FHS families) were not at significantly higher
risk for death from breast cancer than those families with no family history of the disease. As
shown before, compared with women whose families had high FHSs, women whose families had
low FHSs were more likely to be from families with more and older family members; these
families had a higher expected number of breast cancer cases. The simple method of classifying
families by the number of the women with breast cancer would not be able to distinguish these
families which had a positive family history of breast cancer but were not at higher risk of breast
cancer mortality. In addition, the FHS also showed a dose-response relationship with the
increased risk for breast cancer mortality overall and in each age group. The adjusted relative
hazard of breast cancer increased from 1.0 (95% CI, 0.8-1.4) for women from families with a low
FHS to 2.3 (95% CI, 1.6-2.6) for women from families with a high FHS.

Both R² and adjusted R²  were larger when we used the FHS in the model as a continuous
variable than when we used the number of observed affected relatives in the family to predict
breast cancer mortality. The C statistics also increased from 0.73 to 0.75, representing a 5 percent
increase of the area under the ROC curve (Table 4). We found the same pattern when we
compared using three equal positive FHS categories to predict breast cancer mortality with using
categories of 0, 1, or 2+ for the observed number of cases of breast cancer in the family. For the
130 families in which 3 or more first degree relatives had breast cancer, none of the women
participants developed fatal breast, so we were unable to calculate the odds ratios by logistic
regression. Instead, we combined these families with those in which two or more relatives had
breast cancer (Table 4). It is clear that by using FHS in the analysis the models fit the data better
and gave an incremental improvement of predictive accuracy than would have resulted from
classifying the family on the basis of the number of women in the family with breast cancer.

Discussion

In this study, we used relative hazard, which was virtually identical to the relative risk, to
evaluate the FHS as a predictor of breast cancer mortality. Our analyses suggest that FHS gave a
better fit to the data and provided a higher degree of predictive accuracy of breast cancer
mortality than simply predicting that risk by designating family history as either positive or
negative.

Because FHS is a continuous variable, every family was ranked by the FHS and used in
the analysis. Studies conducted for other diseases (23, 35) have suggested that, when estimating
the relative risk of any specific risk factor in disease, using continuous FHS ranking to control for
effects of family history should be more powerful than using either the observed number of
breast cancer cases in a family or a two-or-three category grouping based on the number of
affected individuals.

We calculated FHS on the basis of information about nuclear families. Presumably, the
possible effects of family structure and age on familial risk of breast cancer would be greater
among extended families than among nuclear families. The number of breast cancer cases would
be greater among extended families than among nuclear families. The value of using FHS to
assess the impact of a positive family history on breast cancer risk should increase with a greater
number of relatives and with the complexity of the pedigrees. In our study, we assumed that
those 1,428 eligible cases (170 cases had family history of breast cancer) were from different
families. If those cases were not from different families, the FHS could overestimate the strength
of association of FHS with fatal breast cancer mortality.

We excluded from our study 26 percent of CPS-II participants for whom family history
information was incomplete; it is possible that the relative risk could differ between those with
completed family information and those without it, and such a difference could bias the results. A
previous study using a full data set of CPS-II on family history, age, and risk for breast cancer (6)
showed similar relative risks for breast cancer by age groups such as those in our study. Such
findings may suggest that the families for whom family information is incomplete were more
likely to be not substantial different from other families. It should also be pointed out that the end
point of CPS-II study was to determine breast cancer mortality. By deleting all breast cancer
cases at baseline (1982), we limited fatal cases to those which were diagnosed and become fatal 
within nine years of follow-up. This represented a group of more aggressive breast cancer cases.
It is unclear how FHS would predict breast cancer mortality at a longer period of follow-up. In
addition, the ability of FHS to predict breast cancer incidence remains unknown.

Other studies have shown that the family history of breast cancer, even among first
degree relatives, is not perfectly reported (36-38). To assess the extent of possible
underascertainment, we compared the reported prevalence of breast cancer among first degree
relatives of CPS-II participants with estimates of expected prevalence based on breast cancer
age-specific prevalence rates from the Connecticut Tumor Registry (39). The reported prevalence
of a mother with breast cancer was 99% of the expected prevalence and the reported prevalence
of sister( s) with breast cancer was 86% of the expected. If the probability of developing fatal
breast cancer are nondifferential between reported families and not-reported families with family
history of breast cancer, the estimates of relative risk using FHS will be diluted towards null.
Differential probabilities of developing fatal breast cancer between reported and not-reported
families would affect the estimation in either direction.

The FHS method has been shown to be capable of identifying "high-risk families"
(families with positive family history of breast cancer) who may have no increased risk for breast
cancer and of identifying an unaffected women's increased risk of developing breast cancer in the
future. This knowledge would provide a better rationale for identifying the women who are most
likely to be at high risk for fatal breast cancer. As a quantitative measure of relative risk for each
family, the FHS can be used as a covariate in risk-factor analysis or as a categorical variable to
stratify families by FHS. For example, if we classify the positive FHS into 20 groups (five
percentiles), compared with women without family history of breast cancer, the adjusted risk of
breast cancer increased from 1.0 [95% CI, 0.7-1.5] for women of first five percentile group to 2.1 (95% CI, 1.3-3.1] for women tenth five percentile group to 5.4 [95% CI, 1.7-17.2) for women of last five percentile group. This method of cross-classifying families may allow researchers to better identify those who would benefit from further genetic analysis and to test the effects of genetic factors, environmental exposures and gene-environment interaction on breast cancer etiology.

Acknowledgments

The authors thank J. David Erickson and Jim Buehler for their helpful suggestions and
Michael Atkinson for his technical assistance. They also thank two anonymous reviewers for
their constructive comments.

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TABLE 1.
Distribution of families by the observed number of first degree relatives with breast cancer and by family history score (FHS): Cancer Prevention Study II, United States, 1982- States, 1982-91

TABLE 2.
Family characteristics by different methods of classifying family history of breast cancer:  Cancer Prevention Study II, United States, 1982-1991

* The family includes mothers and sisters only.
H SD = Standard deviation; FHS, family history score.
I We divided all families with positive family history score (FHS) into three equal groups (1 = low, first 33%; 2 = medium, second 33%; and 3 = high FHS, third 33%)

TABLE 3.
Comparison of the effect of different family history definitions on the risk of fatal breast cancer:  Cancer Prevention Study II, United States, 1982-1991

* FHS, family history score; CI, confidence interval.
H All families with positive FHS were divided into three equal groups, I.e., 1 = low, first 33%; 2 = medium, second 33%; and 3 = high FHS, third 33%.
I The relative hazard can not be calculated because there were no cases of breast cancer in the category.
x Estimates were adjusted for menopausal status; age at menarche; age when first living child was born; history of breast cysts; oral contraceptive use; other estrogen use; body-mass index; diethystilbestrol (DES); education; religion; race; alcohol use; smoking status; and among postmenopausal women, the age at which periods stopped.

* Estimates were adjusted for menopausal status; age at menarche; age when first living child was born; history of breast cysts; oral contraceptive use; other estrogen use; body-mass index; diethystilbestrol (DES); education; religion; race; alcohol use; smoking status; and among postmenopausal women, the age at which periods stopped.
H CI, confidence interval; FHS, family history score.
I Observed breast cancer cases and FHS used as continuous variables.
x Observed breast cancer cases and FHS used as categorical variables. All families with positive FHS were divided into three equal groups, i.e., 1 = low, first 33%; 2 = medium, second 33%; and 3 = high FHS, third 33%.