American Jouna) of Eptdenuotogy Copyright ©1991 by Tne Johns Hopkins University School of Hygrane and Public Health All rights reserved
Voi 134, No 11 Printed in U S.A
Heterogeneity of Breast Cancer Risk in Families of Young Breast Cancer Patients and Controls
Ann Grossbart Schwartz,1-2 Rachel Kaufmann,3 and Patricia P. Moll3'
Familial heterogeneity of breast cancer risk was assessed among 4,159 first-degree female relatives of 1,074 population-based, young breast cancer cases (aged 20-54 years) diagnosed from December 1,1980 to December 31,1982 and 4,120 first-degree female relatives of 998 age- and race-matched, population-based controls from the metropolitan Detroit, Michigan, area. The family risk index method used for analysis considers family size, age, and race differences among families in the assessment of family risk. Families of cases showed a higher risk of breast cancer than did families of controls, with case families 1.80 to 4.24 times more likely to be defined as high risk than control families; the magnitude of the risk differential was dependent on the definition of high risk. Within the case families only, familial heterogeneity of risk was suggested, with a small proportion of families (less than 5%) at lower risk of breast cancer than most case families. A number of reproductive risk factors, age, race, and histologic type of cancer for the proband, and several family characteristics were investigated to help characterize the case families at higher and lower risk. Am J Epidemiol 1991 ;134:1325-34. breast neoplasms; family characteristics; genetics
The association between family history of breast cancer and breast cancer risk has been well-documented in the epidemiologic literature (I-5). It has also been recognized that breast cancer risk varies with the characteristics of the disease in affected family members. Specifically, risk has been shown to be higher among relatives of cases diagnosed at Received for publication January 18, 1990, and in final form June 18, 1991. ' Division of Epidemiology, Michigan Cancer Foundation, Detroit, Ml 2 Current address: Department of Clinical Epidemiology and Preventive Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 3 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Ml. 4 Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, Ml Reprint requests to Dr. Ann G. Schwartz, Department of Clinical Epidemiology and Preventive Medicine, School of Medicine, M200 Scaife Hal, University of Pittsburgh, Pittsburgh, PA, 15261. This research was supported in part by Centers for Disease Control contract 200-80-0555, National Cancer Institute contract CN-55423, and the United Foundation of Detroit
an early age and with bilateral disease than among relatives of older, unilateral cases (1, 5). More recently, studies have provided evidence for heterogeneity in the inheritance of breast cancer, with selected families demonstrating risk consistent with a dominantly inherited form of the disease (6-8). In addition, recessive inheritance for synchronous onset, bilateral, premenopausal breast cancer has been reported (9). The variation in risk among families of young breast cancer cases has not been well-defined. In this study, a new measure of familial heterogeneity of risk is used to assess breast cancer risk among first-degree relatives of young breast cancer cases (aged 20-54 years) and among first-degree relatives of population-based controls. The family risk index method of analysis allows for consideration of family size and structure in the assessment of family risk. Familial heterogeneity implies that a genetic or environmental factor related to family membership is contributing
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Schwartz et a).
to disease risk. Both the number of cancers per family and the age at diagnosis of breast cancer contribute to familial heterogeneity of risk. Families at lower risk of breast cancer, with fewer cancers than expected or cancers diagnosed at later-than-expected ages, contribute to familial heterogeneity of risk. Families at higher risk, with more cancers than expected or cancers diagnosed at earlier-than-expected ages, also contribute to familial heterogeneity of risk. Risk differences between families of cases and families of controls are evaluated, as well as risk differences among just the families of young breast cancer cases, to address the following questions: 1) Is the risk of breast cancer greater in families of young breast cancer cases than in families of agematched controls? 2) Is the risk of breast cancer in relatives of young breast cancer cases heterogeneous? If there is no familial heterogeneity of breast cancer risk, then cancer occurrence does not vary among families after family size, race, and age differences among families are considered. The method utilized allows for the identification of relatively higher- and lower-risk families. Associations between heterogeneity in familial risk and variability in other risk factors for breast cancer in the probands with breast cancer also are investigated. MATERIALS AND METHODS
Data were collected for the metropolitan Detroit, Michigan, segment of the Cancer and Steroid Hormone Study, a collaborative case-control study conducted by eight participants in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, a network of populationbased cancer surveillance systems (10). Study participants for the current analyses included first-degree female family members (mothers, sisters, and daughters) identified through case and control women (probands) who participated in the Cancer and Steroid Hormone Study. The cases included female residents of metropolitan Detroit who were diagnosed at ages 20-54 years with invasive, microscopically confirmed primary breast cancer between December 1, 1980 and De-
cember 31, 1982. This group of women was identified through the Metropolitan Detroit Cancer Surveillance System of the Michigan Cancer Foundation Division of Epidemiology. Of the 1,324 breast cancer cases identified, 1,089 (82.3 percent) completed interviews. Thirteen of the cases reported races other than black or white, and their families were excluded from the analyses. Relatives with incomplete information were excluded as were two entire families. After the exclusions described above, the sample for this study included 1,074 case probands (880 white and 194 black), 1,065 of their mothers, 1,748 of their sisters, and 1,346 of their daughters. The remainder of the study population consisted of female family members ascertained through controls who were free of cancer and were chosen randomly from the same geographic area as the cases by using the random digit dialing method of Waksberg (11). Controls were frequency matched to the cases by 5-year age group and race. Of the 1,317 controls selected, 1,024 (77.8 percent) completed an interview. Ten controls were excluded later because two members of the same family had participated; eliminating these controls was necessary to avoid duplicating family members in the data set. An additional 13 families were excluded because the controls reported races other than black or white. Three families were later eliminated because of lack of complete data as were individual relatives with missing data. After the exclusions described above, the sample for this study included 998 control probands (787 white and 211 black), 985 of their mothers, 1,627 of their sisters, and 1,508 of their daughters. The interviews administered in the probands' homes included questions concerning the cancer status of female family members, detailing the site of cancer and age at diagnosis, as well as vital status of female family members and age at interview, if alive, or age at death. The occurrence of cancer among relatives was not verified. Cases and controls were questioned about reproductive history and other factors known to influence risk of breast cancer.
Familial Heterogeneity of Breast Cancer Risk Information regarding the breast cancer histologic type of the cases was obtained from the Metropolitan Detroit Cancer Surveillance System. Additional details concerning the study design and execution have been published elsewhere (12). To examine familial heterogeneity of risk for breast cancer, we adapted the family risk index method for a case-control study. The family risk index method provides an assessment of heterogeneity of cancer risk among families, while allowing for differences in family size and composition. The method is based on the ranking of a standardized risk measure, the family risk index, for families compared with randomly generated age-, race-, and size-matched unrelated groups. In this study, only first-degree female relatives are included. The calculation of the family risk index, as applied in another populationbased study of cancer, and its validation are described in detail elsewhere (13). Briefly, the family risk index is a standardized Poisson variable calculated as the sum of the observed number of cancers for a family minus the sum of the expected number of cancers for the family, divided by the square root of the sum of the expected number of cancers for the family. The expected numbers are obtained by multiplying age-, sex-, and race-specific cancer incidence rates by each individual's person-years at risk. Person-years at risk are accumulated from birth until age at interview or age at death for persons without cancer, or age at diagnosis for persons with cancer. For this analysis, the rates used to calculate the expected numbers of cancers were average annual age, race-, and sex-specific breast cancer incidence rates for the metropolitan Detroit area from 1978 to 1981 and were obtained from the Metropolitan Detroit Cancer Surveillance System. The family risk index was calculated for each of the families in the study. For each family, 99 comparison groups of unrelated individuals were created through a permutation procedure (13). The comparison groups were composed of randomly chosen individuals from families in the study and had the same size, race, and age com-
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position (in 5-year age groups) as the biologic families. Risk indices were calculated for each of the 99 comparison groups. The risk indices for the biologic families were compared with the risk indices of their 99 comparison groups and assigned a rank from one to 100, providing a comparative measure of risk for each family. High ranks for the biologic families indicated that biologic families were at higher risk of cancer than random groups of the same race, age, and size. Low ranks for the biologic families indicated that families were at lower risk than random groups. Ranking also provided a means of testing the statistical significance of familial heterogeneity of cancer risk for the entire study population. If there were no familial heterogeneity of risk, then cancer occurrence would not be expected to vary among families after the size, race, and age differences among families were taken into account, and the ranks of families relative to their random groups would be expected to be approximately uniformly distributed on the integers 1 , 2 , . . . , 100. Deviations from the uniform distribution would imply familial heterogeneity of cancer risk. Because biologically important variation would be expressed as higher or lower risk, a chi-square goodnessof-fit test focusing on the tails of the distribution was used. Because the selection of higher and lower risk cutpoints in the distribution of ranks is somewhat arbitrary and may depend on the prevalence of the disease under study, three different cutpoints were tested. The strategy was to look for consistency of findings or the appearance of a trend toward heterogeneity of risk. The three cutpoints utilized were the 10 percent tails (ranks grouped 1-10, 11-90, and 91-100), the 5 percent tails (ranks grouped 1-5, 695, and 96-100), and the 2 percent tails (ranks grouped 1-2, 3-98, and 99-100). This analysis proceeded in two steps to address the following questions: 1) Is the risk of breast cancer greater in families of young breast cancer cases than in families of agematched controls? 2) Is the risk of breast cancer in relatives of young breast cancer cases heterogeneous?
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To answer question 1, the permutation, assignment of randomly generated comparison groups and the ranking of the risk indices were carried out using the entire sample. Case and control probands were excluded from all steps of the analysis partly to account for the ascertainment scheme. First, the ranks for the control families and the ranks for the case families were separately compared with uniform distributions by using chi-square tests to locate deviations from uniformity in the tails, as described above. Then the magnitude of the differences in the distribution of ranks between case and control families was evaluated by comparing the observed number of case families within the highest rank groups with the expected number of case families under the assumption that the distribution of ranks for the case families is the same as the distribution of ranks for the control families. The expected number was calculated as the proportion of control families observed within the highest rank group multiplied by the total number of case families. A chisquare goodness-of-fit test was used to test for significant differences between the observed number of case families compared with the expected number of case families under the null hypothesis that risk of breast cancer among case families was equivalent to risk of breast cancer among control families in the upper 10 percent tail, the upper 5 percent tail, and the upper 2 percent tail. The permutation, assignment of randomly generated comparison groups, and the ranking of the risk indices was repeated within only the case families to address question 2. Comparison of these ranks with a uniform distribution was used to test for heterogeneity of breast cancer risk among families who were all ascertained through one family member with breast cancer. RESULTS Sample description
A brief description of the families in the sample is presented in table 1. Case families and control families were largely similar in terms of size (number of sisters and number
TABLE 1. Description of families identified through breast cancer case and control probands, metropolitan Detroit, Michigan, 1980-1982 Case families (n - 1,074)
Control famffies (n = 998)
Age of proband (years) (14.0) 20-34 (11.2)* (27.2) 35-44 (32.5) (56.3) (58.8) 45-54 Race (81.9) (78.9) White (18.1) (21.1) Black Mean no. of sisters per proband 1.7 1.8 Mean no. of daughters per proband 1.3 1.5 Mean age at breast cancer diagnosis of proband (years) 44.5 Mean age at breast cancer diagnosis among firstdegree female relatives (years) 54.3 54.6 No. and percent of breast cancers diagnosed among first-degree female relatives per family 952 (95.4) 0 966 (89.9) 1 100 (9.3) 45 (4.5) 8 (0.7) 2 1 (0.1) • Numbers in parentheses, percentages.
of daughters). Case families were slightly more likely than control families to be white (82 vs. 79 percent) and to have been identified through probands in the age group 3544 years (33 vs. 27 percent). The mean age at diagnosis of breast cancer for probands was 44.5 years. Only 4.6 percent of the control families reported at least one member with breast cancer, while 10.0 percent of the case families reported one or more family members with cancer. Relatives in case families were approximately the same mean age at diagnosis of breast cancer as relatives of controls (54.3 and 54.6 years, respectively). Heterogeneity of risk between families of breast cancer cases and families of controls
The family risk index indicated that families of breast cancer cases were at higher
Familial Heterogeneity of Breast Cancer Risk
which presents a plot of the distribution of ranks for families of cases and figure 2 which presents a similar plot for families of controls. Utilizing all but one of the three cutpoints tested (the 10 percent tail for case
risk of breast cancer than families of controls. The mean rank for families of breast cancer cases was 48.9, while the mean rank among families of controls was 46.9. This risk differential is illustrated in figure I,
1-5
0-10
11-15
16-20
21-25
20-30
31-35
38 40
41-45
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40-50
51-55
50-00
01-05
00-70
71-75
70-10
61 -»5
00-00
01 0 5
00-100
Rank
FIGURE 1. Distribution of ranks for risk of breast cancer for first-degree female relatives of 1,074 breast cancer cases when compared with the total sample of relatives, metropolitan Detroit, Michigan, 1980-1982.
1 5
0 10 1115
10 2 0 21-25 20-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76 6 0 61-15 16-90 01 9 5 9 6
100
Rank
FIGURE 2. Distribution of ranks for risk of breast cancer for first-degree female relatives of 998 controls when compared with the total sample of relatives, metropolitan Detroit, Michigan, 1980-1982.
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TABLE 2. Observed and expected numbers of families by rank and family type when compared with the total sample of first-degree female relatives, metropolitan Detroit, Michigan, 1980-1982 Control families
CasefamSes Rank Observed
10% tails 1-10 11-90 91-100 Total 5% tails 1-5 6-95 96-100 Total 2% tails 1-2 3-98 99-100 Total
Observed
Expected
1.72 0.39 0.20
117 823 58
99.8 798.4 99.8
2.96 0.76 17.51
2.31*
998
998
21.23***
9.26 1.71 6.24
71 899 28
49.9 898.2 49.9
1,074
17.21"
998
998
18.53***
21.5 1,031.0 21.5
68.94 3.26 17.69
41 948 9
20.0 958.0 20.0
22.05 0.10 6.05
1,074
89.89***
998
998
28.20***
Expected
107.4 859.2 107.4
121 841 112 1,074
1,074
53.7 966.6 53.7
76 926 72 1,074
60 973 41 1,074
Chi-square
Chi-square
8.92 0.00 9.61
• p > 0 05; **p < 0.001; ••• p< 0.0001.
families) produced significant results for both case and control families, indicating that cancer occurrence was not randomly distributed among these families (table 2). Fewer families of controls ranked in the upper tail of the distribution than expected, indicating lower risk of breast cancer among relatives of controls than among random groups of individuals of the same age, race, and size generated from relatives of cases and controls combined. The higher-thanexpected ranks for the case families indicated that biologic families of cases were at higher risk of breast cancer than groups of women of the same age, race, and size randomly selected from the total study population of relatives. The magnitude of the differences between points in the distribution of ranks for case and control families was described in terms of the observed number of families of cases in the high end of the distribution divided by the expected number of case families. Concentrating on the upper end of the distribution in each of the three tests performed, we found that 112 case families ranked in the upper 10 percent tail while
62.3 were expected (the proportion of control families observed in the upper 10 percent tail (5.8 percent) multiplied by the number of case families (1,074) gives an expected number of 62.3; observed/expected = 1.80, p < 0.001), 72 case families ranked in the upper 5 percent tail while 30.2 were expected (observed/expected = 2.38, p < 0.001), and in the upper 2 percent tail, 41 case families were observed and 9.7 were expected (observed/expected = 4.24, p < 0.001). Heterogeneity of risk within families of breast cancer cases
Within the case families only, heterogeneity of risk for breast cancer (as determined by deviations from the uniform distribution) depended on the cutpoints tested (at the 10 percent tails, chi-square = 5.94, 2 df, p = 0.051; at the 5 percent tails, chi-square = 18.47, 2 df, p < 0.0001; at the 2 percent tails, chi-square = 66.75, 2 df, p < 0.0001). These results suggested that a small proportion of case families may be experiencing differential risk compared with the majority
Familial Heterogeneity of Breast Cancer Risk
of the families identified through young breast cancer cases. Deviations from uniformity existed primarily at the low end of the distribution, as evidenced by more families than expected at lower risk of breast cancer. If heterogeneity of breast cancer risk exists among these families, it is evidenced by variability among a small percentage of the families identified through young breast cancer cases. In an effort to characterize the breast cancer case families at higher and lower risk, we compared the families who ranked in the upper and lower 5 percent of the distribution from the analysis using only case families with middle-ranking families in terms of race, histologic type of cancer in the proband, age of diagnosis in the proband, age at breast cancer diagnosis in the relatives, and number of relatives per family. Also evaluated were a number of reproductive factors and other putative risk factors for breast cancer as reported for the proband. Continuous variables were tested for significance by using analysis of variance. Discrete variables were tested for significance by using chi-square tests. Family rank was not significantly related to any of the characteristics considered. When the effects of the above-mentioned variables were tested simultaneously in a logistic regression model comparing case probands whose families ranked I-5 with case probands whose families ranked 6-100, no statistically significant results were obtained. DISCUSSION
Family heterogeneity of breast cancer risk was demonstrated in this study of firstdegree female relatives of young breast cancer cases (aged 20-54 years) and first-degree female relatives of age- and race-matched population-based controls. Families of breast cancer cases were 1.80 to 4.24 times more likely to be defined as high risk than were families of controls. The magnitude of the observed differences increased as the definition of high risk moved from the top 10 percent to the top 2 percent of the distribution. The family risk index method pro-
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vided similar results in the comparison of cancer risk among relatives of cases with risk among relatives of controls as seen using more conventional statistical approaches (1, 3-5), namely that relatives of young breast cancer cases are at higher risk of breast cancer than are relatives of controls. In this study, as in most studies of family history of cancer, cancer occurrence among relatives was not verified; however, family reports of breast cancer occurrence among relatives have been shown to be very accurate in other studies. Love et al. (14) found that 91 percent of all breast cancers reported among first-, second- and third-degree relatives were accurate, and Schwartz (15) reported 92 percent accuracy. Even so, it is possible that cases were more likely than controls to recall positive histories of cancer among relatives, resulting in an inflated estimate of the excess risk of breast cancer among case families compared with control families. To assess the completeness of breast cancer reporting among controls, we compared the reported number of breast cancers among sisters (the group most likely to have been diagnosed close to the study period) with the expected number based on age-specific incidence rates for metropolitan Detroit for 1978-1981. The reported number of breast cancers among sisters was not significantly different than expected (p > 0.05). Although differential recall may exist, the results are consistent with those of other studies. Some variation in risk among case families only also was suggested in this study, although none of the factors considered (e.g., race, histologic type of cancer in the proband, age at breast cancer diagnosis in the relatives, and number of relatives per family) were associated with family rank. Differential recall is unlikely to present a problem in the analysis restricted to case families. Heterogeneity of risk is consistent with multiple etiologies for breast cancer, some familial and some individual. Traditionally, the focus has been directed toward age at breast cancer diagnosis. In early epidemiologic studies of family history of breast cancer, premenopausal breast cancer cases (aged
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Schwartz et al.
less than 55 years) were shown to be more likely to have a family history of breast cancer than were postmenopausal breast cancer cases (I). This premenopausal or young breast cancer subset has been treated as if risk associated with family history were uniform. Recent findings utilizing the Cancer and Steroid Hormone Study participants are difficult to compare given the variety of approaches taken to the measurement of family risk. Sattin et al. (4), in a case-control study that did not take into account family size or the age distribution of family members at risk, reported that risk of breast cancer for women with a first-degree relative diagnosed at age 45 years or younger was greater, although not statistically significantly greater, than risk to women whose first-degree relatives were diagnosed after age 45 years. Using proportional hazards and cumulative probability methods which take into account the number of family members and their ages in the calculation of family risk, Schwartz et al. (3) and Claus et al. (16) have demonstrated increased breast cancer risk to relatives of the youngest (under age 40 years) breast cancer cases as compared with relatives of the youngest controls. No variation in risk was demonstrated in this study when mean age of diagnosis in the case probands was examined. The approaches taken in the latter two studies differ from the method applied in our study in one important aspect. Families are viewed in total, as a unit, in this study, instead of the entire sample of family members being treated as independent observations. That is, in our study, the unit of inference is the family. This study also allows for the identification of those specific families at higher and lower risk by means of the family rank. While the effect of age at diagnosis in probands aged 20-54 years may have some impact on breast cancer risk among relatives, it is unlikely that age alone can be used to distinguish between the higher and lower risk families. The number of cancers per family also is not likely to distinguish risk groups without utilizing information about family size and the ages of the relatives. The validation stud-
ies of the family risk index method (13) demonstrated that families with multiple cancer cases will not always be identified as high risk after adjustment for family size and time at risk for each family member. The family risk index method provides additional discrimination for identifying risk groups among small families when there is only one family member with cancer or when there are no family members with cancer. This is seen in our study when families without cancer range in rank from one to 95 and families with one cancer range in rank from 66 to 100, reflecting variation in breast cancer risk based on the age of the relatives in addition to the number of cancers. A simple count of the number of cancers in a family cannot adequately classify families at different risk levels. Few clues about the underlying differences between high- and low-risk families were obtained by looking at the distribution of selected risk factors among probands. There are certain limitations in describing breast cancer risk among family members on the basis of characteristics of the proband. Most established risk factors for breast cancer are associated with only modest increases in risk, and it has been estimated that only 25 percent of the breast cancer occurrence can be attributed to known risk factors (17). Adding information about the presence or absence of risk factors among all family members can contribute to separating genetic influences from environmental influences. Pedigree studies have found evidence for heterogeneity in the segregation pattern of breast cancer in selected families (6-8, 18). Newman et al. (6) performed segregation analysis using nuclear families identified through the metropolitan Detroit and San Francisco Bay area portions of the Cancer and Steroid Hormone Study. The data fit an autosomal dominant model of inheritance. The frequency of the susceptibility allele was 0.0006 in the general population. On the basis of the age distribution of the probands and the probability that a woman with breast cancer carries the susceptibility allele, Newman et al. (6) estimated that approximately
Familial Heterogeneity of Breast Cancer Risk
4 percent of the breast cancer families in their sample were genetically susceptible. Extending this type of analysis for all families included in the Cancer and Steroid Hormone Study, Claus et al. (8) reported the existence of a rare autosomal dominant allele at a frequency of 0.0033, with genotype effects related to age at onset. In addition to heterogeneity in genetic susceptibility, there is heterogeneity in the mode of genetic transmission. There have been reports of both autosomal dominant and autosomal recessive inheritance among subsets of breast cancer families (7, 9, 18, 19). The search for molecular and genetic markers for breast cancer susceptibility is complicated by the heterogeneity of familial risk for this disease (20, 21). Not only is individual breast cancer risk associated with family history of breast cancer, but also in some families breast cancer risk has been found in association with other cancers among relatives, including ovarian cancer (22) and soft-tissue sarcomas (23). The other cancers observed among family members in our study include a wide range of sites, although only data for female relatives were collected. This points out the importance of obtaining complete family cancer history, including enumeration of allfirst-degreerelatives by age, sex, and year of birth. The identification of risk factors associated with familial disease is an important step in the process of understanding breast carcinogenesis. While family membership is used as a marker for unmeasured genetic and environmental contributions to disease risk, it will be necessary to incorporate environmental risk factor data for family members if we are to move beyond the current limitations of family studies (24). The family risk index method provides a means of identifying families at high and low risk for further evaluation of shared environmental factors among family members and genetic contributions to risk.
REFERENCES 1. Anderson DE. Genetic study of breast cancer identification of a high-risk group. Cancer 1974; 34:1090-7.
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2. Kelsey JL. A review of the epidemiology of human breast cancer. Epidemiol Rev 1979; 1:74-109. 3. Schwartz AG, King MC, Belle SH, et al. Risk of breast cancer to relatives of young breast cancer patients. J Natl Cancer Inst 1985;75:665-8. 4. Sattin RW, Rubin GL, Webster LA, et al. Family history and the risk of breast cancer. J Am Med Assoc 1985;253:19O8-13. 5. Ottman R, Pike MC, King MC, et al. Practical guide for estimating risk for familial breast cancer. Lancet 1983^2:556-8. 6. Newman B, Austin MA, Lee M, et al. Inheritance of human breast cancer evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A 1988;85:3044-8. 7. Andrieu N, Demenais F, Martinez M. Genetic analysis of human breast cancer implications for family study designs. Genet Epidemiol 1988;5:22533. 8. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the Cancer and Steroid Hormone Study. Am J Hum Genet 1991;48:23242. 9. Goldstein AM, Haile RWC, Hodge SE, et al. Possible heterogeneity in the segregation pattern of breast cancer in families with bilateral breast cancer. Genet Epidemiol 1988;5:121-33. 10. Young JL, Percy CL, Asire AJ, eds. Surveillance, epidemiology, and end results: incidence and mortality data, 1973-1977. Bethesda, MD: Nati Cancer Institute, 1981. (NCI monograph no. 57). 11. Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc 1976,73:40-6. 12. The Centers for Disease Control Cancer and Steroid Hormone Study. Long-term oral contraceptive use and the risk of breast cancer. J Am Med Assoc 1983;249:1591-5. 13. Schwartz AG, Boehnke M, Moll PP. Family risk index as a measure of familial heterogeneity of cancer risk. A population-based study in metropolitan Detroit. Am J Epidemiol 1988; 128:524-35. 14. Love RR, Evans AM, Josten DM. The accuracy of patient reports of a family history of cancer. J Chronic Dis 1985;38:289-93. 15. Schwartz AG. A new method for detecting familial heterogeneity of cancer risk: a population-based study in metropolitan Detroit. PhD dissertation. The University of Michigan, School of Public Health, Ann Arbor, MI, 1986. 16. Claus EB, Risch NJ, Thompson WD. Age of onset as an indicator of familial risk of breast cancer. Am J Epidemiol 1990; 131:961-72. 17. Kelsey JL, Berkowitz GS. Breast cancer epidemiology. Cancer Res 1988;48:5615-23. 18. Bishop DT, Cannon-Albright L, McLellan T, et al. Segregation and linkage analysis of nine Utah breast cancer pedigrees. Genet Epidemiol 1988;5:151-69. 19. Go RCP, King MC, Bailey-Wilson JE, et al. Genetic epidemiology of breast cancer and associated cancers in high risk families. I. Segregation analysis. J Natl Cancer Inst 1983;71:455-61. 20. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-9. 21. Skolnick MH, Cannon-Albright LA, Goldgar DE, et al. Inheritance of proliferative breast disease in breast cancer kindreds. Science 1990-^50:1715-20.
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22. Schildkraut JM, Thompson WD. Relationship of epithelial ovarian cancer to other malignancies within families. Genet Epidemiol l988;5:355-67. 23. Li FP, Fraumeni JF. Soft-tissue sarcomas, breast cancer and other neoplasms. A familial syndrome?
Ann Intern Med 1969;71:747-52. 24. Bailey-Wilson JE, Cannon LA, King M-K. Genetic analysis of human breast cancer a synthesis of contributions to GAW IV. Genet Epidemiol 1986; l(suppl): 15-35.
Voi 134, No 11 Printed in U S.A
Heterogeneity of Breast Cancer Risk in Families of Young Breast Cancer Patients and Controls
Ann Grossbart Schwartz,1-2 Rachel Kaufmann,3 and Patricia P. Moll3'
Familial heterogeneity of breast cancer risk was assessed among 4,159 first-degree female relatives of 1,074 population-based, young breast cancer cases (aged 20-54 years) diagnosed from December 1,1980 to December 31,1982 and 4,120 first-degree female relatives of 998 age- and race-matched, population-based controls from the metropolitan Detroit, Michigan, area. The family risk index method used for analysis considers family size, age, and race differences among families in the assessment of family risk. Families of cases showed a higher risk of breast cancer than did families of controls, with case families 1.80 to 4.24 times more likely to be defined as high risk than control families; the magnitude of the risk differential was dependent on the definition of high risk. Within the case families only, familial heterogeneity of risk was suggested, with a small proportion of families (less than 5%) at lower risk of breast cancer than most case families. A number of reproductive risk factors, age, race, and histologic type of cancer for the proband, and several family characteristics were investigated to help characterize the case families at higher and lower risk. Am J Epidemiol 1991 ;134:1325-34. breast neoplasms; family characteristics; genetics
The association between family history of breast cancer and breast cancer risk has been well-documented in the epidemiologic literature (I-5). It has also been recognized that breast cancer risk varies with the characteristics of the disease in affected family members. Specifically, risk has been shown to be higher among relatives of cases diagnosed at Received for publication January 18, 1990, and in final form June 18, 1991. ' Division of Epidemiology, Michigan Cancer Foundation, Detroit, Ml 2 Current address: Department of Clinical Epidemiology and Preventive Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA. 3 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Ml. 4 Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, Ml Reprint requests to Dr. Ann G. Schwartz, Department of Clinical Epidemiology and Preventive Medicine, School of Medicine, M200 Scaife Hal, University of Pittsburgh, Pittsburgh, PA, 15261. This research was supported in part by Centers for Disease Control contract 200-80-0555, National Cancer Institute contract CN-55423, and the United Foundation of Detroit
an early age and with bilateral disease than among relatives of older, unilateral cases (1, 5). More recently, studies have provided evidence for heterogeneity in the inheritance of breast cancer, with selected families demonstrating risk consistent with a dominantly inherited form of the disease (6-8). In addition, recessive inheritance for synchronous onset, bilateral, premenopausal breast cancer has been reported (9). The variation in risk among families of young breast cancer cases has not been well-defined. In this study, a new measure of familial heterogeneity of risk is used to assess breast cancer risk among first-degree relatives of young breast cancer cases (aged 20-54 years) and among first-degree relatives of population-based controls. The family risk index method of analysis allows for consideration of family size and structure in the assessment of family risk. Familial heterogeneity implies that a genetic or environmental factor related to family membership is contributing
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Schwartz et a).
to disease risk. Both the number of cancers per family and the age at diagnosis of breast cancer contribute to familial heterogeneity of risk. Families at lower risk of breast cancer, with fewer cancers than expected or cancers diagnosed at later-than-expected ages, contribute to familial heterogeneity of risk. Families at higher risk, with more cancers than expected or cancers diagnosed at earlier-than-expected ages, also contribute to familial heterogeneity of risk. Risk differences between families of cases and families of controls are evaluated, as well as risk differences among just the families of young breast cancer cases, to address the following questions: 1) Is the risk of breast cancer greater in families of young breast cancer cases than in families of agematched controls? 2) Is the risk of breast cancer in relatives of young breast cancer cases heterogeneous? If there is no familial heterogeneity of breast cancer risk, then cancer occurrence does not vary among families after family size, race, and age differences among families are considered. The method utilized allows for the identification of relatively higher- and lower-risk families. Associations between heterogeneity in familial risk and variability in other risk factors for breast cancer in the probands with breast cancer also are investigated. MATERIALS AND METHODS
Data were collected for the metropolitan Detroit, Michigan, segment of the Cancer and Steroid Hormone Study, a collaborative case-control study conducted by eight participants in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, a network of populationbased cancer surveillance systems (10). Study participants for the current analyses included first-degree female family members (mothers, sisters, and daughters) identified through case and control women (probands) who participated in the Cancer and Steroid Hormone Study. The cases included female residents of metropolitan Detroit who were diagnosed at ages 20-54 years with invasive, microscopically confirmed primary breast cancer between December 1, 1980 and De-
cember 31, 1982. This group of women was identified through the Metropolitan Detroit Cancer Surveillance System of the Michigan Cancer Foundation Division of Epidemiology. Of the 1,324 breast cancer cases identified, 1,089 (82.3 percent) completed interviews. Thirteen of the cases reported races other than black or white, and their families were excluded from the analyses. Relatives with incomplete information were excluded as were two entire families. After the exclusions described above, the sample for this study included 1,074 case probands (880 white and 194 black), 1,065 of their mothers, 1,748 of their sisters, and 1,346 of their daughters. The remainder of the study population consisted of female family members ascertained through controls who were free of cancer and were chosen randomly from the same geographic area as the cases by using the random digit dialing method of Waksberg (11). Controls were frequency matched to the cases by 5-year age group and race. Of the 1,317 controls selected, 1,024 (77.8 percent) completed an interview. Ten controls were excluded later because two members of the same family had participated; eliminating these controls was necessary to avoid duplicating family members in the data set. An additional 13 families were excluded because the controls reported races other than black or white. Three families were later eliminated because of lack of complete data as were individual relatives with missing data. After the exclusions described above, the sample for this study included 998 control probands (787 white and 211 black), 985 of their mothers, 1,627 of their sisters, and 1,508 of their daughters. The interviews administered in the probands' homes included questions concerning the cancer status of female family members, detailing the site of cancer and age at diagnosis, as well as vital status of female family members and age at interview, if alive, or age at death. The occurrence of cancer among relatives was not verified. Cases and controls were questioned about reproductive history and other factors known to influence risk of breast cancer.
Familial Heterogeneity of Breast Cancer Risk Information regarding the breast cancer histologic type of the cases was obtained from the Metropolitan Detroit Cancer Surveillance System. Additional details concerning the study design and execution have been published elsewhere (12). To examine familial heterogeneity of risk for breast cancer, we adapted the family risk index method for a case-control study. The family risk index method provides an assessment of heterogeneity of cancer risk among families, while allowing for differences in family size and composition. The method is based on the ranking of a standardized risk measure, the family risk index, for families compared with randomly generated age-, race-, and size-matched unrelated groups. In this study, only first-degree female relatives are included. The calculation of the family risk index, as applied in another populationbased study of cancer, and its validation are described in detail elsewhere (13). Briefly, the family risk index is a standardized Poisson variable calculated as the sum of the observed number of cancers for a family minus the sum of the expected number of cancers for the family, divided by the square root of the sum of the expected number of cancers for the family. The expected numbers are obtained by multiplying age-, sex-, and race-specific cancer incidence rates by each individual's person-years at risk. Person-years at risk are accumulated from birth until age at interview or age at death for persons without cancer, or age at diagnosis for persons with cancer. For this analysis, the rates used to calculate the expected numbers of cancers were average annual age, race-, and sex-specific breast cancer incidence rates for the metropolitan Detroit area from 1978 to 1981 and were obtained from the Metropolitan Detroit Cancer Surveillance System. The family risk index was calculated for each of the families in the study. For each family, 99 comparison groups of unrelated individuals were created through a permutation procedure (13). The comparison groups were composed of randomly chosen individuals from families in the study and had the same size, race, and age com-
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position (in 5-year age groups) as the biologic families. Risk indices were calculated for each of the 99 comparison groups. The risk indices for the biologic families were compared with the risk indices of their 99 comparison groups and assigned a rank from one to 100, providing a comparative measure of risk for each family. High ranks for the biologic families indicated that biologic families were at higher risk of cancer than random groups of the same race, age, and size. Low ranks for the biologic families indicated that families were at lower risk than random groups. Ranking also provided a means of testing the statistical significance of familial heterogeneity of cancer risk for the entire study population. If there were no familial heterogeneity of risk, then cancer occurrence would not be expected to vary among families after the size, race, and age differences among families were taken into account, and the ranks of families relative to their random groups would be expected to be approximately uniformly distributed on the integers 1 , 2 , . . . , 100. Deviations from the uniform distribution would imply familial heterogeneity of cancer risk. Because biologically important variation would be expressed as higher or lower risk, a chi-square goodnessof-fit test focusing on the tails of the distribution was used. Because the selection of higher and lower risk cutpoints in the distribution of ranks is somewhat arbitrary and may depend on the prevalence of the disease under study, three different cutpoints were tested. The strategy was to look for consistency of findings or the appearance of a trend toward heterogeneity of risk. The three cutpoints utilized were the 10 percent tails (ranks grouped 1-10, 11-90, and 91-100), the 5 percent tails (ranks grouped 1-5, 695, and 96-100), and the 2 percent tails (ranks grouped 1-2, 3-98, and 99-100). This analysis proceeded in two steps to address the following questions: 1) Is the risk of breast cancer greater in families of young breast cancer cases than in families of agematched controls? 2) Is the risk of breast cancer in relatives of young breast cancer cases heterogeneous?
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To answer question 1, the permutation, assignment of randomly generated comparison groups and the ranking of the risk indices were carried out using the entire sample. Case and control probands were excluded from all steps of the analysis partly to account for the ascertainment scheme. First, the ranks for the control families and the ranks for the case families were separately compared with uniform distributions by using chi-square tests to locate deviations from uniformity in the tails, as described above. Then the magnitude of the differences in the distribution of ranks between case and control families was evaluated by comparing the observed number of case families within the highest rank groups with the expected number of case families under the assumption that the distribution of ranks for the case families is the same as the distribution of ranks for the control families. The expected number was calculated as the proportion of control families observed within the highest rank group multiplied by the total number of case families. A chisquare goodness-of-fit test was used to test for significant differences between the observed number of case families compared with the expected number of case families under the null hypothesis that risk of breast cancer among case families was equivalent to risk of breast cancer among control families in the upper 10 percent tail, the upper 5 percent tail, and the upper 2 percent tail. The permutation, assignment of randomly generated comparison groups, and the ranking of the risk indices was repeated within only the case families to address question 2. Comparison of these ranks with a uniform distribution was used to test for heterogeneity of breast cancer risk among families who were all ascertained through one family member with breast cancer. RESULTS Sample description
A brief description of the families in the sample is presented in table 1. Case families and control families were largely similar in terms of size (number of sisters and number
TABLE 1. Description of families identified through breast cancer case and control probands, metropolitan Detroit, Michigan, 1980-1982 Case families (n - 1,074)
Control famffies (n = 998)
Age of proband (years) (14.0) 20-34 (11.2)* (27.2) 35-44 (32.5) (56.3) (58.8) 45-54 Race (81.9) (78.9) White (18.1) (21.1) Black Mean no. of sisters per proband 1.7 1.8 Mean no. of daughters per proband 1.3 1.5 Mean age at breast cancer diagnosis of proband (years) 44.5 Mean age at breast cancer diagnosis among firstdegree female relatives (years) 54.3 54.6 No. and percent of breast cancers diagnosed among first-degree female relatives per family 952 (95.4) 0 966 (89.9) 1 100 (9.3) 45 (4.5) 8 (0.7) 2 1 (0.1) • Numbers in parentheses, percentages.
of daughters). Case families were slightly more likely than control families to be white (82 vs. 79 percent) and to have been identified through probands in the age group 3544 years (33 vs. 27 percent). The mean age at diagnosis of breast cancer for probands was 44.5 years. Only 4.6 percent of the control families reported at least one member with breast cancer, while 10.0 percent of the case families reported one or more family members with cancer. Relatives in case families were approximately the same mean age at diagnosis of breast cancer as relatives of controls (54.3 and 54.6 years, respectively). Heterogeneity of risk between families of breast cancer cases and families of controls
The family risk index indicated that families of breast cancer cases were at higher
Familial Heterogeneity of Breast Cancer Risk
which presents a plot of the distribution of ranks for families of cases and figure 2 which presents a similar plot for families of controls. Utilizing all but one of the three cutpoints tested (the 10 percent tail for case
risk of breast cancer than families of controls. The mean rank for families of breast cancer cases was 48.9, while the mean rank among families of controls was 46.9. This risk differential is illustrated in figure I,
1-5
0-10
11-15
16-20
21-25
20-30
31-35
38 40
41-45
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40-50
51-55
50-00
01-05
00-70
71-75
70-10
61 -»5
00-00
01 0 5
00-100
Rank
FIGURE 1. Distribution of ranks for risk of breast cancer for first-degree female relatives of 1,074 breast cancer cases when compared with the total sample of relatives, metropolitan Detroit, Michigan, 1980-1982.
1 5
0 10 1115
10 2 0 21-25 20-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76 6 0 61-15 16-90 01 9 5 9 6
100
Rank
FIGURE 2. Distribution of ranks for risk of breast cancer for first-degree female relatives of 998 controls when compared with the total sample of relatives, metropolitan Detroit, Michigan, 1980-1982.
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TABLE 2. Observed and expected numbers of families by rank and family type when compared with the total sample of first-degree female relatives, metropolitan Detroit, Michigan, 1980-1982 Control families
CasefamSes Rank Observed
10% tails 1-10 11-90 91-100 Total 5% tails 1-5 6-95 96-100 Total 2% tails 1-2 3-98 99-100 Total
Observed
Expected
1.72 0.39 0.20
117 823 58
99.8 798.4 99.8
2.96 0.76 17.51
2.31*
998
998
21.23***
9.26 1.71 6.24
71 899 28
49.9 898.2 49.9
1,074
17.21"
998
998
18.53***
21.5 1,031.0 21.5
68.94 3.26 17.69
41 948 9
20.0 958.0 20.0
22.05 0.10 6.05
1,074
89.89***
998
998
28.20***
Expected
107.4 859.2 107.4
121 841 112 1,074
1,074
53.7 966.6 53.7
76 926 72 1,074
60 973 41 1,074
Chi-square
Chi-square
8.92 0.00 9.61
• p > 0 05; **p < 0.001; ••• p< 0.0001.
families) produced significant results for both case and control families, indicating that cancer occurrence was not randomly distributed among these families (table 2). Fewer families of controls ranked in the upper tail of the distribution than expected, indicating lower risk of breast cancer among relatives of controls than among random groups of individuals of the same age, race, and size generated from relatives of cases and controls combined. The higher-thanexpected ranks for the case families indicated that biologic families of cases were at higher risk of breast cancer than groups of women of the same age, race, and size randomly selected from the total study population of relatives. The magnitude of the differences between points in the distribution of ranks for case and control families was described in terms of the observed number of families of cases in the high end of the distribution divided by the expected number of case families. Concentrating on the upper end of the distribution in each of the three tests performed, we found that 112 case families ranked in the upper 10 percent tail while
62.3 were expected (the proportion of control families observed in the upper 10 percent tail (5.8 percent) multiplied by the number of case families (1,074) gives an expected number of 62.3; observed/expected = 1.80, p < 0.001), 72 case families ranked in the upper 5 percent tail while 30.2 were expected (observed/expected = 2.38, p < 0.001), and in the upper 2 percent tail, 41 case families were observed and 9.7 were expected (observed/expected = 4.24, p < 0.001). Heterogeneity of risk within families of breast cancer cases
Within the case families only, heterogeneity of risk for breast cancer (as determined by deviations from the uniform distribution) depended on the cutpoints tested (at the 10 percent tails, chi-square = 5.94, 2 df, p = 0.051; at the 5 percent tails, chi-square = 18.47, 2 df, p < 0.0001; at the 2 percent tails, chi-square = 66.75, 2 df, p < 0.0001). These results suggested that a small proportion of case families may be experiencing differential risk compared with the majority
Familial Heterogeneity of Breast Cancer Risk
of the families identified through young breast cancer cases. Deviations from uniformity existed primarily at the low end of the distribution, as evidenced by more families than expected at lower risk of breast cancer. If heterogeneity of breast cancer risk exists among these families, it is evidenced by variability among a small percentage of the families identified through young breast cancer cases. In an effort to characterize the breast cancer case families at higher and lower risk, we compared the families who ranked in the upper and lower 5 percent of the distribution from the analysis using only case families with middle-ranking families in terms of race, histologic type of cancer in the proband, age of diagnosis in the proband, age at breast cancer diagnosis in the relatives, and number of relatives per family. Also evaluated were a number of reproductive factors and other putative risk factors for breast cancer as reported for the proband. Continuous variables were tested for significance by using analysis of variance. Discrete variables were tested for significance by using chi-square tests. Family rank was not significantly related to any of the characteristics considered. When the effects of the above-mentioned variables were tested simultaneously in a logistic regression model comparing case probands whose families ranked I-5 with case probands whose families ranked 6-100, no statistically significant results were obtained. DISCUSSION
Family heterogeneity of breast cancer risk was demonstrated in this study of firstdegree female relatives of young breast cancer cases (aged 20-54 years) and first-degree female relatives of age- and race-matched population-based controls. Families of breast cancer cases were 1.80 to 4.24 times more likely to be defined as high risk than were families of controls. The magnitude of the observed differences increased as the definition of high risk moved from the top 10 percent to the top 2 percent of the distribution. The family risk index method pro-
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vided similar results in the comparison of cancer risk among relatives of cases with risk among relatives of controls as seen using more conventional statistical approaches (1, 3-5), namely that relatives of young breast cancer cases are at higher risk of breast cancer than are relatives of controls. In this study, as in most studies of family history of cancer, cancer occurrence among relatives was not verified; however, family reports of breast cancer occurrence among relatives have been shown to be very accurate in other studies. Love et al. (14) found that 91 percent of all breast cancers reported among first-, second- and third-degree relatives were accurate, and Schwartz (15) reported 92 percent accuracy. Even so, it is possible that cases were more likely than controls to recall positive histories of cancer among relatives, resulting in an inflated estimate of the excess risk of breast cancer among case families compared with control families. To assess the completeness of breast cancer reporting among controls, we compared the reported number of breast cancers among sisters (the group most likely to have been diagnosed close to the study period) with the expected number based on age-specific incidence rates for metropolitan Detroit for 1978-1981. The reported number of breast cancers among sisters was not significantly different than expected (p > 0.05). Although differential recall may exist, the results are consistent with those of other studies. Some variation in risk among case families only also was suggested in this study, although none of the factors considered (e.g., race, histologic type of cancer in the proband, age at breast cancer diagnosis in the relatives, and number of relatives per family) were associated with family rank. Differential recall is unlikely to present a problem in the analysis restricted to case families. Heterogeneity of risk is consistent with multiple etiologies for breast cancer, some familial and some individual. Traditionally, the focus has been directed toward age at breast cancer diagnosis. In early epidemiologic studies of family history of breast cancer, premenopausal breast cancer cases (aged
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Schwartz et al.
less than 55 years) were shown to be more likely to have a family history of breast cancer than were postmenopausal breast cancer cases (I). This premenopausal or young breast cancer subset has been treated as if risk associated with family history were uniform. Recent findings utilizing the Cancer and Steroid Hormone Study participants are difficult to compare given the variety of approaches taken to the measurement of family risk. Sattin et al. (4), in a case-control study that did not take into account family size or the age distribution of family members at risk, reported that risk of breast cancer for women with a first-degree relative diagnosed at age 45 years or younger was greater, although not statistically significantly greater, than risk to women whose first-degree relatives were diagnosed after age 45 years. Using proportional hazards and cumulative probability methods which take into account the number of family members and their ages in the calculation of family risk, Schwartz et al. (3) and Claus et al. (16) have demonstrated increased breast cancer risk to relatives of the youngest (under age 40 years) breast cancer cases as compared with relatives of the youngest controls. No variation in risk was demonstrated in this study when mean age of diagnosis in the case probands was examined. The approaches taken in the latter two studies differ from the method applied in our study in one important aspect. Families are viewed in total, as a unit, in this study, instead of the entire sample of family members being treated as independent observations. That is, in our study, the unit of inference is the family. This study also allows for the identification of those specific families at higher and lower risk by means of the family rank. While the effect of age at diagnosis in probands aged 20-54 years may have some impact on breast cancer risk among relatives, it is unlikely that age alone can be used to distinguish between the higher and lower risk families. The number of cancers per family also is not likely to distinguish risk groups without utilizing information about family size and the ages of the relatives. The validation stud-
ies of the family risk index method (13) demonstrated that families with multiple cancer cases will not always be identified as high risk after adjustment for family size and time at risk for each family member. The family risk index method provides additional discrimination for identifying risk groups among small families when there is only one family member with cancer or when there are no family members with cancer. This is seen in our study when families without cancer range in rank from one to 95 and families with one cancer range in rank from 66 to 100, reflecting variation in breast cancer risk based on the age of the relatives in addition to the number of cancers. A simple count of the number of cancers in a family cannot adequately classify families at different risk levels. Few clues about the underlying differences between high- and low-risk families were obtained by looking at the distribution of selected risk factors among probands. There are certain limitations in describing breast cancer risk among family members on the basis of characteristics of the proband. Most established risk factors for breast cancer are associated with only modest increases in risk, and it has been estimated that only 25 percent of the breast cancer occurrence can be attributed to known risk factors (17). Adding information about the presence or absence of risk factors among all family members can contribute to separating genetic influences from environmental influences. Pedigree studies have found evidence for heterogeneity in the segregation pattern of breast cancer in selected families (6-8, 18). Newman et al. (6) performed segregation analysis using nuclear families identified through the metropolitan Detroit and San Francisco Bay area portions of the Cancer and Steroid Hormone Study. The data fit an autosomal dominant model of inheritance. The frequency of the susceptibility allele was 0.0006 in the general population. On the basis of the age distribution of the probands and the probability that a woman with breast cancer carries the susceptibility allele, Newman et al. (6) estimated that approximately
Familial Heterogeneity of Breast Cancer Risk
4 percent of the breast cancer families in their sample were genetically susceptible. Extending this type of analysis for all families included in the Cancer and Steroid Hormone Study, Claus et al. (8) reported the existence of a rare autosomal dominant allele at a frequency of 0.0033, with genotype effects related to age at onset. In addition to heterogeneity in genetic susceptibility, there is heterogeneity in the mode of genetic transmission. There have been reports of both autosomal dominant and autosomal recessive inheritance among subsets of breast cancer families (7, 9, 18, 19). The search for molecular and genetic markers for breast cancer susceptibility is complicated by the heterogeneity of familial risk for this disease (20, 21). Not only is individual breast cancer risk associated with family history of breast cancer, but also in some families breast cancer risk has been found in association with other cancers among relatives, including ovarian cancer (22) and soft-tissue sarcomas (23). The other cancers observed among family members in our study include a wide range of sites, although only data for female relatives were collected. This points out the importance of obtaining complete family cancer history, including enumeration of allfirst-degreerelatives by age, sex, and year of birth. The identification of risk factors associated with familial disease is an important step in the process of understanding breast carcinogenesis. While family membership is used as a marker for unmeasured genetic and environmental contributions to disease risk, it will be necessary to incorporate environmental risk factor data for family members if we are to move beyond the current limitations of family studies (24). The family risk index method provides a means of identifying families at high and low risk for further evaluation of shared environmental factors among family members and genetic contributions to risk.
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2. Kelsey JL. A review of the epidemiology of human breast cancer. Epidemiol Rev 1979; 1:74-109. 3. Schwartz AG, King MC, Belle SH, et al. Risk of breast cancer to relatives of young breast cancer patients. J Natl Cancer Inst 1985;75:665-8. 4. Sattin RW, Rubin GL, Webster LA, et al. Family history and the risk of breast cancer. J Am Med Assoc 1985;253:19O8-13. 5. Ottman R, Pike MC, King MC, et al. Practical guide for estimating risk for familial breast cancer. Lancet 1983^2:556-8. 6. Newman B, Austin MA, Lee M, et al. Inheritance of human breast cancer evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A 1988;85:3044-8. 7. Andrieu N, Demenais F, Martinez M. Genetic analysis of human breast cancer implications for family study designs. Genet Epidemiol 1988;5:22533. 8. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the Cancer and Steroid Hormone Study. Am J Hum Genet 1991;48:23242. 9. Goldstein AM, Haile RWC, Hodge SE, et al. Possible heterogeneity in the segregation pattern of breast cancer in families with bilateral breast cancer. Genet Epidemiol 1988;5:121-33. 10. Young JL, Percy CL, Asire AJ, eds. Surveillance, epidemiology, and end results: incidence and mortality data, 1973-1977. Bethesda, MD: Nati Cancer Institute, 1981. (NCI monograph no. 57). 11. Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc 1976,73:40-6. 12. The Centers for Disease Control Cancer and Steroid Hormone Study. Long-term oral contraceptive use and the risk of breast cancer. J Am Med Assoc 1983;249:1591-5. 13. Schwartz AG, Boehnke M, Moll PP. Family risk index as a measure of familial heterogeneity of cancer risk. A population-based study in metropolitan Detroit. Am J Epidemiol 1988; 128:524-35. 14. Love RR, Evans AM, Josten DM. The accuracy of patient reports of a family history of cancer. J Chronic Dis 1985;38:289-93. 15. Schwartz AG. A new method for detecting familial heterogeneity of cancer risk: a population-based study in metropolitan Detroit. PhD dissertation. The University of Michigan, School of Public Health, Ann Arbor, MI, 1986. 16. Claus EB, Risch NJ, Thompson WD. Age of onset as an indicator of familial risk of breast cancer. Am J Epidemiol 1990; 131:961-72. 17. Kelsey JL, Berkowitz GS. Breast cancer epidemiology. Cancer Res 1988;48:5615-23. 18. Bishop DT, Cannon-Albright L, McLellan T, et al. Segregation and linkage analysis of nine Utah breast cancer pedigrees. Genet Epidemiol 1988;5:151-69. 19. Go RCP, King MC, Bailey-Wilson JE, et al. Genetic epidemiology of breast cancer and associated cancers in high risk families. I. Segregation analysis. J Natl Cancer Inst 1983;71:455-61. 20. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-9. 21. Skolnick MH, Cannon-Albright LA, Goldgar DE, et al. Inheritance of proliferative breast disease in breast cancer kindreds. Science 1990-^50:1715-20.
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22. Schildkraut JM, Thompson WD. Relationship of epithelial ovarian cancer to other malignancies within families. Genet Epidemiol l988;5:355-67. 23. Li FP, Fraumeni JF. Soft-tissue sarcomas, breast cancer and other neoplasms. A familial syndrome?
Ann Intern Med 1969;71:747-52. 24. Bailey-Wilson JE, Cannon LA, King M-K. Genetic analysis of human breast cancer a synthesis of contributions to GAW IV. Genet Epidemiol 1986; l(suppl): 15-35.
