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Epidemiology Division, Department of Medicine, University of California, Irvine, Irvine, California 92697-7550 [A. Z., M. G., P. C., D. Br., T. H. T., S-Y. L., B. N., T. K., H. A-C.]; Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland 20892-7417 [D. S.]; Department of Physiology, University of Utah, Salt Lake City, Utah 84108 [D. Ba.]; Cleveland Clinic Foundation, Cleveland, Ohio 44195 [G. C.]; and Department of Preventive Medicine, University of Southern California, Los Angeles, California 90033 [R. H., D. T.]
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Abstract |
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Introduction |
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A major risk factor for breast cancer is family history of the disease (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) . Studies have shown consistently that a history of breast cancer in a first-degree relative increases a woman’s risk of breast cancer compared to women without such a family history. If both the mother and a sister have had breast cancer, the risk is further increased (particularly if either the mother or sister was diagnosed at a young age, less than 50 years). Identification of BRCA1 and BRCA2 mutations associated with autosomal dominant breast and ovarian cancer predisposition (13 , 14) has confirmed what was previously suggested using segregation analysis (15 , 16) . Hereditary breast cancer is estimated to account for 5–10% of all breast cancers in the United States (13 , 15) . Early studies estimated that germ-line mutations of the BRCA1 gene appear to be a predisposing factor in up to 80% of families with early onset breast and ovarian cancer and in 45% of families with site-specific breast cancer (17) . Similarly, germ-line mutations in the BRCA2 gene estimated from early studies appeared to be a predisposing factor in approximately 25–30% of site-specific breast cancer, particularly in males (14) . However, more recent studies performed on families that may not be suitable for linkage analysis but are typical of families referred to clinics because of strong history of cancer in their relatives suggest that BRCA1 mutations account for only 10–20% of inherited breast cancers and that BRCA2 mutations account for half this fraction of families (18) . There have been a number of other genes with very rare mutations that explain a small proportion (<1%) of hereditary breast cancer, such as TP53 (19) , whereas other breast cancer susceptibility gene(s) may yet be identified.
More than half a million American women are estimated to be carriers of a breast cancer susceptibility gene; these women may have between 55% and 85% probability of developing breast cancer and perhaps additional cancers at other sites over their lifetime (15 , 17 , 20, 21, 22, 23) . For these women, a prevention and early detection strategy is an essential aspect of managing their risk. In breast cancer, it is estimated that the proportion of cases attributable to a breast and ovarian cancer susceptibility gene decreases dramatically with age [33% of cases were 20–29 years of age compared to only 2% of cases at 70–79 years (20) ]. The age-specific risk of ovarian cancer in carriers was shown to be 15 times higher than that in noncarriers (20) .
In this study, we present the design and methods used to develop what is, as far as we know, the first population-based breast and ovarian cancer family registry for genetic epidemiology studies. This family registry is designed to investigate the hereditary component of breast and ovarian cancer and gene-environment interactions in their etiology. In this report, we present descriptive results on the family registry with regard to familial characteristics with classification by age at onset of the proband, race/ethnicity, histology, and multiple primaries. Risk estimates of breast and ovarian cancer in family members of breast and ovarian cancer probands are described with respect to their relationship to the proband, age at onset, parity, and number of affected first-degree relatives. Previous studies have investigated the distribution of various risk factors by using case-control studies in which family history was defined based on the cancer status among first-degree relatives of the proband. In this study, we use information from a population-based family registry study on first-degree relatives, second-degree relatives, and first cousins.
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Materials and Methods |
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Identification of Breast and Ovarian Cancer Patients Using the
Population-based Cancer Registry
Breast and ovarian cancer probands were ascertained through the
population-based cancer registry of the CSPOC. Description of CSPOC and
details of data collection methods have been reported previously
(24, 25, 26)
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For ascertainment of breast cancer, patients were identified through CSPOC within 6 months of diagnosis. However, we incorporated a rapid reporting system to identify ovarian cancer cases within 4 weeks of diagnosis. Patient identification (name, address, and phone number), birth date, race/ethnicity, sex, date of diagnosis, cancer site, histological type, diagnostic/pathology confirmation, stage of disease, and physician information were recorded for each case to link with the GRIS described below.
Eligible Probands.
In the current study, all population-based consecutive incident cases
of breast and ovarian cancer with age at diagnosis less than or equal
to 75 years diagnosed between March 1, 1994 and February 28, 1995 were
eligible for inclusion in the UCI breast and ovarian cancer family
registry. In this study, we report data on 1567 breast cancer cases and
328 ovarian cancer cases for a total of 1895 cases. A description of
the cases by race/ethnicity shows that 84.8% were non-Hispanic white,
8.2% were Hispanic, 0.6% were African-American, and 6.4% were Asian.
The age distribution of cases was as follows: (a) 9% below
age 40 years; (b) approximately 25% in each 10-year
interval from 40–69 years; and (c) 16% in the 70–75-year
age interval.
Treating physicians were notified of our intent to contact their patients to participate in the study. Patients were then contacted by way of an introductory letter followed by a telephone call to invite them to participate in the study. A family history was obtained from the probands through a telephone interview. Of the 1567 breast cancer probands, 202 (12.9%) were patients whom we were unable to contact, and 258 (16.5%) were patients who declined to participate. For ovarian cancer, 51 (15.5%) were patients whom we were unable to contact, and 52 (15.5%) were patients who declined to participate.
Among the 202 breast cancer probands whom we were unable to contact, 5 (2.5%) were unable to be contacted due to physician refusal, and 63 (31.2%) died before contact. Among the 51 ovarian cancer probands whom we were unable to contact, 2 (3.9%) were unable to be contacted due to physician refusal, and 33 (64.7%) died before contact.
Among the 258 breast cancer probands who declined to participate, the most common reasons given for nonparticipation were "not interested" [86 probands (33.3%)], "time commitment" [48 probands (18.6%)], "bad health" [27 probands (10.5%)], and "emotional reasons" [24 probands (9.3%)]. Similarly, among the 52 ovarian cancer probands who declined to participate, the most common reasons given for nonparticipation were "not interested" [13 probands (25.0%)], "time commitment" [13 probands (25.0%)], "bad health" [5 probands (9.6%)], and "emotional reasons" [7 probands (13.5%)].
Breast cancer proband participants and nonparticipants did not differ
significantly with respect to age at diagnosis, race/ethnicity, or
grade of the disease. There was no difference between participants and
nonparticipants with respect to the proportion of those with in
situ, localized, and regional disease at diagnosis. However, the
proportion of distant disease was higher among nonparticipants (7.0%)
compared to participants (2.4%). In general, the proportion of distant
disease accounts for only 3.7% of all breast cancer. There was an age
difference between participants and nonparticipants among ovarian
cancer probands, with older cases being less likely to participate.
Participants and nonparticipants among ovarian cancer probands did not
differ significantly with respect to race/ethnicity and grade and stage
of the disease. Tables 1
and 2
present the distribution of race/ethnicity, age, and cancer site
in participating and nonparticipating breast and ovarian cancer
probands.
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Data Processing and Management.
The GRIS database developed by our group is a multi-user, menu-driven
system designed for interviewer, research, and management personnel to
evaluate progress and data quality. A verification table and a pedigree
diagram summarizing the family history interview were produced for each
proband and used for follow-up to complete missing data on their
relatives. Interviewers also used the GRIS system to verify, expand,
and manage information on families as new data were collected. GRIS
automated merge functions to create personalized study cards and
physician and patient letters as needed. In addition to the family
history interview, participants completed a food frequency
questionnaire and an epidemiological risk factor questionnaire. The
response rates for the food frequency and epidemiological risk factor
questionnaires were 81% and 77%, respectively. The results of these
questionnaires are not included in this report.
Vital Statistics.
For deceased relatives in families, we obtained death certificates to
assess the presence or absence of cancer in the four grandparents and
in relatives who were reported to have died before age 60 years.
Information on the places and dates of death for relatives was obtained
from the proband or from the next of kin of deceased individuals.
Biospecimen Bank: Pathology and Tumor Tissue Samples.
Reported malignancies for the study in probands and family members were
verified by obtaining pathology reports, tumor tissue samples, clinical
records, and death certificates; a signed authorization form from the
patient or next of kin accompanied these requests. For probands, we
verified all tumors by pathology. In particular, among probands, we
collected 689 (51.7%) tissue blocks, and an additional 460 tissue
blocks (34.5%) have been requested. We verified 257 first-degree
relatives (76.0%) with breast or ovarian cancer, 328 second-degree
relatives (64.4%) with breast or ovarian cancer, and 107 first cousins
(54.3%) with breast or ovarian cancer. Among the 257 verified tumors
within first-degree relatives, 56 (21.8%) were verified by pathology,
70 (27.2%) were verified by death certificate, 20 (7.8%) were
verified by personal interview of the affected relative, and 111
(43.2%) were verified by interview of another family member in
addition to the proband. Among the 328 verified tumors within
second-degree relatives, 13 (4.0%) were verified by pathology, 77
(23.5%) were verified by death certificate, 10 (3.0%) were verified
by personal interview of the affected relative, and 228 (69.5%) were
verified by interview of another family member in addition to the
proband. Among the 107 verified tumors within first cousins, 11
(11.3%) were verified by pathology, 11 (11.3%) were verified by death
certificate, 2 (1.9%) were verified by personal interview of the
affected relative, and 83 (77.6%) were verified by interview of
another family member in addition to the proband.
Statistical Methods
Descriptive statistics were computed with SAS statistical
procedures (SAS Institute, Inc.). Comparisons of proportions were made
using Fisher’s exact test with a two-sided significance level of 0.05.
The numbers of cancers expected in female relatives of probands were
calculated using age-specific incidence rates in Orange County for
1984–1994. Because of the January 1, 1984 starting date of the Cancer
Surveillance Program of Orange County, expected numbers of cancers in
female relatives of probands were calculated using age-specific
incidence rates in Connecticut for the time period prior to 1984.
(Age-specific incidence rates for breast and ovarian cancer in
Connecticut in 1984–1994 were similar to those in Orange County for
the same time period.) The cumulative hazards of breast and ovarian
cancer were calculated for each family member and summed to determine
the expected numbers of cancers in mothers, sisters, maternal and
paternal grandmothers, and maternal and paternal aunts. In addition, we
right-censored at age 85 years for all individuals. CIs were calculated
using the exact Poisson distribution. Analyses of the RR of breast and
ovarian cancer in family members of probands were restricted to the
families in which age at diagnosis of the proband was less than or
equal to 75 years of age and in which dates of birth, death, and
diagnosis were known in relatives of the proband. Subsets of those for
whom expected numbers of cancers were calculated were similar to the
entire breast cancer family registry with respect to family history of
cancer. In addition, we excluded 29 families in which either the
probands were adopted with no knowledge of family history or the family
history was incomplete on one side of the family.
The Cox proportional hazards model was used to estimate hazards ratios for probands’ mothers and sisters. The dependent variable in the proportional hazards model was years to onset of breast or ovarian cancer in first-degree relatives. Independent variables tested included the age at diagnosis of the proband and whether each relative had any additional family member besides the proband with breast or ovarian cancer. Interaction terms between variables were also considered.
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Results |
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summarizes the number of families by the number of first-degree
relatives with breast or ovarian cancer (n = 292).
Among familial probands, there were five families (1.7%) with four or
more members with breast or ovarian cancer and two families (0.7%)
with five or more members with breast or ovarian cancer (four plus the
proband). Prevalence of a history of ovarian cancer in a first-degree
relative was significantly higher among ovarian cancer probands
compared to breast cancer probands (P = 0.005).
Similarly, prevalence of a first-degree relative with breast cancer was
significantly higher in breast cancer families compared to ovarian
cancer families (P = 0.027).
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shows the distribution of familial cases by proband status (female
breast cancer, ovarian cancer, and male breast cancer). The data are
also shown separately for probands who had a personal history of
multiple primaries of breast, ovarian, or other cancer. The proportion
of familial cases in breast cancer probands with multiple primary
malignancies of the breast was significantly greater than that in
probands with a single primary cancer (P < 0.009;
Table 4
). When we stratified by the age at diagnosis of the proband,
the above-mentioned association was true only among young probands
(<50 years). Positive family history was not significantly different
among non-Hispanic whites compared to other race/ethnicities (Table 4)
.
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. Probands with in situ carcinoma had a higher familial rate
(28.9%) than probands with invasive carcinoma (21.7%); this
difference was statistically significant (P = 0.045).
In situ lobular carcinoma probands had a higher familial
rate (42.9%) compared to the familial rate of probands with nonlobular
histological types of in situ carcinoma (23.5%). However,
this difference was not statistically significant.
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). The RR of ovarian cancer in mothers and sisters was lower than that
for breast cancer (1.0 and 1.7, respectively). No difference was
observed in breast cancer risk among paternal and maternal
second-degree relatives.
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Family Members of Ovarian Cancer Probands.
Among mothers of non-Hispanic white ovarian cancer probands, 10.2%
were affected with breast cancer, and 5.1% were affected with ovarian
cancer. Among sisters, 7.3% were affected with breast cancer, and
1.0% were affected with ovarian cancer.
In families of non-Hispanic white ovarian cancer probands with age at
diagnosis 
75 years, mothers were at increased risk of ovarian cancer
(Table 6)
; the estimated RR is 4.6 (95% CI, 2.1–8.7). When we
stratified by age at onset of the proband, the RR of ovarian cancer in
mothers among younger probands (<45 years) was 8.6 (95% CI, 1.8–25),
whereas the RR was 4.0 (95% CI, 1.5–8.7) among older probands. RR of
breast cancer in mothers was estimated to be 1.5. The RR of ovarian and
breast cancer in sisters was 1.6 and 1.8, respectively. In the 26
families of ovarian cancer probands who were Hispanic, there were 2.0
observed ovarian cancers in mothers compared to 0.17 expected. Among
the 12 Asian families, there were no observed ovarian cancers among
mothers of the proband.
Female Relatives with Multiple Primaries.
In considering the familial association between breast and ovarian
cancer, one group of interest was families of probands with both breast
and ovarian cancer. Such a group should be enriched in carriers of
genes predisposing to breast or ovarian cancer, so one would expect
higher RRs in relatives of these probands. There were 14 families with
probands diagnosed with breast and ovarian cancer. Among their 36
first-degree relatives, there were 2.0 observed breast cancers compared
to 1.5 cases expected. However, among the 89 first-degree relatives of
probands with multiple primary breast cancers, there were 16 observed
breast cancers compared to 4.8 cases expected (RR, 3.3; 95% CI,
1.9–5.4).
Female First-Degree (Mothers and Sisters), Second-Degree
(Grandparents and Aunts), and First Cousins of Breast Cancer Probands.
Table 8
compares hazards ratios of breast cancer among second-degree relatives
and first cousins of breast cancer probands. Because second-degree
relatives and first cousins were not part of the "familial"
definition, hazards ratios were tabulated by familiality status (as in
sporadic versus familial). We further classified the
familial cases into those who had no first-degree relative < 50
years old with breast cancer and those who had at least one
first-degree relative < 50 years old with breast cancer.
In general, there was a gradation of hazards ratios among relatives,
with hazards ratios decreasing with increasing age of the proband, and
hazards ratios increasing with increasing degree of familiality.
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presents hazards ratios for relatives of breast cancer probands with
various combinations of family history and proband’s age at onset. For
example, the hazards ratio for a relative with at least two affected
first-degree relatives of a non-Hispanic white breast cancer proband
with age at onset between 45 and 54 years of age was 8.5 (95% CI,
6.0–12.0) compared to a relative with no affected first-degree
relatives and age at onset of the proband of more than 65 years of age.
In addition, there was an increasing trend in risk of breast cancer
with increasing number of affected first-degree relatives (test for
trend, P = 0.0001). Similarly, there was an increasing
trend in ovarian cancer risk with increasing number of affected
first-degree relatives (test for trend, P = 0.0002).
Moreover, the hazards ratio of breast cancer was 2.1 (95% CI,
1.5–3.0) in a relative with a history of ovarian cancer among her
first-degree relatives, whereas the hazards ratio of ovarian cancer was
3.8 (95% CI, 1.6–8.7) in a relative with history of ovarian cancer
among her first-degree relatives.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Familial Component of Breast and Ovarian Cancer.
The proportion of probands who reported a history of breast or ovarian
cancer in at least one first-degree relative was approximately 23%. To
date, there are 67 (5%) "high-risk" families in the family
registry; these are families with two affected first-degree relatives
in addition to the proband or with at least one first-degree relative
and two second-degree relatives on the same side of the family. Because
of the dynamic nature of the family registry, the number of high-risk
families described above reflects what was available in this study as
of the writing of the manuscript. Among the more than 184,000 new cases
of breast cancer to be diagnosed in the nation this year, we estimate
that 9,200 (5%) will have a potentially hereditary form of the
disease. Family history was studied in approximately 2,000 patients in
an ongoing care program for breast cancer patients in the Stockholm
area (27)
; these investigators reported that
6.7% of patients had a hereditary form of the disease. In Canada, it
has been estimated that 5% of breast cancer cases have a hereditary
basis (28)
. In 1986, Lynch and Lynch (29)
reported that among 328 consecutive breast cancer patients seen in an
oncology clinic, 9% had disease consistent with hereditary breast
cancer. Thus, our results are consistent with these studies. However,
it should be noted that our results are likely to be more applicable to
the general population because this study included a population-based
series in contrast to cases from an oncology clinic, where high-risk
patients are likely to be overrepresented.
Risk Estimates of Breast and Ovarian Cancers by Ethnicity,
Histological Type, and Relationship to the Proband.
Because hereditary breast cancers tend to occur at early ages (3
, 6
, 10
, 15
, 22
, 30, 31, 32, 33)
, there is great potential for loss in
person-years of life and for suffering in the families of these young
women. The data presented in this study suggest a significant excess RR
of breast cancer in mothers and sisters of breast cancer probands [1.7
(95% CI, 1.4–2.0) and 2.8 (95% CI, 2.3–3.3), respectively]. Our
data also show that in families of ovarian cancer probands, mothers
were at increased risk of ovarian cancer, with an estimated RR of 4.6
(95% CI, 2.1–8.7). In addition, we observed an increase in ovarian
cancer risk with decreasing age at onset of the proband. This
decreasing trend was also observed in relatives of breast cancer
probands. This finding is consistent with the results of familial risk
by Claus (10
, 15)
.
Other factors that may be associated with increased familial risk in breast cancer were also observed in our data. Probands who had multiple primaries of breast and ovarian cancer showed a significantly higher familial rate compared to probands with a single primary cancer. This is consistent with a number of studies showing an association between increased frequency of multiple primary tumors and familial cancers (34, 35, 36) . Familial cases with multiple affected relatives were important as an indication of the contribution of highly penetrant genes to familial clustering of the disease. In addition, the familial rate by race/ethnicity followed the same patterns as age-adjusted incidence rates, where non-Hispanic whites had a higher familial rate than that of other race/ethnic groups. However, our data showed the RRs of breast and ovarian cancer in mothers of Hispanic probands to be elevated and similar to those in mothers of non-Hispanic white probands. In particular, RR of breast cancer in mothers of Hispanic probands was significantly higher than the population risk among Hispanics (RR, 4.9; 95% CI, 2.6–8.5).
There have been several reports of a positive relationship between ductal carcinoma in situ and family history of breast cancer (37, 38, 39) . The population-based family registry breast cancer data reported here show similar breast cancer familial rates in probands with ductal carcinoma in situ and with invasive breast cancer. Studies of lobular carcinoma in situ have been inconsistent (40) . In a 1980 study by Erdreich et al. (41) , none of 31 lobular carcinoma in situ patients reported a positive family history. The RR associated with family history of breast cancer was not statistically significant in the large population-based case-control study reported by Weiss et al. (38) in 1996. However, in 1972, Haagensen (42) had reported a higher frequency of mothers having a history of breast cancer in patients with lobular carcinoma in situ compared to patients with invasive breast cancer. Similarly, an increased frequency of sisters with breast cancer among women with lobular carcinoma in situ has been reported (43) . Using data from the Cancer and Steroid Hormone Study, Claus et al. (5) reported that patients with lobular carcinoma in situ were significantly more likely to have a mother and/or sister affected with breast cancer (23.3%) compared to patients with all other histological types (2.9–11.8%). Similar to these latter results, in our study, the relationship between family history and histology was strongest for lobular carcinoma in situ (42.9% versus 23.5% when compared to family history in probands of other in situ carcinomas). Although the proportion of probands with in situ carcinoma reporting a positive family history was higher than that of probands with invasive carcinoma, this difference was not statistically significant and may have been due to heightened surveillance or screening in those with a positive family history.
Conclusions.
Our study showed: (a) in non-Hispanic white breast cancer
probands, RR of breast cancer in mothers and sisters was significantly
elevated [RR = 1.7 (95% CI, 1.4–2.0) and 2.8 (95% CI,
2.3–3.3), respectively]; (b) in families of ovarian cancer
probands, mothers were at increased risk of ovarian cancer (RR, 4.6;
95% CI, 2.1–8.7); (c) RR of breast cancer in mothers of
Hispanic breast cancer probands was significantly elevated (RR, 4.9;
95% CI, 2.6–8.5); however, no elevation of breast or ovarian cancer
risk was observed among relatives of Asian probands; (d)
there was a decrease in RR among mothers and sisters with increase in
age of onset of probands; and (e) in second-degree relatives
and first cousins, the breast cancer hazards ratios increased with
increase in the number of affected first-degree relatives and decreased
with increase in age at onset of the proband.
The investment in this population-based family registry of breast and ovarian cancer will support further etiological studies of breast and ovarian cancer because of extensive characterization of patients and family members, validation of the familial risk, verification of tumors in families, and a biospecimen bank containing both DNA and RNA from blood samples and tumor tissue samples. Furthermore, the population-based family registry of breast and ovarian cancer will be ideal for programs in cancer prevention and control and genetic predisposition testing of BRCA1, BRCA2, and other breast cancer susceptibility genes.
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Acknowledgments |
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Footnotes |
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1 The personal interview data were collected with
support by the NIH, National Cancer Institute Grant CA-58860 and the
Lon V. Smith Foundation Grant LVS-18840. 
2 To whom requests for reprints should be
addressed, at Epidemiology Division, Department of Medicine, 224 Irvine
Hall, University of California, Irvine, CA 92697-7550. Phone: (949)
824-7416; Fax: (949) 824-4773; E-mail: hantoncu{at}uci.edu
3 The abbreviations used are: GRIS, Genetic
Research Information System; UCI, University of California, Irvine; RR,
relative risk; CSPOC, Cancer Surveillance Program of Orange County; CI,
confidence interval.
Received 1/ 4/99; revised 11/12/99; accepted 11/15/99.
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