Affiliations of authors: N. F. Boyd, Division of Epidemiology and Statistics, Ontario Cancer Institute, and Division of Preventive Oncology, Cancer Care Ontario, Toronto, Canada; G. A. Lockwood, L. J. Martin, D. L. Tritchler, Division of Epidemiology and Statistics, Ontario Cancer Institute; J. A. Knight, Division of Preventive Oncology, Cancer Care Ontario; R. A. Jong, Department of Radiology, Mount Sinai Hospital, Toronto; E. Fishell, Women's College Hospital, Toronto; J. W. Byng, M. J. Yaffe, Imaging Research, Sunnybrook Health Sciences Center, Toronto.
Correspondence to: Norman F. Boyd, M.D., F.R.C.P.C., Division of Epidemiology and Statistics, Ontario Cancer Institute, 610 University Ave., Toronto, ON, Canada M5G 2M9.
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ABSTRACT |
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INTRODUCTION |
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Although there is still some uncertainty about the magnitude of this risk, it seems clear from the available data that there are members of high-risk families and carriers of mutations in the BRCA1 and BRCA2 genes who do not develop breast or ovarian cancer and that other factors, genetic and environmental, are likely to exist that modify risk (7).
Differences in the risk of breast cancer created by classifying mammographic densities are larger than for any other risk factor (10-12), except for age and status as a BRCA1 and BRCA2 mutation carrier. We have sought evidence that mammographic densities are associated with the risk of breast cancer among women with a family history of the disease. Because a family history of breast cancer may involve different numbers of affected individuals who have different relationships to the proband, we formed categories of family history of breast cancer using several definitions and examined whether the association of mammographic densities with risk varied according to how family history was defined.
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PATIENTS AND METHODS |
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Selection of Case Patients and Control Subjects for the Nested Case-Control Study
This study was based upon the cohort of 45 000 women aged 40-59 years and allocated to mammography in the NBSS, a multicenter, randomized trial designed to assess the efficacy of screening for breast cancer with mammography (14). We designed a nested case-control study within this cohort in which we selected 354 case patients in whom histologically verified invasive breast cancer, either interval or screen-detected, was diagnosed 12 months or more after entry. Three hundred fifty-four control subjects were selected from the same NBSS study population as case patients and were matched to resemble case patients in the following characteristics: year of entry into the NBSS, age at entry (within 1 year), time in the study, and the NBSS center at which the breast cancer was diagnosed. The average follow-up in the NBSS was approximately 7.5 years at the time subjects were selected for the present study.
Selection of Subjects With a Family History of Breast Cancer for the Present Study
At entry into the NBSS, each participant completed a questionnaire that included questions about relatives who had developed breast cancer and the familial relationship of the affected individuals. For the analyses shown in this report, using the baseline questionnaire, we identified the case patients and control subjects previously selected as having a family history of breast cancer using three different criteria. These criteria were as follows: 1) having at least one first-degree relative with breast cancer, 2) having two or more first- or second-degree relatives with breast cancer, or 3) having at least one first- or second-degree relative with breast cancer. First-degree relatives were mother, sisters, and daughters, and second-degree relatives were grandmothers, aunts, nieces, and half sisters. The resulting family history categories are not mutually exclusive.
Of the 708 case patients and control subjects, 106 (15%) had at least one first-degree relative with breast cancer, 67 (9%) had two or more affected first- or second-degree relatives, and 241 (34%) had an affected first- or second-degree relative. The analysis for each family history category was restricted to comparing those case patients and control subjects who satisfied the criterion for that category. Thus, matching of the larger nested case-control study was not retained.
Classification of Mammographic Density
The mammogram taken at entry into the NBSS was the image used for measurement. All measurements were made on one craniocaudal view from the breast contralateral to the cancer in case patients and on the same view of the corresponding breast of control subjects. All classifications were made without knowledge of the case-control status or knowledge of family history and without access to any other mammograms. The percent of the area of the mammogram occupied by radiologically dense breast tissue was determined by two independent methods. In one method, radiologists estimated visually the proportion of the area of the mammogram occupied by radiologically dense breast tissue. In the other method, mammograms were digitized, images were displayed on a computer monitor, and thresholds were set by an observer (N. F. Boyd) to define the edge of the breast and the edge of dense breast tissue. The areas defined were then measured by the computer, and the percent of the area of the image occupied by dense tissue was calculated. Details of both of these methods have been given elsewhere (15-17).
Statistical Methods
Odds ratios (ORs) to estimate the risk of breast cancer within each category of mammographic density were calculated for each category of a family history of breast cancer. We compared the distribution of mammographic densities in case patients and control subjects who fell into the same family history category. The referent breast-density category in each analysis was density in less than 10% of the breast area. The Cochran-Armitage test for trend was used to determine whether the observed proportion of case patients to control subjects differed in a linear fashion across breast-density categories. We used an unconditional logistic regression model to test mammographic densities as a risk factor for breast cancer within each family history category while we adjusted for age and other risk factors for breast cancer. All statistical tests were two-sided, and P values of .05 or less were considered statistically significant.
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RESULTS |
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Table 1 shows selected characteristics of 60 case
patients and 46 control subjects; both groups had at least one
first-degree relative with breast cancer. Case patients and control
subjects were similar with respect to age, age at menarche, number of
live births, menopausal status, height, and weight. Forty case patients
and 27 control subjects had two or more affected first- or
second-degree relatives, and 125 case patients and 116 control subjects
had at least one affected first- or second-degree relative. The latter
four groups were also similar with respect to these variables (data not
shown).
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Mammographic Densities and Risk of Breast Cancer in Subjects With a Family History of Breast Cancer
Table 2 shows the distribution of mammographic
densities, according to the radiologists' assessment, in case patients
and control subjects for the three family history categories,
unadjusted for other risk factors. In 106 subjects with at least one
first-degree relative with breast cancer, 12 (20%) of the 60 case
patients had density in 75% or more of the breast and 32 (53%) had
density in 50% or more, compared, respectively, with three (6.5%) and
12 (26%) of the 46 control subjects. The OR (an estimate of RR) for
risk of breast cancer in the most extensive category of density
relative to the least extensive category was 4.0, and the 95% CI
included unity. The test for trend was statistically significant
(P for trend = .02).
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The results obtained with the computer-assisted measurement of density are shown in Table
3. Because there were no control subjects in the most extensive category
of density with either first-degree relatives or two or more relatives affected, we could not
calculate a trend test for these categories. Collapsing the top two density categories gave an OR
of 1.91 for the first family history category and an OR of 1.57 for the second family history
category. The tests for trend over four categories of breast density gave P for trend
= .14 and P for trend = .68, respectively. For the category of at least one
affected first- or second-degree relative, the most extensive category of breast density was
associated with a point estimate of risk of 6.00 (95% CI = 1.07-33.66), and the test
for trend was statistically significant (P for trend <.001).
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We examined the possible influence of other risk factors for breast
cancer on the results described above using logistic regression. The
risk of breast cancer according to the extent of mammographic densities
was examined within each family history category, controlling for the
effects of age, age at menarche, number of live births, menopausal
status, weight, and height. One subject was excluded because her age at
menarche was missing. This affected the family history categories of at
least one first-degree relative with breast cancer and at least one
first- or second-degree relative with breast cancer. The results are
given in Table 4. The results obtained by use of the
radiologists' classification were as follows: With family history
defined as at least one first-degree relative, the RR between the most
and least extensive categories of density was 11.14 (95% CI =
1.54-80.39); for at least two affected first- or second-degree
relatives, the RR was 2.57 (95% CI = 0.23-28.22); for any first- or
second-degree relative with breast cancer, the RR was 5.43 (95% CI =
1.85-15.88).
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DISCUSSION |
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Limitations of this study include the relatively small number of subjects, particularly in the
category with two or more affected first- or second-degree relatives, which is likely to be
responsible for our failure to find statistically significant associations between mammographic
densities and risk of breast cancer within this group in the adjusted analysis shown in Table 4. The point estimate of the risks of breast cancer associated with the
family history categories that we examined was somewhat smaller than estimates reported in the
literature. The restricted range of ages of the subjects in the NBSS may have contributed to this
observation. Because the lower age bound for the NBSS was 40 years, we are unable to examine
the association between mammographic densities and breast cancer risk in younger women, in
whom the effect of a family history in increasing risk appears to be greatest (18).
Notwithstanding these limitations, our study also has a number of strengths. Because this study was carried out within a population screened for breast cancer, information about family history and the mammogram used to determine degree of density were obtained at baseline at least 12 months before the development of breast cancer and were, therefore, unbiased by knowledge of disease. Furthermore, because the entire population of subjects was screened at annual intervals, a family history of breast cancer should not influence the frequency of screening and is unlikely to have influenced the detection of cancer. Information about reproductive and other risk factors was available, but this did not modify the conclusion that mammographic densities are associated with risk among women with a family history of breast cancer.
Other risk factors have been shown to be associated with familial risk of breast cancer. For example, differences in the effects of reproductive risk factors according to family history were found in the Iowa Women's Health Study (19). The increased risk of breast cancer associated with a high waist-to-hip ratio, low parity, and a late age at first pregnancy was more pronounced in women with a family history of breast cancer. The gradients in risk created by these factors are, however, much smaller than those seen in our study in association with mammographic densities.
If our finding of gradients in risk of fourfold to 11-fold associated with mammographic densities within family history categories is confirmed, assessment of the mammographic appearance of the breast will be an important aspect of counseling women with a family history of breast cancer.
Radiologically dense breast tissue is seen in the mammogram because of the greater x-ray attenuation of stromal and epithelial cells compared with fat (20). The presence of extensive mammographic densities thus likely indicates a greater number of epithelial and stromal cells in the breast compared with a breast with little or no density. If the malignant transformation of breast cells containing genes that predispose to cancer is a stochastic event, then the greater the number of such cells the greater will be the probability of cancer. We would then expect breast cancer risk to be greatest among women with extensive radiologic densities in the breast, as we have observed in this study. Strategies directed at reducing densities, such as dietary (21) and hormonal (22) interventions, may reduce risk in subjects predisposed because of family history. These results also raise the possibility that mammographic densities might modify the risk of breast cancer among women who carry BRCA1 or BRCA2 gene mutations.
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NOTES |
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We thank Dr. A. B. Miller, Director of the Canadian National Breast Screening Study for allowing us access to the data used in this analysis.
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Manuscript received December 27, 1998; revised June 10, 1999; accepted June 22, 1999.
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