REPORTS

Mammographic Densities and Risk of Breast Cancer Among Subjects With a Family History of This Disease

Norman F. Boyd, Gina A. Lockwood, Lisa J. Martin, Julia A. Knight, Roberta A. Jong, Eve Fishell, Jeff W. Byng, Martin J. Yaffe, David L. Tritchler

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.


    ABSTRACT
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Notes
 References
 
BACKGROUND: A family history of breast cancer is known to increase risk of the disease, but other genetic and environmental factors that modify this risk are likely to exist. One of these factors is mammographic density, and we have sought evidence that it is associated with increased risk of breast cancer among women with a family history of breast cancer. METHODS: We used data from a nested case-control study based on the Canadian National Breast Screening Study (NBSS). From 354 case patients with incident breast cancer detected at least 12 months after entry into the NBSS and 354 matched control subjects, we analyzed subjects who were identified as having a family history of breast cancer according to one of three, nonmutually exclusive, criteria. We compared the mammographic densities of case patients and control subjects by radiologic and computer-assisted methods of measurement. RESULTS: After adjustment for other risk factors for breast cancer, the relative risks (RRs) between the most and least extensive categories of breast density were as follows: For at least one first-degree relative with breast cancer, RR = 11.14 (95% confidence interval [CI] = 1.54-80.39); for at least two affected first- or second-degree relatives, RR = 2.57 (95% CI = 0.23-28.22); for at least one first- or second-degree relative with breast cancer, RR = 5.43 (95% CI = 1.85-15.88). CONCLUSIONS: These results suggest that mammographic density may be strongly associated with risk of breast cancer among women with a family history of the disease. Because mammographic densities can be modified by dietary and hormonal interventions, the results suggest potential approaches to the prevention of breast cancer in women with a family history of breast cancer.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Notes
 References
 
Individuals with a family history of breast cancer are widely recognized to be at increased risk of developing the disease, and increased risk is in some a consequence of inheriting a gene that predisposes to breast cancer. The risk of breast cancer is approximately doubled in women with an affected mother or with an affected sister (1). Carriers of mutations in the BRCA1 and BRCA2 genes are known to be at increased risk for the development of breast and ovarian cancers (2-9).

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.


    PATIENTS AND METHODS
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Notes
 References
 
We used data available from a nested case-control study based on the Canadian National Breast Cancer Screening Study (NBSS), whose methods and results are as described previously (13).

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.


    RESULTS
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Notes
 References
 
Characteristics of Subjects

Table 1Go 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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Table 1. Characteristics of study subjects with at least one first-degree relative with breast cancer*

 
Familial risk of breast cancer within the original case-control study nested in the NBSS (345 case patients and 341 control subjects with complete information on all variables) was calculated after adjustment for age, age at menarche, menopausal status, number of live births, height, and weight. The relative risk (RR) of breast cancer for women with at least one affected first-degree relative was 1.44 (95% confidence interval [CI] = 0.94-2.20) compared with women who did not meet that definition. For women with two or more first- or second-degree relatives with breast cancer, the RR was 1.57 (95% CI = 0.93-2.64) compared with those who did not meet the definition. For women with any first- or second-degree relative with breast cancer, the RR was 1.14 (95% CI = 0.83-1.57).

Mammographic Densities and Risk of Breast Cancer in Subjects With a Family History of Breast Cancer

Table 2Go 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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Table 2. Distribution of percent breast density of case patients and control subjects according to family history category of breast cancer—radiologists' assessment

 
For those with at least two first- or second-degree relatives with breast cancer, the OR for risk of breast cancer in the most extensive category of density relative to the least extensive category was 1.25 (95% CI = 0.16-9.77). The test for a trend in increasing risk with increasing density was not statistically significant (P for trend = .39). In the 241 case patients and control subjects (125 case patients and 116 control subjects) with any first- or second-degree relatives with breast cancer, the OR for the most extensive category of density relative to the least extensive category was 4.03 (95% CI = 1.54-10.60). The test for a trend in increasing risk with increasing density was statistically significant (P for trend <.001).

The results obtained with the computer-assisted measurement of density are shown in Table 3.Go 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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Table 3. Distribution of percent breast density of case patients and control subjects according to family history category of breast cancer—computer-assisted assessment

 
Adjusted Analysis

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.Go 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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Table 4. Relative risks (RRs) comparing extreme categories of percent breast density from logistic regression in case patients and control subjects according to family history category of breast cancer*

 
The results obtained with the computer-assisted measure of density gave point estimates of risk that were similar to the radiologists' for the definitions of family history with two or more first- or second-degree relatives and with at least one affected first- or second-degree relative and appeared lower for the category with at least one affected first-degree relative. However, the CIs for the RRs for the radiologists' and computer-assisted measures overlapped extensively for all definitions of family history. For both measurement methods, the RRs were statistically significantly different from 1 for the category of at least one first- or second-degree relative with breast cancer. They were statistically significantly different from 1, only for the radiologists' measure, for the category of at least one first-degree relative with breast cancer.


    DISCUSSION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Notes
 References
 
Our results suggest that mammographic densities are associated with risk of breast cancer among individuals with a family history of this disease. In each of the three definitions of family history that we examined, comparison of case patients and control subjects with the same familial characteristics showed evidence of an increase in risk of breast cancer associated with extensive mammographic densities, after adjustment for the effects of other risk factors. Gradients in risk were seen whether mammographic densities were assessed by radiologists or by the computer-assisted method. The magnitude and statistical significance of the point estimates of risk varied according to the definition of family history of breast cancer. These estimates varied from 2.42 for those with two or more affected first- or second-degree relatives (which was not statistically significantly different from unity) to 11.14 for those with at least one affected first-degree relative (which was statistically significantly different from 1).

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 4Go. 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.


    NOTES
 
Supported by grants from the National Cancer Institute of Canada and by a Terry Fox Programme Project Grant.

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.


    REFERENCES
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Notes
 References
 

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Manuscript received December 27, 1998; revised June 10, 1999; accepted June 22, 1999.


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