From the Cancer Etiology Program, Cancer Research Center of Hawaii, Honolulu, HI
Correspondence to Dr. Gertraud Maskarinec, Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813 (e-mail: gertraud{at}crch.hawaii.edu).
Received for publication February 16, 2005. Accepted for publication May 13, 2005.
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ABSTRACT |
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breast neoplasms; ethnic groups; mammography
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INTRODUCTION |
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So far, only two case-control studies using quantitative assessment methods (4, 11
) have included substantial numbers of non-Caucasian women, primarily Asian Americans and African Americans. Whereas a study from California described a stronger association between mammographic densities and breast cancer among Chinese, Filipino, and Japanese women than among Caucasian women (4
), our study in Hawaii suggested a weaker association among Japanese women than among Caucasian women (11
). Cross-sectional studies have shown that women of Asian ancestry have higher percent densities than Caucasian women because of their relatively small breast size (12
, 13
), but densities were found to be higher among Japanese Americans in Hawaii than among women in Japan, reflecting the difference in breast cancer risk (14
). Although breast cancer incidence is still considerably lower in Japan than in Western countries (15
), Japanese migrants to California and Hawaii, who have now reached the third and fourth generations, have a risk level similar to that of Caucasians (16
, 17
).
We hypothesized that despite ethnic differences in breast density, the relations between mammographic densities and breast cancer risk would be similar in Caucasian, Japanese, and Native Hawaiian women. The Hawaii component of the Multiethnic Cohort (MEC) Study (18) offered us an opportunity to explore the relation between mammographic density and breast cancer risk among women in these three groups and to investigate the relative importance of percent densities versus the size of the dense area.
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MATERIALS AND METHODS |
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Recruitment
All female members of the MEC Study who resided in Hawaii and were diagnosed with a primary breast cancer between cohort entry and December 2000 were identified as potential cases (n = 1,587). From Hawaii MEC Study participants who were not known to have breast cancer, a similar number of randomly selected controls was identified within the ethnic and 5-year age groups of the cases (n = 1,584). For this nested case-control study, subjects had to be alive at the time of recruitment and sign an informed consent form and a mammogram release form. Exclusion criteria for cases and controls included diagnosis of breast cancer before entry into the cohort study, either by record linkage or by self-report at baseline; no mammogram; and a history of breast augmentation or reduction, but not breast biopsy, as stated in the breast health questionnaire. We learned about deaths that had occurred by the time of recruitment and about additional prevalent cases from the subjects and their mammography records; we excluded these women after obtaining the additional information. Subjects were recruited by mail during 20012002 with a maximum of three reminders; we avoided more aggressive recruitment in order not to jeopardize future participation of subjects in cohort studies. The recruitment package included a study description, a consent form, a mammogram release form, a breast health questionnaire, and a questionnaire assessing the consumption of soy foods. Among the 1,584 potential controls selected from the MEC Study database, 19 had been diagnosed with breast cancer by the time of recruitment and reclassified as cases, but only nine of these women participated in the study.
Of the 3,171 subjects originally identified (table 1), 8.7 percent were ineligible, primarily because of death or preexistent breast cancer. Although 54 percent of eligible women responded to the mailings, only 50.6 percent returned both signed forms. The response rate was slightly higher among cases than among controls. For 127 cases and 64 controls, we had no suitable mammogram to scan, leaving us with 43.5 percent (n = 607) and 44.5 percent (n = 667) of eligible cases and controls, respectively. These proportions were highest for Caucasians (50 percent and 48 percent), followed by Japanese (44 percent for both), and were lowest for Native Hawaiians (34 percent and 47 percent) and others (41 percent and 25 percent). More cases than controls were ineligible, primarily because of death. Japanese cases had an 11 percent ineligibility rate, whereas the rate was 1516 percent for all other groups; for controls, the rates were 35 percent.
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Data collection
At entry into the cohort, all subjects completed a survey, including an extensive food frequency questionnaire especially designed for the MEC Study, that also inquired about demographic background, anthropometric measures, reproductive behavior, and family history of breast cancer (19). The survey information underwent extensive cleaning and editing procedures. As part of the recruitment for the nested case-control study, the women completed a one-page breast health questionnaire that asked about previous breast surgery (especially breast augmentation or reduction), menopausal status, mammography history, and HRT use. The women using HRT were asked to write in the name of their HRT medication, and HRT was classified into estrogen-only or combined estrogen/progesterone therapy.
Mammographic density assessment
Mammograms were requested from all 33 clinics listed on the release forms. These facilities were accredited according to the Mammography Quality Standards Act (20, 21
). Of the 6,478 mammograms in the final data set, 1,615 (25 percent) came from one organization. The other clinics contributed 8571 images each. We did not have suitable mammograms for 191 women, for several reasons (table 1). From the many mammograms available for each woman, we selected films to cover as wide a time frame as possible, using the following criteria. For cases, the goal was to include only films taken before diagnosis; but for five cases, only the contralateral mammogram of the healthy breast taken at the time of diagnosis before initiation of treatment was available. Whenever possible, we scanned at least one mammogram taken before 1995 and one taken after 1995 and at least one mammogram taken during 19902000. However, for five controls and one case, we could only locate a mammogram taken before 1990; and for seven controls, we could only locate an image from 20012003. In the final data set, 86 percent of all mammograms were performed between 1990 and 2000.
All mammographic films from both breasts were scanned with a Kodak LS85 Film Digitizer (absorbance range, 0.0014.1; Eastman Kodak Company, Rochester, New York) at a resolution of 98 pixels per inch (pixel size equal to 260 µm). The 8-bit images are displayed in 256 shades of gray. One of the authors performed computer-assisted density assessment (8, 22
) for batches of 100 mammograms. All images for one woman were assessed during the same session, but the reader was blinded as to group status and year of mammogram. After the reader determined a threshold for the edge of the breast and the edge of the dense tissue (8
), the computer calculated the total number of pixels in the digitized image that constituted the total area and the dense area and computed the ratio between the two values. We converted pixels into square centimeters using a factor of 0.000676.
Since the readings for the two sides were very similar (r = 0.920.97), we averaged the values for the right and the left breast to obtain one mammographic measure when both films were available, but 689 (19.3 percent) measures were based on one side only. This proportion was higher for cases (33.2 percent) than for controls (2.5 percent), because some cases did not have screening mammograms taken before their diagnosis. On average, 3.2 and 2.4 density measures on different dates were available for cases and controls, respectively. Therefore, subjects with at least two mammograms had three different variables: earliest, latest, and mean mammographic reading. The 226 women with only one mammogram taken at one point in time were included in all of these analyses, using the single value each time. The unadjusted mean ages for the earliest, latest, and all mammograms among cases versus controls were 57.0 versus 57.5 years, 62.1 versus 61.7 years, and 59.6 versus 59.7 years, respectively, indicating excellent matching. The mean time between the earliest mammogram and the breast cancer diagnosis was 6.3 years, while the earliest and the latest mammogram were, on average, 4.2 years apart for controls and 5.1 years apart for cases. A random sample of 410 mammograms was read in duplicate to assess the reliability of the mammographic readings. The intraclass correlation coefficients (23) were 0.96 (95 percent confidence interval (CI): 0.95, 0.97) for the size of the dense area and 0.996 (95 percent CI: 0.995, 0.997) for the total breast area, resulting in an intraclass correlation coefficient of 0.974 for percent density (95 percent CI: 0.968, 0.978).
Statistical analysis
Because of our inclusion criteria, there were no missing values for ethnicity or mammographic parameters. On the basis of all ethnic backgrounds reported for both parents, persons with several ethnic backgrounds were classified into one category, giving first priority to Native Hawaiian ancestry and then to Japanese, Caucasian, and other ancestry (18). Because cancer cases and controls were matched on ethnicity and age, these variables were entered only to adjust for incomplete matching, and results were not interpreted. Information on body mass index and reproductive variables was collected at entry into the cohort, and additional information on HRT use was obtained when the women enrolled in the mammographic density study. A comparison of the HRT information obtained from the two questionnaires found good agreement for overlapping years when both questionnaires reported on HRT use. On the basis of the breast health questionnaire, we created an HRT use variable (use or no use) for each year from 1990 to 2000. To classify the type of medication, we first utilized the information from the breast health questionnaire. If a woman indicated that she had used HRT at any time but the write-in field was empty, we assigned the type of HRT from the cohort questionnaire completed at baseline. For the 69 women with missing information on HRT type, we imputed the type based on hysterectomy status (24
): estrogen only for women with a hysterectomy and combined therapy otherwise. As a result, each woman had a binary HRT use variable for each year but only one HRT type variable, because the questionnaire did not allow the entry of more than one type of HRT.
Breast cancer cases and controls were compared overall and within each ethnic group with regard to each of the risk factors. Either the t test or the 2 test was used to assess differences by case status. We used the SAS Logistic procedure (25
) to perform unconditional logistic regression analysis (26
), and we estimated odds ratios and 95 percent confidence intervals for incident breast cancer while adjusting for demographic, anthropometric, and reproductive confounding variables. The mammographic density predictors were modeled as continuous measures and as categorical variables. Analyses were repeated for the earliest mammogram, the latest mammogram, and the mean value of readings from all mammograms, because we wanted to explore whether age at the time of mammogram influences the strength of the association between density and breast cancer risk. Separate analyses were performed for percent density and dense area (cm2). Percent density was classified as less than 10 percent, 1024.9 percent, 2549.9 percent, and 50 percent or more, while for dense area, 15 cm2, 30 cm2, and 45 cm2 were used as the limits of the categories. We chose four categories rather than six, as were used in other reports (2
, 4
), in order to apply the same grouping to all ethnic groups despite the differences in breast density. To compare the ability of percent and the size of the dense area of the earliest mammogram to predict breast cancer, we computed the area under the receiver operating characteristic (ROC) curve (25
), a method used in sensitivity-specificity analyses that assesses the effectiveness of a test for determining the presence of a disease. A plot of the ROC curve is the graph of sensitivity versus 1 minus specificity. If the test is perfect, the area under the ROC curve is equal to 1.0; if it performs no better than chance, the area will be equal to 0.5. Because logistic regression predicts membership in one of two groups (e.g., disease vs. no disease), the ROC curve assesses the goodness of fit of these models.
The following covariates were included in all models because of their known relation to breast cancer risk (17) and breast density (10
, 27
, 28
): ethnicity, age at mammogram as a continuous variable, body mass index at baseline (<22.5, 22.525.0, 25.130.0, or >30), age at first livebirth (<21, 2130, or >30 years, or no children), number of children (01, 23, or
4), age at menarche (<13, 1314, or
15 years), age at menopause (<45, 4549, or
50 years, or premenopausal), HRT use in the year of the mammogram (never, estrogen only, or estrogen with progesterone), and family history of breast cancer (breast cancer in a first-degree relative, or no history). To maximize the number of observations for the case-control analysis, we replaced missing values with the most likely values among subjects in the mammographic density study: age at first livebirth (32 missing), 2130 years; number of children (12 missing), 23; and breast cancer family history (36 missing), no history. For the nine women with missing data on body mass index and 16 women with missing data on age at menarche, we assigned the median values of their respective ethnic groups. All analyses were repeated after stratifying by ethnicity, stratifying by weight status (body mass index <25 vs.
25), including only women without any missing values (n = 1,109), and excluding in situ cases (n = 125).
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RESULTS |
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DISCUSSION |
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Our risk estimates for Caucasians were quite similar to those of other studies using quantitative mammographic density assessment methods (2, 3
, 29
). A previous study in Hawaii based on mammograms performed very close to diagnosis reported substantially lower risk estimates (11
), possibly because of use of a different scanner and software and a lack of information on body mass index and other confounders. Our findings disagree with those of the California study (4
) that estimated a stronger risk for women with Asian ancestry than for Caucasian women, but the number of Asian women in the California study was relatively low (n = 210) and included persons of several ethnicities (Chinese, Filipino, and Japanese).
Although it was not statistically significant, we observed a stronger association between breast cancer risk and mammographic densities among heavier women. The same effect modification was found in all three groups, while Caucasians maintained the highest odds ratios regardless of weight status. Percent density is highly influenced by breast size and body fat (13), and at the same time, body weight is associated with breast cancer risk (30
). The lower risk associated with percent density in Japanese could be due to limitations in the two-dimensional density assessment among Japanese women. Capturing the third dimension of breast density may be more important for breasts with small areas than for large breasts. Newer volumetric methods may allow more accurate measurement of the dense cell mass in the breast (31
).
Our study had a number of unique features, particularly a large number of US-born Japanese-American women, who are at a similarly high risk of developing breast cancer as Caucasian women (16, 17
, 32
). To our knowledge, this is the first study exploring the breast density-breast cancer relation with a sufficient number of Native Hawaiian women, an ethnic group with an extremely high breast cancer risk (17
). The collection of multiple mammograms over many years for a large proportion of subjects made it possible to conduct separate analyses for mammograms taken many years before diagnosis and mammograms taken closer in time to diagnosis. In our analysis, the timing of the mammograms made very little difference; the odds ratios did not change materially.
A serious limitation of our project was the low participation rate (50.6 percent), which cannot be explained by a lack of mammographic screening; almost 90 percent of women in the cohort reported a previous mammogram at baseline. More intense follow-up may have increased the response rate, but we limited our recruitment efforts to mailings in order not to jeopardize subject participation in future investigations within the MEC Study. Although the success of including women in the study differed slightly by age, ethnicity, and reproductive behavior, we could not detect a systematic bias. Except for ineligibility due to death, similar proportions of cases and controls were included in the final analysis. It appears unlikely that these small differences between eligible subjects and recruited subjects biased the robust risk estimates or that response status would confound the association between mammographic density and breast cancer. The comparison between included women and excluded women did not identify major differences. The assessment of HRT use had serious limitations in that we had to rely on self-reported HRT use and assume a constant type of use during all years. A similar problem existed for body mass index; information on weight was self-reported and was collected only once at entry into the cohort. The use of body mass index categories did not lead to residual confounding; an analysis using body mass index as a continuous variable gave identical results.
This study confirmed the substantial breast cancer risk associated with higher mammographic densities. The magnitudes of risk estimates were similar for percent density and the size of the dense area. Although the finding was not statistically significant, the association between breast density and cancer risk appeared weaker in Japanese women than in Caucasian and Native Hawaiian women. This finding suggests that, if breast density were to be added to risk prediction models (33), it might be necessary to develop different models for ethnic groups whose mammographic features differ substantially from those of Caucasians.
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ACKNOWLEDGMENTS |
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The authors are very grateful to Jihae Noh for her outstanding work in mammogram retrieval and scanning, to Andrew Williams for the excellent database and its management, and to Maj Earle for providing data from the Multiethnic Cohort Study.
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References |
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