1 Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA.
2 Institute for Nutrition Research, University of Oslo, Oslo, Norway.
Received for publication February 6, 2003; accepted for publication July 21, 2003.
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ABSTRACT |
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breast neoplasms; case-control studies; ethnic groups; mammography; regression analysis
Abbreviations: Abbreviations: BMI, body mass index; CARE, Contraceptive and Reproductive Experiences.
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INTRODUCTION |
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Increased mammographic density has consistently been shown to represent a strong independent risk factor for breast cancer (711). However, the extent to which the lower breast cancer incidence rates of Asians are reflected in mammographic density is unclear (1219). Two studies found that Asian-American women had significantly more favorable Wolfes parenchymal patterns than White women did (18, 19); other studies reported that ethnicity was unrelated to Wolfes parenchymal patterns (16, 17) or that percent density was higher in Asian-American women than in Whites (1215). To our knowledge, only one study has examined differences in mammographic density between African-American and White women; these investigators reported that African Americans were statistically significantly more likely to have dense mammograms than were Whites aged 2079 years (15).
Part of the discrepancy in Asian-White differences in mammographic density may be due to different methods of assessing this density across studies. Quantitative measurement of mammographic density may be a more sensitive method for detecting differences in breast cancer risk (7), but this method was, to our knowledge, used in only three studies conducted in Hawaii (1214).
To shed further light on the possible ethnic differences in mammographic density, we compared absolute and percent mammographic densities among Asian-American, African-American, and White women without breast cancer by using a quantitative measurement. We also determined whether any ethnic differences in density were explained by other breast cancer risk factors.
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MATERIALS AND METHODS |
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Participants in the current study were eligible if they had had a mammogram during the 5 years preceding their reference date (the date of household census for controls in the Womens CARE Study and the date on which the control was identified for the Asian-American study). The rate of refusing review of their mammograms was about 7 percent in the Womens CARE Study and 5 percent in the breast cancer case-control study of Asian Americans. Each participant provided a signed consent allowing review of her previous mammograms in this study. We identified 770 women who were eligible to participate. We obtained and scanned one or more mammograms for 493 of these women (64.0 percent). The success rate for obtaining mammograms was 75 percent for Whites, 59 percent for African Americans, and 50 percent for Asian Americans. We were unable to retrieve the mammograms of 277 women because the facility had no record of the woman (n = 59), the mammograms were no longer available at the facility (n = 93), no mammograms had been obtained during the eligible time period (n = 73), the facility no longer existed (n = 32), or the facility did not respond to our request before the study ended (n = 20). The study was approved by the Institutional Review Board at the University of Southern California.
Data collection and mammographic density assessment
We requested the subjects most recent mammograms that had been obtained no later than 12 months after the reference date. We scanned craniocaudal mammograms using an Omnimedia XRS 6cx scanner (Lumisys, Sunnyvale, California) or a Cobrascan CX312T scanner (Radiographic Digital Imaging, Torrance, California). The mammograms were scanned at a resolution of 150 pixels/inch (59 dots/cm). The eight-bit (256 shades of gray) images from the two scanners were indistinguishable with respect to density assessment. For controls in both parent studies, we randomly scanned the right or left breast. We used the computer-assisted method, "Madena," that we developed and validated previously (22) to assess absolute and percent mammographic densities quantitatively. With this method, the total area of the breast is outlined by using a computerized outlining tool, and the software estimates the number of pixels in the outlined area. The dense area is assessed by having a reader outline a region of interest that includes the entire breast but excludes artifacts such as the pectoralis muscle and prominent veins as well as fibrous strands. The reader then searches for the best threshold X where all pixels X within the region of interest are considered to represent mammographic density. The software estimates the area of the pixels above the threshold within the region of interest, which represents the dense area or the "absolute density." "Percent density," or the fraction (percentage) of the breast with densities, is the ratio of absolute density to the total breast area. The dense area was determined by one of the authors (G. U.), while the total area of the breast was determined by a research assistant trained by that author. We included 443 blind duplicates in batches. The coefficients of variation for breast size, absolute mammographic density, and percent mammographic density were 2.7 percent, 18.4 percent, and 19.1 percent, respectively.
The scanned mammogram files of five women could not be assessed for density because the digitized files were unusable and we were unable to obtain their films a second time. Therefore, we obtained mammographic density results for 488 women. Details regarding mammographic density as a measure of breast cancer risk in these ethnic groups can be found in Ursin et al. (11).
We obtained risk factor information from the parent case-control studies (20, 21). In both parent studies, a female interviewer used a structured questionnaire and a life events calendar to conduct in-person interviews with all subjects. The questionnaires for both studies were quite similar. Both studies obtained from each participant complete histories of menstrual and reproductive factors, use of oral contraceptives and hormone replacement therapy, weight 5 years prior to the date on which the subject was identified, medical history, and family history of breast cancer.
Statistical analysis
We treated percent and absolute mammographic densities as continuous and categorical variables. Age was defined as a subjects age at the time of her mammogram. Body mass index (BMI) was calculated as body weight (in kilograms) divided by height squared (in meters) and was obtained on average 3.7 years before the date of a subjects mammogram, with a range of from less than 6 years before to half a year after the date of the mammogram. The variables age, BMI, age at menarche, and duration of oral contraceptive use were treated as continuous. A full-term pregnancy was defined as any pregnancy that lasted more than 26 weeks. Number of full-term pregnancies and age at first full-term pregnancy were included as continuous variables in our analyses. Family history of breast cancer was categorized as follows: no first- or second-degree family history, breast cancer history for at least one first-degree relative (mother or sister), or breast cancer history for at least one second-degree relative but not a first-degree relative. We created a six-category variable combining menopausal status and hormone replacement therapy use at the time of the mammogram (premenopausal or, among postmenopausal women, never used hormone replacement therapy, currently using estrogen replacement therapy, currently using estrogen and progestin replacement therapy, previously used estrogen replacement therapy, or previously used estrogen and progestin replacement therapy). On the basis of additional information, we have classified seven controls differently regarding menopausal status/hormone replacement therapy use since our previous paper was published (11). We performed t tests, chi-square tests, and analyses of variance to determine whether there were any significant differences in the characteristics of subjects across the three ethnic groups.
To maintain a consistent sample size for all analyses, we excluded 46 women for the following reasons: menopausal status unknown (n = 26), missing BMI information (n = 2), age at first full-term pregnancy missing (n = 3), oral contraceptive use information missing (n = 1), age at menarche missing (n = 3), and adopted or did not know the family history of breast cancer for more than half of their first-degree family members (n = 11). After these exclusions, 442 women remained for analysis: 67 Asian Americans, 149 African Americans, and 226 Whites. For an additional 11 women, family history for one or two family members was unknown but a negative family history was known for the rest. We included these 11 women in the analyses, coding them as having no known family history of breast cancer. Excluding them yielded results similar to those presented in this paper. To assess whether included participants were similar to all nonincluded women, we conducted ethnic-specific analyses. The distributions of main risk factors of interest were similar in the two groups of African-American and Asian-American women. Several differences were noted for White women. Compared with Whites who were not included, Whites who were included were on average 3.6 years older (t-test p = 0.0002) and 1.3 kg/m2 heavier (t-test p = 0.04), and 20.5 percent more of them used hormone replacement therapy (chi-square test p = 0.0006).
We used a multivariate linear regression model approach (23) to compare least-squares means of breast size, absolute mammographic density, and percent mammographic density across ethnic groups; analysis of covariance methods were used to adjust for covariates. We evaluated pairwise differences between ethnic groups by using Tukeys method, and we present the overall p value for all comparisons and p values of <0.05 for pairwise comparisons in the tables. The SAS statistical package (SAS Institute, Inc., Cary, North Carolina) was used for all data management and analysis. Since our sample size (N = 442) was relatively large, and since the residuals from the methods satisfied the normality and homoscedasticity assumptions, we treated percent and absolute mammographic densities as continuous variables without any transformation. In this paper, we describe the distribution of percent and absolute mammographic densities by ethnicity and age (>50 vs. 50 years). Chi-square tests were performed to determine whether the categorical distributions of percent or absolute mammographic density differed by ethnicity overall and within each age group. Since the results of nonparametric and parametric analyses were similar, only the parametric results are presented.
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RESULTS |
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Breast size was statistically significantly correlated with percent density (Pearsons correlation r = 0.35, p < 0.0001) and absolute density (Pearsons correlation r = 0.25, p < 0.0001) for all women combined. Additional adjustment for breast size had little effect on the percent density results presented in table 4. For Asian Americans, African Americans, and Whites, respectively, the values for percent density became 29.2 percent, 30.8 percent, and 28.0 percent for all women combined, and 32.5 percent, 30.2 percent, and 27.4 percent for women under 50 years of age and 27.7 percent, 32.0 percent, and 31.5 percent for women aged 50 years or more. The differences between the ethnic groups remained statistically nonsignificant after adjustment for breast size (all p 0.39).
Additional adjustment for breast size diminished the statistically significant results across ethnicity and made the results for absolute density similar to those for percent density. Absolute density remained lowest in Asian Americans for all women combined (109,200 pixels vs. 137,100 pixels in African Americans and 117,700 pixels in Whites). In younger women, the density levels were 119,000 pixels in Asian Americans versus 136,300 pixels in African Americans and 110,100 pixels in Whites; in older women, there were 107,600 pixels in Asian Americans versus 140,000 pixels in African Americans and 134,000 pixels in Whites. None of these findings was statistically significant either (all p 0.22).
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DISCUSSION |
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Studies examining ethnic differences in the mammographic density of women without breast cancer provide conflicting evidence on whether Asian women differ from Whites in this regard (1219). The largest known study so far used a binary assessment of mammograms, with mammograms assigned a BI-RADS (Breast Imaging Reporting and Data System; American College of Radiology, Reston, Virginia) score of I or II as "fatty" and III or IV as "dense" (15). This study found that, of women older than age 55 years, Asian Americans were statistically significantly more likely than Whites to have "dense" breasts (15). However, Turnbull et al. (19) reported that women from Bombay, India, were significantly more likely than White women in the United Kingdom to have favorable Wolfes parenchymal patterns (N1, P1). Similarly, Gravelle et al. (18) found that healthy premenopausal Japanese women in suburban Tokyo were significantly more likely than premenopausal British women to have favorable N1 and P1 Wolfes parenchymal patterns. The other reports by Grove et al. (16, 17) suggested no significant association between ethnicity and Wolfes parenchymal patterns.
To our knowledge, only three other studies (1214) have used a quantitative method to investigate ethnic differences in absolute and percent mammographic densities. Maskarinec et al. (1214) used the same Madena method we used and found that Asian Americans had a statistically significantly higher percent mammographic density and a nonsignificantly lower absolute mammographic density than Caucasians and Native Hawaiians did. These ethnic differences in mammographic density diminished after adjustment for BMI, age at menarche, diet, estrogen use, and family history. Our results are consistent with these results. We found no significant differences in absolute mammographic density between Asian Americans and Whites and that the significant differences in percent mammographic density disappeared after adjustment for BMI and age. The only other published study known to compare mammographic density in African-American and White women found that, in women 65 years of age or younger, African Americans were more likely than Whites to have mammograms that were "dense" (BI-RADS scores of III and IV) versus "fatty" (BI-RADS scores of I and II) (14). In our study, African Americans had a similar percent mammographic density as Whites in both age groups. African Americans had a higher absolute mammographic density than Whites among all women aged 3564 years after we adjusted for age and BMI. These trends were similar for both younger and older women and whether age 45 or 50 years was used as the cutoff point (data not shown). The crossover in breast cancer incidence rates between African Americans and Whites that occurs at about age 4045 years (5) therefore does not appear to be reflected in mammographic density.
Our study suggests that absolute mammographic density reflects the lower breast cancer incidence rates in Asian Americans better than percent mammographic density does because, in our full model, Asian Americans had a lower absolute, but similar percent mammographic density as African Americans or Whites. This result is consistent with the report from Maskarinec et al. (14) in which the absolute mammographic density was lowest in Japanese in Japan, intermediate in Japanese in Hawaii, and highest in Whites in Hawaii, but percent mammographic density was higher in Japanese than in Caucasians. Percent mammographic density has been reported to be a stronger breast cancer risk factor than absolute mammographic density (7). However, in our study, the risk estimates were fairly similar for absolute and percent mammographic densities (11). Percent density may not be a good predictor of ethnic differences because it is greatly influenced by breast size and body fat, which show substantial ethnic differences.
One limitation of our study is that we included few Asian-American women. Although Asian-American controls and African-American and White controls were selected by using well-accepted approaches in population-based studies, the former group was identified from neighborhood walks while the latter groups were recruited through random digit dialing. However, the studies were conducted during approximately the same time period in the 1990s, and the risk factor information, including mammogram history, was obtained by asking similar questions. Thus, it is unlikely that differences in control selection methods would have biased our results. Another potential weakness of our study is that we were unable to obtain mammograms from all eligible women. As mentioned above, women whose mammograms were available were similar to women whose mammograms were not available regarding most breast cancer risk factors. The differences in age and BMI among Whites who were included and those who were not are unlikely to have caused any of our results.
Another limitation is that we did not have information on body weight or BMI at the date of the mammograms. However, when we restricted our analyses to women who had reported their weight at an age that corresponded to 03 years within the mammogram date, our results were similar, although, with the smaller sample size, the differences across ethnic groups were no longer statistically significant. This finding suggests that any residual confounding of our results by body weight due to the lack of information on body weight at the time of the mammogram is likely to be minimal.
We found no statistically significant differences in absolute density across ethnic groups after adjustment for breast size. However, for all women combined, Asian-American women still had the lowest absolute density, while African Americans had the highest.
In summary, our study suggests that absolute but not percent mammographic density reflects the substantially lower breast cancer incidence rates of Asian Americans relative to those of African Americans and Whites. Neither percent nor absolute mammographic density reflects the crossover in breast cancer incidence rates between African Americans and Whites that occurs around age 4045 years. Both absolute and percent mammographic densities should be reported in future studies, especially when multiethnic populations are included.
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ACKNOWLEDGMENTS |
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Data collection for the Asian-American study was supported by the California Breast Cancer Research Program (grants 1RB-0287 and 3PB-0102).
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NOTES |
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REFERENCES |
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