Ethnic differences in mammographic densities

Gertraud Maskarineca, Lixin Menga and Giske Ursinb

aCancer Research Center of Hawaii, Honolulu, Hawaii, USA.
bDepartment of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Gertraud Maskarinec, Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813, Hawaii, USA. E-mail: gertraud{at}crch.hawaii.edu

Abstract

Background Breast cancer incidence is considerably lower among Japanese and Chinese women than among Caucasian and Native Hawaiian even in second and third generation migrants. Mammographic densities, which refer to the radiological appearance of the healthy female breast, are related to breast cancer risk. The purpose of this project was to explore the hypothesis that women from ethnic groups at high breast cancer risk are more likely to have high levels of densities than women from low breast cancer risk groups.

Methods In a cross-sectional design, 514 pre- and post-menopausal women recruited at mammography screening clinics completed a self-administered questionnaire. We used a computer-assisted method to measure the dense and the total areas of the breast and to compute per cent breast density. Student's t-tests and multiple linear regression were applied to examine ethnic differences and to explore determinants of mammographic densities, respectively.

Results The unadjusted mean dense area was 15% smaller in Chinese and Japanese women than in the Caucasian/Hawaiian group. However, because of their smaller breast size, the per cent of the breast occupied by dense tissue in Chinese and Japanese women was 20% higher than in Caucasian women. Body mass index, age, menopausal status, parity, and oestrogen therapy were associated with mammographic densities, but they did not account for all ethnic differences.

Conclusions Whereas this study detected some ethnic differences in mammographic densities, the importance of dense areas and per cent densities as indicators of breast cancer risk in ethnically diverse populations remains to be clarified.

Keywords Ethnic groups, breast neoplasms, mammography, risk factors, comparative study, regression analysis

Accepted 5 July 2000

Breast cancer risk differs greatly by ethnicity. In 1988–1992,1 the US breast cancer incidence rates per 100 000 (invasive cases only, age-adjusted to 1970 US population) were 112 for Caucasian women, 106 for Native Hawaiian women, 82 for Japanese women, 73 for Filipina, and 55 for Chinese women. From Japan,2 incidence rates between 23 and 31 per 100 000 (age-adjusted to the World Standard population) have been reported for the same period. Migration studies3–7 have clearly demonstrated the effect of a new environment on breast cancer risk. However, in contrast to colorectal cancer8 it appears to take several generations to reach the risk of the host population. Although the majority of Chinese and Japanese women living in Hawaii are second or third generation migrants, 1990– 1992 data from the Hawaii Tumor Registry (age-adjusted rates per 100 000: 82.1 for Chinese, 90.6 for Japanese, 116.4 for Caucasian) suggest that a lower breast cancer risk persists in this population, possibly a result of retaining parts of their traditional culture.3,9

Mammographic densities which refer to the amount of fat, connective, and epithelial tissue in the female breast have been shown to be related to breast cancer risk.10 They are not abnormalities but variations of healthy breast tissue. Fat appears dark on film-screen mammograms. The radiographically light areas represent epithelial and connective tissue and are relevant to breast cancer risk. A high percentage of mammographic densities appears to confer a fourfold risk of developing breast cancer.10 Therefore, the hypothesis was proposed that women from ethnic groups with high breast cancer risk are more likely to have a high percentage of mammographic densities than women from ethnic groups at low risk for breast cancer. The purpose of this report is to investigate ethnic differences in and determinants of mammographic densities among a population of women with Caucasian, Chinese, Filipino, Japanese, and Native Hawaiian ancestry living in Hawaii.

Methods

Recruitment and data collection
In a cross-sectional study design, women were recruited at five mammography facilities on the island of Oahu, which together provide more than half of all mammograms on the island (unpublished data). As a result of a greater than 90% insurance coverage among Hawaii's population11 and a 1991 legislative mandate for health plans to cover screening mammography, self-reported mammography utilization among women 40 years and older has been above 70%.12 Participation has been slightly lower for Filipino women, but similar among Caucasian, Native Hawaiian, and Japanese women.12 Flyers describing the study were mailed with the appointment reminder or handed to the women at the time of their appointment. Because the clinics did not distribute flyers to all eligible women, neither the total number of potential study subjects nor their ethnic distribution is known. Interested women returned their address to the mammography clinic or to the Cancer Research Center. In the second year, we added a rural clinic serving primarily Native Hawaiians in an effort to increase the number of Native Hawaiian women enrolled in this study. In addition, we mailed invitation letters to women who had received a mammogram through the Breast and Cervical Cancer Screening Program funded by the Centers for Disease Control and Prevention and administered by the Hawaii Department of Health. The study protocol was approved by the Committee on Human Subjects at the University of Hawaii and by the research boards of all participating institutions. All study participants signed informed consent and completed a questionnaire that included items on ethnicity, body weight and height, reproductive, medical, and family history. Women who did not speak English, women who reported a history of breast cancer or augmentation surgery, and women with suspicious lesions on the mammograms were excluded from the study.

We received responses from 773 women who had received a letter or a study flyer in a mammography clinic. Of these, 521 (68%) agreed to participate in the study and returned the study questionnaires. The return rates differed by clinic with a high of 78% and a low of 29%. Seven of the 521 women had to be excluded from the analysis: for five women their mammograms could not be located and two mammograms showed previous breast augmentation. The final study population for analysis was 514. We used the subjects' self-assigned ethnicity, but we checked it using the reported ethnicity for both parents. With the exception of the Native Hawaiian women who all reported mixed ancestries, only 9% of subjects had parents with different ethnic backgrounds. Of the 156 Japanese participants, 133 women were born in the US, 13 women have lived more than 25 years in the US, and for 123 women, at least one parent was also born in the US. Similarly, of the 73 Chinese women, 54 were born in the US, 12 had lived more than 25 years in the US, and for 50 women at least one parent was born in the US.

Mammogram density assessment
Left and right cranio-caudal views of the mammogram were obtained from the mammography clinics after the radiological evaluation had been completed and ruled out any malignancy. The films were scanned into a PC using an X-ray digitizer (Cobrascan CX-612-T) at a resolution of 300 pixels per inch. Pixels were converted into square millimetres (one mm = 11.8 pixels). Computer-assisted mammographic density assessment was performed using a method that was first developed in Toronto13 and later modified at the University of Southern California in Los Angeles.14 The reader first draws the outline of the breast (using an outlining tool) and then searches for the best threshold grey level value X where all pixels with values above X are considered to represent mammographic densities. The pixel count corresponding to the area coloured within the outline of the breast is determined by the computer, as is the total area within the outline of the breast. The proportion of the breast with densities is calculated as the ratio of the coloured area to the total area of the breast. Two readers (GM and LM) read all mammograms and a third reader (GU) checked a sample of mammograms. The correlation between the two readers for the size of the dense areas was 0.92. The mean of the two readings was used for analysis.

Statistical analysis
Several variables showed non-normal distributions and were transformed using their natural logarithms. Indicator variables for ethnicity (Chinese, Filipino, Japanese, Native Hawaiian) were created. We calculated the body mass index (BMI) (weight [kg]/ height [m2]). We calculated a Gail score15 (a woman's individualized risk of developing breast cancer within the next 5 years) for every study subject using a software program distributed by the National Cancer Institute.16 The risk estimate is based on age, family history of breast cancer, age at menarche, age at first live birth, and previous breast biopsies. Student's t-tests17 were applied to assess differences between ethnic groups. Multiple linear regression17 was used to explore the relation of BMI and reproductive factors with mammographic densities. The least-squares means, or population marginal means, of mammographic measures by ethnicity were estimated in the PROC GLM procedure.18 These predicted values were the expected ethnic means of mammographic measures controlling for BMI, menopausal status, age, hormone replacement therapy, and parity in the regression models.19 All analyses were performed using PC-SAS®, release 6.12 (SAS Institute, Cary, NC).

Results

The mean age of the 514 study participants was 53.9 years (range: 35–85 years) (Table 1Go). Caucasian and Japanese women represented the largest groups. We observed considerable differences in mean BMI with Native Hawaiian women reporting the highest body weight and Chinese and Japanese the lowest body weight. More than 10% of participants reported a family history of breast cancer. Reproductive behaviour differed slightly among ethnic groups. Women with Chinese and Japanese ancestry had children at an older age, while Native Hawaiian women gave birth earliest in life and to the greatest number of children. Current hormone replacement therapy among postmenopausal women varied between a high of 57% among women with Japanese ancestry and a low of 35.7% among women with Filipino ancestry. Oral contraceptive use was quite low in all groups of premenopausal women.


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Table 1 Characteristics of the study population
 
The breast size as measured on the mammographic image was approximately 50% larger for Caucasian and Native Hawaiian than for Japanese and Chinese women (Table 2Go). The size of the dense area in the breast was similar in Caucasian and Native Hawaiian women and also in Chinese and Japanese women. Although not statistically significant, the mean dense area was 15% smaller in Japanese and Chinese women. The per cent densities were 20% higher in Japanese and Chinese women than in Caucasian and Native Hawaiian women. The non-dense areas, i.e. the area of the breast with fatty tissue, was considerably smaller in the Chinese and Japanese women than in all other groups. For all mammographic parameters except for the dense areas, the differences between Chinese and Caucasian women as well as between Japanese and Caucasian women were statistically significant. As demonstrated by the estimated least-square means (Table 2Go), adjustment for BMI, age, menopausal status, oestrogen use, and parity reduced the differences, but did not eliminate them.


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Table 2 Mammographic measures by ethnicity
 
We observed a strong relation between BMI and per cent densities (Figure 1AGo). As expected, women with higher BMI had larger breasts than women with BMI below 25 (P = 0.0001 for all groups). As a result, per cent densities were nearly twice as high in light women as in heavy women. The size of the dense areas was statistically significantly greater among women with BMI below 25 than for heavier women, but this relation was limited to Caucasian and Native Hawaiian women (P = 0.006 and P = 0.03). The dense areas and the per cent densities were larger in pre- than in post-menopausal women (P = 0.0001) (Figure 1BGo). However, within ethnic groups, the difference in dense areas between pre- and postmenopausal women was only statistically significant for Caucasian (P = 0.001) and for Filipino (P = 0.03) women. The difference in per cent densities was significant for Caucasian (P = 0.0001) and for Native Hawaiian (P = 0.04) women, as well as borderline significant for Chinese (P = 0.06) women. Current hormone replacement therapy (Figure 1CGo) was related to larger dense areas among Caucasian (P = 0.01), Filipino (P = 0.05), and Native Hawaiian (P = 0.04) women. However, the association with per cent densities was only borderline significant for Caucasians (P = 0.055) and Filipinos (P = 0.09). For Chinese and Japanese women, mammographic densities did not differ significantly by menopausal status or by use of hormone replacement therapy.



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Figure 1 Dense area (left) and per cent densities (right) stratified by covariates. (A) Bodymass index (kg/m2), (B) menopausal status, (C) oestrogen use. Ethnicity: C = Caucasian; Ch = Chinese; F = Filipino; N = Native Hawaiian; J = Japanese

 
The model with dense area as a dependent variable explained 12% of the variance (Table 3Go). Body mass index, age, and postmenopausal status were inversely related to the size of the dense areas, whereas hormone replacement therapy showed a positive relation. More than half of the variance in the size of the non-dense areas could be explained. Body mass index, age, height, and parity of >=3 children predicted higher non-dense areas; Chinese, Japanese, Native Hawaiian, and family history of breast cancer ethnicity were related to smaller non-dense areas. Per cent density was negatively associated with BMI, age, parity of >=3 children, and postmenopausal status, whereas it showed a direct relation with Native Hawaiian ethnicity and family history of breast cancer. The model explained 42% of the variance. Comparing the full models to simple models containing only ethnicity variables indicates that the importance of ethnicity was greatly reduced after including the other variables in the model for non-dense areas and for per cent densities.


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Table 3 Determinants of mammographic patterns. Results of multiple linear regression
 
Discussion

The results of this study indicate that the area of dense tissue in the breast appears to be smaller in Japanese and Chinese women, although not statistically significant, than in Caucasian and Native Hawaiian women. However, because of the considerably smaller size of the non-dense areas, the per cent of the breast occupied by dense tissue in Chinese and Japanese women was 20% higher than in Caucasian and Native Hawaiian women. The relation between BMI, menopausal status, and hormone replacement therapy and mammographic densities was primarily observed among Caucasian and Native Hawaiian women. Ethnicity had the strongest association with the size of the non-dense areas. Adjustment for BMI and reproductive factors reduced the importance of ethnicity in the regression models considerably. This suggests that ethnicity may not be an independent determinant of mammographic densities, but a result of other risk factors, including BMI, reproductive behaviour, and other yet undetermined factors.

This is the first report comparing mammographic density in women with Chinese and Japanese ancestry to density in Caucasian women using the quantitative assessment method. So far, the majority of the small number of publications describing mammographic densities among non-Caucasian populations used Wolfe's classification scheme.20 Wolfe described four patterns of breast parenchyma: the N1 pattern refers to predominantly fatty breasts, the P1 and P2 patterns are characterized by increasing ductal prominence, and the DY pattern is distinguished by diffuse or nodular densities.20 To some extent, high Wolfe grades correspond to high per cent densities in the quantitative assessment method although the quantitative assessments have been associated with a higher risk of breast cancer than the qualitative classification method.21 Our findings disagree with reports22,23 suggesting that the proportion of the breast corresponding to dense tissue is lower among Japanese than among Caucasian women. The current report suggests that per cent densities are higher in Chinese and Japanese women, but that the size of the area may differ between low- and high-risk ethnic groups. Results from a mammography screening study in Tokushima, Japan23 suggested a very low prevalence of Wolfe's DY (mammary dysplasia) pattern. Normal premenopausal Japanese women were found to have significantly more favourable mammographic patterns when Wolfe grades were assigned than British women,22 but in two studies from Hawaii,24,25 ethnicity was not significant in predicting the proportion of high-risk mammograms classified by Wolfe's categories.

Because the published literature10 has focused on per cent densities, little is known about the importance of the dense areas' size as a predictor of breast cancer risk. A dietary intervention study from Toronto suggested that a decrease in dense tissue occurred as the result of the dietary change.26 Given that previous studies10 were conducted in predominantly Caucasian populations with relatively large breasts, little is known about the importance of dense areas as a predictor in such a diverse population as ours. Our own results from a case-control study27 suggest that the associations of breast cancer risk with the size of the dense areas and with per cent densities are of similar strength. The higher per cent densities in Chinese and Japanese women probably do not translate into a higher breast cancer risk. Our report agrees with other studies that have shown lower densities after menopause,28–30 an inverse relation between body weight and mammographic densities,31–35 a positive relation between mammographic densities and hormone replacement therapy36–38 as well as a family history of breast cancer.39–41

This study had several limitations. Despite our recruitment efforts in a variety of settings, the selection of study participants may not represent the general population in Hawaii very well. The high educational levels42 and the low smoking rates (18% among women)12 in Hawaii partly explain the low prevalence of risk factors in the study population. Recruitment through mammography clinics did not exclude women with lower socioeconomic status because of the high health insurance coverage11 and mammography participation.12 We made a particular effort to include women with diverse backgrounds by including a community health centre and the Breast and Cervical Cancer Screening programme. As in many epidemiological studies, the response rates for Native Hawaiian and Filipino women were relatively low due to a large refusal rate and language problems among Filipino women. The high BMI of the small number of Filipino women in the study suggests that these women were not representative of this population with a low breast cancer risk.1 Therefore, no conclusions about Filipino women can be drawn from this study. However, the large number of women with Japanese and Chinese ancestry who use the same mammography clinics as the Caucasian women and have high mammography participation rates12 justify conclusions for these ethnic groups. Due to the unknown response rate and the question of how well the study sample represents the general population, the results of this study have to be regarded as preliminary.

Differences in the quality of films between clinics and subjects may have introduced some measurement error. Recently, mammography has moved toward high-contrast films to improve detection of abnormalities. This made it harder to detect the skinline. We had to apply a special feature in the scanning software to make the skinline visible and to measure the size of the breast. Because we applied the same techniques to all mammograms, the size of the breast may have been slightly overestimated resulting in lower per cent densities. Therefore, our density distribution may be systematically lower than in the Canadian study29 which utilizes different hard- and soft-ware. To minimize the subjective component of the assessment method, we trained the readers and compared the results between readers frequently. The high correlation coefficient indicates a high level of standardization in mammographic assessment.

Although breast cancer incidence still differs among ethnic groups in Hawaii, the differences have become smaller as the majority of women with Chinese and Japanese descent are at least second generation migrants. For example, the breast cancer incidence rate per 100 000 for Japanese women has increased from 41 in 1973–197743 to 88 in 1988–1992.1 Assuming that Chinese and Japanese women with a higher breast cancer risk are more likely to participate in mammography screening and in a research study, the Japanese and Chinese women in this study may have a breast cancer risk that is fairly close to the risk experienced by Caucasian women. The number of recent immigrants whose breast cancer risk is still close to that of their country of origin is quite small in Hawaii; in fact, 91% of study participants were born in the US. Individual risk as predicted with the Gail model,15,16 which has limited ability to predict risk for Asian population because it is based on the occurrence of breast cancer in Caucasian women,44 indicated that the mean risk to develop breast cancer in the next 5 years was quite similar for the different ethnic groups: 1.17 for Caucasians, 1.35 for Chinese, and 1.26 for Japanese. The current analysis supports our hypothesis that women at low risk for breast cancer have fewer mammographic densities. However, low breast cancer risk appears to be characterized by smaller dense areas rather than by a lower percentage of mammographic densities. Whereas several risk factors, especially BMI, contribute to the ethnic differences, a portion of the variation cannot be explained with anthropometric and reproductive risk factors and requires further investigation.


KEY MESSAGES Breast cancer incidence is considerably lower among Japanese and Chinese women than among Caucasian and Native Hawaiian even in second and third generation migrants. In this cross-sectional study of mammographic densities, a predictor of breast cancer risk, the unadjusted mean dense area was 15% smaller in Chinese and Japanese women, but the per cent of the breast occupied by dense tissue was 20% higher than in Caucasian and Native Hawaiian women. Whereas this study detected some ethnic differences in mammographic densities, the importance of dense areas and per cent densities as indicators of breast cancer risk in ethnically diverse populations remains to be clarified.

 

Acknowledgments

We greatly appreciate the time and effort contributed by the participating women. This research was supported by the US Army Medical Research and Material Command under DAMD17-96–1–6284, by NIH grant 5-K12 CA 01708, and by ACS grant IRG-92–025-IRG. Thanks to Li-Ching Lyu, PhD for her data from the pilot study.

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