ARTICLE

Ethnicity and Breast Cancer: Factors Influencing Differences in Incidence and Outcome

Rowan T. Chlebowski, Zhao Chen, Garnet L. Anderson, Thomas Rohan, Aaron Aragaki, Dorothy Lane, Nancy C. Dolan, Electra D. Paskett, Anne McTiernan, F. Alan Hubbell, Lucile L. Adams-Campbell, Ross Prentice

Affiliations of authors: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (RTC); Mel & Enid Zuckerman Arizona College of Public Health, University of Arizona, Tucson (ZC); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (AM, GLA, AA, RP); Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (TR); Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook (DL); Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL (NCD); School of Public Health, The Ohio State University, Columbus (EDP); Department of Medicine, University of California at Irvine, Irvine (FAH); Department of Medicine, Howard University Cancer Center, Washington, DC (LLA-C)

Correspondence to: Rowan T. Chlebowski, MD, PhD, at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson St., Building J-3, Torrance, CA 90502 (e-mail rchlebow{at}whi.org).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background: The lower breast cancer incidence in minority women and the higher breast cancer mortality in African American women than in white women are largely unexplained. The influence of breast cancer risk factors on these differences has received little attention. Methods: Racial/ethnic differences in breast cancer incidence and outcome were examined in 156 570 postmenopausal women participating in the Women's Health Initiative. Detailed information on breast cancer risk factors including mammography was collected, and participants were followed prospectively for breast cancer incidence, pathological breast cancer characteristics, and breast cancer mortality. Comparisons of breast cancer incidence and mortality across racial/ethnic groups were estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazard models. Tumor characteristics were compared as odds ratios (ORs) and 95% confidence intervals in logistic regression models. Results: After median follow-up of 6.3 years, 3938 breast cancers were diagnosed. Age-adjusted incidences for all minority groups (i.e., African American, Hispanic, American Indian/Alaskan Native, and Asian/Pacific Islander) were lower than for white women, but adjustment for breast cancer risk factors accounted for the differences for all but African Americans (HR = 0.75, 95% CI = 0.61 to 0.92) corresponding to 29 cases and 44 cases per 10 000 person years for African American and white women, respectively. Breast cancers in African American women had unfavorable characteristics; 32% of those in African Americans but only 10% in whites were both high grade and estrogen receptor negative (adjusted OR = 4.70, 95% CI = 3.12 to 7.09). Moreover, after adjustment for prognostic factors, African American women had higher mortality after breast cancer than white women (HR = 1.79, 95% CI = 1.05 to 3.05) corresponding to nine and six deaths per 10 000 person-years from diagnosis in African American and white women, respectively. Conclusion: Differences in breast cancer incidence rates between most racial/ethnic groups were largely explained by risk factor distribution except in African Americans. However, breast cancers in African American women more commonly had characteristics of poor prognosis, which may contribute to their increased mortality after diagnosis.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Recent data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)1 program indicate that the age-adjusted breast cancer incidence rates for women of racial/ethnic minority groups are substantially lower than those for white women, with 141 cases per 100 000 in white women, 122 in African Americans, 97 in Asian/Pacific Islanders, 90 in Hispanics, and 58 in American Indians/Alaskan Natives (1,2). In addition, African American women are likelier to be diagnosed at a more advanced stage (2) and to have larger tumors that are more commonly estrogen receptor negative (3,4) and high grade (36) than those in white women. African American women also have higher breast cancer mortality than white women (7). All these differences remain largely unexplained (8).

The influence of breast cancer risk factor distribution on differences in incidence and clinical characteristics associated with ethnicity/race has received limited attention (9). Consequently, we explored these relationships in a cohort from the ethnically diverse Women's Health Initiative (WHI) study (10). Our primary aim was to examine whether known and/or presumptive breast cancer risk factors would explain the difference in breast cancer incidence between white women and women of minority groups. Our secondary aims were to describe the pathologic features of cancers diagnosed in the various racial/ethnic groups and to compare breast cancer mortality in African American and white women.


    METHODS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study Population

The WHI is a large longitudinal study of postmenopausal women's health. It includes an observational study and randomized clinical trials that are evaluating effects on clinical outcomes of estrogen plus progestin, estrogen alone, dietary modification, and calcium and vitamin D supplementation (10,11). Women were recruited at 40 clinical centers across the United States, largely through direct mailings (12). Women were eligible to participate if they were postmenopausal, aged 50 to 79 years, unlikely to move or to die within 3 years, and provided written informed consent. The clinical trials had additional eligibility requirements related to safety, competing risks, and potential adherence. In addition, all clinical trials excluded women with a breast cancer history and required that the baseline mammogram and clinical breast exam not be suspicious for breast cancer. Neither baseline mammogram nor clinical breast exam was required for participation in the observational study.

In general, potential WHI participants were recruited into the clinical trial component. Women who were not interested in being randomly assigned to an intervention or who were ineligible for the clinical trial component were offered enrollment in the observational study. Although women were not excluded from clinical trials based on breast cancer risk factors, the opportunity to self-select the type of participation resulted in some variation in risk factor distributions between study components, with women participating in the hormone clinical trials having fewer breast cancer risk factors than participants in the other trials (data not shown).

A total of 161 809 participants enrolled in either the observational study (N = 93 676) or clinical trial (N = 68 133) components of the WHI between October 1, 1993, and December 31, 1998 (13). Of these, 5238 women reported a history of breast cancer or mastectomy at baseline. Although these women were eligible for participation in the observational study, they were excluded from this analysis, leaving 156 570 women.

Human Subjects Review Committees at each participating institution approved the WHI study protocol.

Baseline Data Collection

Baseline self-administered questionnaires were used to collect information on demographics; medical, reproductive, and family history; personal habits such as smoking and alcohol use; and physical activity as metabolic equivalents. Food intakes were assessed using a semiquantitative food frequency questionnaire (14). Body mass index (BMI) was calculated as weight (kg)/height (m)2.

Information about use of postmenopausal hormone therapy, oral contraceptives, medications, and dietary supplements was collected during in-person interviews. Hormone therapy users (past and current) were defined as those who used estrogen-containing pills or patches after menopause for at least 3 months. Current users were using hormone therapy at baseline and/or were randomly assigned to the hormone arms of the two WHI menopausal hormone therapy trials (15). Hormone use was further classified as use of estrogen alone or of combined estrogen plus progestin.

By self-report, women identified their ethnicity/race selecting from six offered categories: American Indian/Alaskan Native; Asian/Pacific Islander; Black/African American; Hispanic; white; and Unknown.

Follow-Up and Breast Cancer Ascertainment

Medical history was updated annually (for women in the observational study) or semiannually (for women in the clinical trials) by mail and/or telephone questionnaires. For women in the clinical trial component of the WHI, the frequency of clinical breast exam and mammography was protocol defined as occurring annually for women in hormone trials and biennially for women in the dietary trial. For women in the observational study, clinical breast exam and mammography were not protocol defined. Information regarding frequency of clinical breast exam and mammography was collected annually from all participants.

Breast cancers were verified by medical record and pathology report review by centrally trained WHI physician adjudicators (16,17). Central adjudication and coding of histology, extent of disease, and estrogen receptor (ER) and progesterone receptor (PR) status (positive or negative per pathology report) were performed at the Clinical Coordinating Center using the SEER coding system (18). Only invasive breast cancer cases confirmed by central review were included.

Statistical Analyses

Descriptive analyses were conducted for breast cancer risk factors and other covariates by racial/ethnic groups and by breast cancer status in each group. Model development focused on determining the extent to which breast cancer risk factors and other covariates accounted for differences in breast cancer incidence rates among racial/ethnic groups. To this end, we fit a series of nested proportional-hazard models to assess the association between ethnicity and risk of breast cancer after accounting for established and putative risk factors. The initial set of models provided age-adjusted comparisons of breast cancer incidence among racial/ethnic groups. The second set of models incorporated established risk factors used in the Gail model (19) (age; number of first-degree relatives with breast cancer; ages at menarche, first birth, and menopause; and prior breast biopsy for benign breast disease). The final set of models incorporated other breast cancer risk factors and covariates, including educational level; income level; health insurance status; number of second-degree relatives with breast cancer; BMI; physical activity at baseline and at 18 years of age; alcohol intake; smoking status; parity; total months of breast feeding; prior or current use of oral contraceptives, of non-steroidal anti-inflammatory drugs, and of hormone therapy (HT); dietary intakes, including energy intake from fat; folic acid intake; bilateral oophorectomy and or hysterectomy status; hormone therapy x BMI interaction; history of mammography; and mammography during follow-up (as a time-dependent covariate). Wald chi-square tests were used to test whether individual hazard ratios comparing minority groups to whites (referent category) were different from unity and for a global test to determine if any of these hazard ratios were different from unity.

To adjust for potential effects of age and study design, the proportional-hazards models were stratified by 5-year age groups, hormone therapy use, and clinical trial versus observational study participation. Further adjustments included fitting both categorical and linear terms for BMI and a linear term for age, in addition to the age stratification. Potential effect modification between race/ethnicity and risk factors was examined using tests for each interaction calculated from the final model. The power to detect such interactions was low, given the small number of breast cancers occurring among some groups of minority women.

Because inferences from this model rely on the use of the multivariable Cox regression models, the assumption of proportionality was examined using a two-step procedure. The initial step involved fitting a flexible Cox regression model that allowed both baseline incidence rates and effects of known risk factors to differ among ethnic groups, ry(t;z) = r0y(t)exp(zBy), where y represents ethnicity, z represents a vector of known risk factors, and By represents an ethnicity-specific regression coefficient. A score test was then used to determine whether the effects of established risk factors differed for African Americans, Hispanics, or Asian/Pacific Islanders compared with whites. (Insufficient sample size precluded comparative testing of American Indians/Alaskan Natives.) In a second step, we verified the proportional hazards assumption by visually comparing cumulative baseline incidence rates, and testing whether there was a statistically significant interaction between time and ethnicity under the assumption of a common baseline incidence function. Because there was no evidence that r0y(u) differed among ethnic groups, a common baseline incidence function was subsequently used.

Missing data were handled via a procedure known as complete case analysis. To examine the possible impact of missing data, we compared rates of missing data by race/ethnicity. Differences among racial/ethnic groups in rates of missing data were detected for several variables, including age at menopause, family history of breast cancer, prior benign breast disease, and income level. With the exception of income, the missing data were considered to be missing at random (MAR), after taking race/ethnicity into account. Under the MAR assumption, a sensitivity analysis was performed using multiple imputation. Covariate data were imputed five times, regression models were fit, and the resulting parameter estimates were combined [via SAS PROC MI and PROC MIANALYZE, as described by Rubin (20)]. The combined imputation results (not presented) agreed with our main complete case analysis; the breast cancer hazard ratios for each racial/ethnic group compared with white women were all less than 1 but were statistically significant only for African Americans.

For analysis of women diagnosed with invasive breast cancer, logistic regression models were used to explore associations between race/ethnicity and tumor characteristics, after adjustment for age, BMI, hormone therapy use, health insurance status, income level, and educational level. When evidence of racial differences in tumor characteristics was found, multivariable Cox regression models were fit to compare incidence rates of disease subtypes. Comparisons of survival after breast cancer diagnosis between racial/ethnic subgroups were based on a proportional hazards model that was stratified by age, enrollment in the observational study versus clinical trial component, and cancer stage at diagnosis, with age (linear) and BMI (categorical and linear) as covariates. All analyses were conducted using SAS version 9.00. All statistical tests were two-sided.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Baseline characteristics for this cohort of 156 570 postmenopausal women by ethnicity are presented in Table 1. African American, Hispanic, and American Indian/Alaskan Native women were younger and had higher BMI than white or Asian/Pacific Islander women or women with unknown ethnicity/race. More than 50% of African American women were obese (defined as BMI ≥ 30 kg/m2), and over 10% of African American women had BMI of 40 kg/m2 or higher (data not shown). Women of every minority group were less likely to drink alcohol than white women. White women and women in the Asian/Pacific Islander group had a higher age at first birth than women in the other groups. Except for women in the Asian/Pacific Islander group, minority women were less likely than white women to have ever been on hormone therapy or to have a college or higher degree.


View this table:
[in this window]
[in a new window]
 
Table 1.  Baseline characteristics and breast cancer risk factors by race/ethnicity

 
Although mammogram frequency was protocol defined for women in the clinical trial component of the WHI, mammogram frequency differed across racial/ethnic groups, both among the population as a whole and for participants in the observational study and in the clinical trials (Table 2, P<.001). White women had a higher rate of mammography than women of any other racial/ethnic group.


View this table:
[in this window]
[in a new window]
 
Table 2.  Average rate of mammograms per year during follow-up by race/ethnicity and study component*

 
During the follow-up period (median of 6.3 years), 3938 new invasive breast cancers were identified in 3455 white, 242 African American, 103 Hispanic, 88 Asian/Pacific Islander, and 11 American Indian/Native Alaskan women and in 39 women of unknown race/ethnicity. Age and cohort (i.e., clinical trial versus observational study)–stratified breast cancer hazard ratios varied statistically significantly by ethnicity. With white women as the referent group, hazard ratios were statistically significantly lower than 1 among Asian/Pacific Islanders, African Americans, and Hispanics (Fig. 1, P<.001 for global test of whether any of the estimated hazard ratios were equal to unity). The adjusted hazard ratio in American Indians/Native Alaskans relative to whites was also lower than 1 but not statistically significantly so, possibly because of the small numbers of cases.



View larger version (20K):
[in this window]
[in a new window]
 
Fig. 1. Hazard ratios and P values of invasive breast cancer incidence by race/ethnicity after adjusting for breast cancer risk factors and other covariates. The age-adjusted model was adjusted for age only; the "Gail"-adjusted model was adjusted for age, number of first-degree relatives with breast cancer, age at menarche, age at first birth, and prior breast biopsy for benign disease; and the final model was adjusted for the covariates in Gail model plus education, BMI, physical activity, number of second-degree relatives with breast cancer, parity, hormone therapy (HT) use, prior contraceptive use, alcohol, smoking, dietary intake, HTxBMI interaction, and mammography (as a time-dependent covariate). P values on the right indicate a global test of whether breast cancer incidence differs by race/ethnicity; because of sparse data, tests did not include American Indians/Native Alaskans.

 
After adjusting for the risk factors in the Gail model (age; number of first-degree relatives with breast cancer; ages at menarche, first birth, and menopause; and prior breast biopsy for benign breast disease), all hazard ratios comparing minority groups with whites were attenuated. Although all hazard ratios remained below 1, indicating lower risk in minority women (global test of race/ethnicity, P = .05), the results were statistically significant only for African American women (P = .05). The results were close to statistical significance for Hispanic women (P = .07).

In the final model, adjustment for additional risk factors and covariates, including mammography, further moderated the differences between minorities and white women. Hazard ratios for both Hispanics and Asian/Pacific Islanders (0.98 and 0.94, respectively) were statistically indistinguishable from 1. Only African American women had a statistically significantly (P = .006) lower breast cancer risk than white women when the additional risk factors were included (hazard ratio relative to white women = 0.75, 95% confidence interval [CI] = 0.61 to 0.92).

When the influence of age, family history, reproductive history, higher education, and alcohol intake on breast cancer risk was examined across ethnicity/race in expanded Cox models, no statistically significant interactions between race/ethnicity and these breast cancer risk factors on breast cancer incidence were seen (data not shown). Further, no evidence of interaction between race/ethnicity and study component (i.e., observational study versus clinical trial) with respect to breast cancer incidence was found.

Tumor histology, size, and stage did not differ statistically significantly by race/ethnicity (Table 3). However, there were highly statistically significant (P<.001) differences in the distribution of hormone receptor status and tumor grade by race/ethnicity; the differences between white women and African American women were especially great. Consequently, we determined hazard ratios of these disease subtypes for African American women compared with those in white women. African American women had a lower incidence of both well-differentiated (HR = 0.52, 95% CI = 0.35 to 0.77) and moderately differentiated (HR = 0.59, 95% CI = 0.43 to 0.80) tumors than white women and a higher incidence of poorly differentiated tumors (HR = 1.36, 95% CI = 1.06 to 1.75). African American women also had lower incidences of ER-positive and PR-positive tumors than white women (HR = 0.72, 95% CI = 0.59 to 0.87 and HR = 0.63, 95% CI = 0.50 to 0.79, respectively) and a higher incidence of ER-negative tumors (HR = 1.54, 95% CI = 1.11 to 2.14). The incidence of PR-negative tumors was slightly higher in African American women than in white women (HR = 1.29, 95% CI = 1.00 to 1.67). African American women also had substantially higher rates of ER-negative cancers and high-grade cancers than women of the other racial/ethnic groups. For example, among African American women, 43% of breast cancers were poorly differentiated (grade 3), compared with 27% or less in women of all other ethnic/racial groups.


View this table:
[in this window]
[in a new window]
 
Table 3.  Characteristics of invasive breast cancers by race/ethnicity

 
Because tumor grade and ER status independently influence breast cancer outcome (21), we also examined the joint distribution of these factors by race/ethnicity. Nearly one-third of all breast cancers in African American women were both high grade (poorly differentiated) and ER negative, a frequency substantially greater than that in women of other races/ethnicities (Table 4). In a multinomial logistic regression model that incorporated age, BMI, HT use, socioeconomic factors (health insurance status, income level, educational level), and ethnicity, BMI was only a modest, non–statistically significant (P = .10) predictor of high-grade plus ER-negative status, whereas ethnicity was a highly statistically significant (P<.001) predictor of this status. For example, the odds ratio for high-grade, ER-negative tumors in African American versus white women was 4.70 (95% CI = 3.12 to 7.09).


View this table:
[in this window]
[in a new window]
 
Table 4.  Grade and receptor status of breast cancers by race/ethnicity*

 
Finally, we compared mortality outcomes among white and African American racial/ethnic groups. After a median of 3.1 years following a breast cancer diagnosis, the cumulative mortality rate among African American women with breast cancer was 8.7% (21/242), whereas that among white women was 5.5% (191/3455). After adjusting for age, BMI, tumor stage, and study component, the risk of death after breast cancer in African American women remained statistically significantly elevated (HR = 1.79, 95% CI = 1.05 to 3.05).


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this large cohort of postmenopausal women, we found that all ethnic/racial groups had a lower age-adjusted breast cancer incidence than white women. However, the lower incidence in Hispanic, Asian/Pacific Islander, and American Indian/Native Alaskan women was mostly attenuated after adjustment for the distribution of other breast cancer risk factors. Dietary (22,23) and/or physical activity factors (24) may account for some of the remaining variability, but limitations in the precision of the tools that are available to estimate these factors (23) preclude definitive assessment.

Adjustment for breast cancer risk factors also explained some of the difference in breast cancer incidence between African American and white women. However, even in the final model, which adjusted for differential mammography screening rates, the breast cancer incidence was statistically significantly lower in African Americans than whites (HR = 0.75, P = .006). A potential factor mediating the lower breast cancer incidence in African American women is their mammographic breast density, which has been reported to be lower than that in white and Hispanic women (25).

The lower breast cancer incidence rates in racial/ethnic minority groups than in whites observed in the WHI cohort reflect the pattern previously reported in the general population (18). However, a comparison of age-adjusted rates from WHI with those for women in the SEER program indicates that breast cancer rates for all racial/ethnic subgroups except African Americans are somewhat higher for women in WHI than for women in SEER. That is, annualized age-adjusted incidence rates (in cases /10 000 per year) for WHI and SEER, respectively, are white, 44 versus 41; African American, 29 versus 34; Hispanics, 31 versus 25; American Indians, 28 versus 16; and Asian/Pacific Islanders, 38 versus 25 (18). These modest differences may arise from higher educational status and greater access to health care, including screening mammography, for healthy women volunteering for placebo-controlled clinical prevention studies such as the WHI clinical trials.

Both SEER data and prior observational studies of associations between breast cancer incidence and ethnicity have been limited by the absence of comprehensive information on breast cancer screening. It is known that both Hispanic (26) and African American women (27,28) are less likely to undergo breast cancer screening than white women, but accurate assessment of this behavior in traditional case–control studies is difficult because retrospectively recalled frequency of mammography over long intervals has proven unreliable (29). In this WHI study, by contrast, information on mammography use was collected prospectively and incorporated in the final model. Even though the frequency of mammography was specified in the WHI protocol for the clinical trial participants (representing 58% of the study population), mammogram frequency still differed by ethnicity, with each racial/ethnic group having a somewhat lower rate of mammograms than white women.

The breast cancer risk model of Gail and colleagues is used widely, especially in the United States, to determine clinical prevention trial eligibility and in clinical practice as well (30,31). However, the Gail model was developed in a largely white population of women receiving regular mammograms (19) and has not been validated in other racial/ethnic groups (32). Indeed, the Gail model was recently adjusted to reflect a lower risk among Hispanic women (33,34). The results in this article suggest that further adjustments of the Gail model incorporating additional risk factors may provide more accurate risk calculation in minority populations.

Few studies have considered ethnicity as an integral component of comprehensive breast cancer risk assessment. In one multiethnic cohort, consideration of seven risk factors (ages at menarche and first birth, parity, age and type of menopause, weight, menopausal hormone therapy, and alcohol use) resulted in similar breast cancer risk in postmenopausal white, Hispanic, and African American women (35). However, that analysis did not incorporate several variables that are strongly related to breast cancer risk and that commonly vary by ethnicity (36), including breast cancer family history, prior benign breast disease, socioeconomic status, physical activity, and mammogram screening frequency. In the WHI population, a model incorporating only the same seven risk factors (data not shown) resulted in estimates of a slightly lower risk of breast cancer for African Americans than for whites (HR = 0.84, 95% CI = 0.73 to 0.98). That HR moved further away from unity in our final model, which included the full range of breast cancer risk factors and covariates (HR = 0.75, 95% CI = 0.61 to 0.92).

Despite the lower incidence of breast cancer among African American women than among white women, we found that, among women who developed breast cancer, African Americans had higher mortality than white women. Several factors have been suggested to contribute to the higher breast cancer mortality in African American women than in white women (7,37), including poorer socioeconomic status with reduced access to health care (38,39), a lower frequency of mammography with delayed diagnosis (27,28), and reduced chemotherapy dosage related to underlying neutropenia (40). However, a disparity in survival between white and African American women with breast cancer treated in the same health care systems (41,42) as well as in the same cancer clinical trial group (43) suggests that factors other than access to health care or mammography or treatment differences play a role in this process.

One such factor could be differences in rates of obesity and high-grade cancer. In the WHI population analyzed for this study, the rate of obesity (defined as BMI ≥ 30 kg/m2) among African American women (51%) was nearly twice that among white women (28%, P<.001), and their rate of high-grade cancers was also much greater (43% vs. 25%, P<.001). A previously identified association between BMI and high-grade cancers (4446) therefore provides a potential explanation for at least some of the poor outcomes of African American women with breast cancer. In addition, the African American women in the WHI cohort were nearly five times likelier than the white women to have breast cancers that were both high grade and ER negative. The higher incidence of poor-prognosis cancers in African American women persisted even after adjustment for BMI and socioeconomic factors. However, obesity was only a modest (P = .10) predictor of unfavorable breast cancer grade and ER status compared with African American ethnicity, which was strongly (P<.001) associated with risk of high-grade, ER-negative cancers. Therefore, obesity does not fully explain the higher rate of poor-prognosis cancers in African American women.

It remains to be determined whether differences in unidentified environmental exposures, genetic makeup, or other factors lead to the higher frequency of high-grade, ER-negative cancers in African Americans. The gradient in frequency of high-grade, ER-negative breast cancers seen comparing native Africans in Nigeria (who have the highest frequency) to African Americans (who have an intermediate frequency) to whites (who have the lowest frequency) (46) is consistent with involvement of either environmental or genetic differences in this process. Gene expression assay studies have identified breast cancer subtypes representing biologically distinct disease entities (47). The high-grade, ER-negative cancers seen in African American women may represent the "basal-like subtype," which has a poor prognosis and is receptor negative and commonly high grade (47,48). Comparative analyses of gene expression in breast cancers by race/ethnicity are needed to evaluate the possibility that basal-like breast tumors are more common in African American than in women of other racial/ethnic groups.

Several genetic factors have the potential to influence the different breast cancer characteristics of African Americans and whites. One is BP1, a homeobox-containing gene that is associated with ER-negative breast cancer (49) and breast cancer aggressiveness (50). BP1 is more frequently expressed in breast tumors from African American women than in white women (P = .04) (51). Further exploration of BP1 and of other genetic factors (5153) that differ by ethnicity could potentially lead to an explanation of the disproportionate development of poor-prognosis breast cancers in African American women.

Our study has several limitations. These include a small number of participants in some of the racial/ethnic subgroups, which limits the ability to make conclusions in these groups. In addition, we had no information on breast cancer therapy. Finally, the findings apply only to postmenopausal women.

The study also had a number of strengths. These include its prospective design; a large, ethnically diverse study population recruited from a relatively homogeneous socioeconomic background; detailed baseline assessment of a large range of breast cancer risk factors; effective follow-up for breast cancer outcome; regular assessment of mammography use; and central blinded adjudication of breast cancers via pathology report review and description of breast cancer histologic characteristics.

The results of this study indicate that differences in breast cancer incidence rates between most racial/ethnic groups can be largely explained by difference in risk factors except in African American women. The results also provide a unifying concept for the unfavorable breast cancer outcome seen in African American women despite a lower incidence. That is, breast cancers diagnosed in African American women are more commonly high-grade with negative ER status than breast cancers diagnosed in women of other racial/ethnic groups. The more common development of such poor-prognosis cancers in African American women contributes to their increased breast cancer mortality, independent of differential access to health care or mammography.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. Back

Funding/support: This study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, and received support from National Institutes of Health and GCRC Grant M01-RR00425 National Centers for Research Resources.

Acknowledgment: The dedicated efforts of the WHI participants and of the WHI investigators and staff at the Clinical Centers and Clinical Coordinating Center (CCC) are acknowledged. A full listing of the WHI investigators can be found at http://www.whi.org.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

(1) Jemal A, Murray Y, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics 2003. CA Cancer J Clin 2003;53:5–26.[Abstract/Free Full Text]

(2) Ghafoor A, Jemal A, Ward E, Cokkinides V, Smith P, Thun M. Trends in breast cancer by race and ethnicity. CA Cancer J Clin 2003;53:342–55.[Abstract/Free Full Text]

(3) Li CI, Malone KE, Daling JR. Differences in breast cancer hormone receptor status and histology by race and ethnicity among women 50 years of age and older. Cancer Epidemiol Biomarkers Prev 2002;11:301–7.

(4) Joslyn SA. Hormone receptors in breast cancer: racial differences in distribution and survival. Breast Cancer Res Treat 2002;73:45–59.[CrossRef][ISI][Medline]

(5) Elledge RM, Clark GM, Chamness GC, Osborne CK. Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States. J Natl Cancer Inst 1994;86:1352–3.[Medline]

(6) Middleton LP, Chen V, Perkins GH, Pinn V, Page D. Histopathology of breast cancer among African-American women. Cancer 2003;97 (1 Suppl):253–7.[CrossRef][Medline]

(7) Newman LA, Mason J, Cote D, Vin Y, Carolin K, Bouwman D, et al. African-American ethnicity, socioeconomic status, and breast cancer survival: a meta-analysis of 14 studies involving over 10 000 African-American and 40 000 White American patients with carcinoma of the breast. Cancer 2002;94:2844–54.[CrossRef][ISI][Medline]

(8) Weir HK, Thun MJ, Hankey BF, Ries LA, Howe HL, Wingo, et al. Annual report to the nation on the status of cancer, 1975–2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 2003;95:1276–99.[Abstract/Free Full Text]

(9) Vastag B. Breast cancer racial gap examined: no easy answers to explain disparities in survival. JAMA 2003;290:1838–42.[Free Full Text]

(10) The Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61–109.[CrossRef][ISI][Medline]

(11) Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative. JAMA 2002;288:321–33.[Abstract/Free Full Text]

(12) Hays J, Hunt JR, Hubbell FA, Anderson GL, Limacher M, Allen C, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol 2003;13:18–77.[CrossRef]

(13) Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M. The Women's Health Initiative observational study: baseline characteristics of participants and reliability on baseline measures. Ann Epidemiol 2003;13:S107–21.[CrossRef][ISI][Medline]

(14) Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women's Health Initiative food frequency questionnaire. Ann Epidemiol 1999;9:178–87.[CrossRef][ISI][Medline]

(15) Anderson GL, Manson J, Wallace R, Lund B, Hall D, Davis S, et al. Implementation of the Women's Health Initiative study design. Ann Epidemiol 2003;13 (9 Suppl):S5–17.[CrossRef][ISI][Medline]

(16) Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence of estrogen plus progestin on breast cancer mammography in healthy postmenopausal women. The Women's Health Initiative randomized trial. JAMA 2003;289:3243–53.[Abstract/Free Full Text]

(17) Curb JD, McTiernan A, Heckbert SR, Kooperberg C, Stanford J, Nevitt M, et al. Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol 2003;13:233–8.

(18) Ries LAG, Eisner MP, Kosary CL. SEER Cancer Statistics Review, 1975–2001, National Cancer Institute. Bethesda, MD. Available at http://seer.cancer.gov/csr/1975_2001. [Last accessed: February 13, 2005.]

(19) Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for White females who are being examined annually. J Natl Cancer Inst 1989;81:1879–86.[Abstract]

(20) Rubin DB. Multiple imputation for nonresponse in surveys. New York (NY):Wiley;1987. p. 75–153.

(21) Fisher B, Fisher ER, Redmond C, Brown A. Tumor nuclear grade and estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer. Breast Cancer Res Treat 1986;7:147–60.[ISI][Medline]

(22) Prentice RL. Methodologic challenges in chronic disease population research. Biostatistics 2001;2:365–81.[Abstract/Free Full Text]

(23) Bingham SA, Luben R, Welch A, Wareham N, Khaw KT, Day N. Are imprecise methods obscuring a relation between fat and breast cancer? Lancet 2003;362:212–214.[CrossRef][ISI][Medline]

(24) Forshee RA, Storey ML, Ritenbaugh C. Breast cancer risk and lifestyle differences among premenopausal and postmenopausal African-American women and white women. Cancer 2003;97:280–8.[CrossRef][Medline]

(25) del Carmen MG, Hughes KS, Halpern E, Rafferty E, Kopans D, Parisky YR, et al. Racial differences in mammographic breast density. Cancer 2003;98:590–6.[CrossRef][ISI][Medline]

(26) Thompson B, Coronado GD, Solomon CC, McClerran DF, Neuhouser ML, Feng Z. Cancer prevention behaviors and socioeconomic status among Hispanics and non-Hispanic whites in a rural population in the United States. Cancer Causes Control 2002;13:719–28.[CrossRef][ISI][Medline]

(27) McCarthy EP, Burns RB, Coughlin SS, Freund KM, Rice J, Marwill SL, et al. Mammography use helps to explain differences in breast cancer stage at diagnosis between older black women and white women. Ann Intern Med 1998;128:729–36.[Abstract/Free Full Text]

(28) Schneider EC, Zaslavsky AM, Epstein AM. Racial disparities in quality of care for enrollees in medicare managed care. JAMA 2002;287:1288–94.[Abstract/Free Full Text]

(29) Gordon NP, Hiatt RA, Lampert DI. Correspondence of self-reported data and medical record audit for six cancer screening procedures. J Natl Cancer Inst 1993;85:566–70.[Abstract]

(30) Chlebowski RT. Reducing the risk of breast cancer. N Engl J Med 2000;343:191–8.[Free Full Text]

(31) Armstrong K, Eisen A, Weber T. Assessing the risk of breast cancer. N Engl J Med 2000;342:564–71.[Free Full Text]

(32) Adams-Campbell L, Makambi K, Palmer J, Rosenberg L. The Gail Model as a diagnostic indicator in African-American women: truth or consequence. Proc Am Soc Clin Oncol 2004;23:1017 (abstract).

(33) Gail MH, Costantino JP. Validating and improving models for projecting the absolute risk of breast cancer. J Natl Cancer Inst 2001;93:334–5.[Free Full Text]

(34) National Cancer Institute. 2001. Breast Cancer Risk Assessment Tool v.2 for Health Care Providers. Available at http://bcra.nci.nih.gov/brc/questions.htm. [Last accessed: February 13, 2005.]

(35) Pike MC, Kolonel LN, Henderson BE, Wilkens LR, Hankin JH, Feigelson HS, et al. Breast cancer in a multiethnic cohort in Hawaii and Los Angeles: risk factor-adjusted incidence in Japanese equals and in Hawaiians exceeds that in Whites. Cancer Epidemiol Biomarkers Prev 2002;11:795–800.[Abstract/Free Full Text]

(36) Bernstein L, Teal CR, Joslyn S, Wilson J. Ethnicity-related variation in breast cancer risk factors. Cancer 2003;97:222–9.[CrossRef][Medline]

(37) Henson DE, Chu KC, Levine PH. Histologic grade, stage, and survival in breast carcinoma: comparison of African American and Caucasian women. Cancer 2003;98:908–17.[CrossRef][ISI][Medline]

(38) Li CI, Malone KE, Daling JR. Differences in breast cancer stage, treatment, and survival by race and ethnicity. Arch Intern Med 2003;163:49–56.[Abstract/Free Full Text]

(39) O'Malley CD, Le GM, Glaser SL, Shema SJ, West DW. Socioeconomic status and breast carcinoma survival in four racial/ethnic groups: a population-based study. Cancer 2003;97:1303–11.[CrossRef][ISI][Medline]

(40) Hershman D, Weinberg M, Rosner Z, Alexis K, Tiersten A, Grann VR, et al. Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer. J Natl Cancer Inst 2003;95:1545–8.[Abstract/Free Full Text]

(41) Jatoi I, Becher H, Leake CR. Widening disparity in survival between white and African-American patients with breast carcinoma treated in the U.S. Department of Defense Healthcare system. Cancer 2003;98:894–9.[CrossRef][ISI][Medline]

(42) Yood MU, Johnson CC, Blount A, Abrams J, Wolman E, McCarthy BD, et al. Race and differences in breast cancer survival in managed care population. J Natl Cancer Inst 1999;91:1487–91.[Abstract/Free Full Text]

(43) Albain KS, Unger JM, Hutchins LF, et al. Outcome of African Americans on Southwest Oncology Group (SWOG) breast cancer adjuvant therapy trials. Breast Cancer Res Treat 2003;77:21 (abstract).[CrossRef]

(44) Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403–10.[ISI][Medline]

(45) Cui Y, Whiteman MK, Langenberg P, Sexton M, Tkaczuk KH, Flaws JA, et al. Can obesity explain the racial difference in stage of breast cancer at diagnosis between black and white women? J Womens Health Gend Based Med 2002;11:527–36.[CrossRef][ISI][Medline]

(46) Ikpatt OF, Dignan JJ, Khramtsov A, Grushko T, Fackenthal J, Sveen L, et al. Breast tumor morphometry in relation to race reveals significant differences among Nigerians, African-American and Caucasian Americans. Proc Am Soc Clin Oncol 2004;23:9567 (abstract).

(47) Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418–23.[Abstract/Free Full Text]

(48) Carey LA, Perou CM, Dressler LG, Livasy CA, Geradts J, Cowan D, et al. Race and the poor prognosis basal breast tumor (BBT) phenotype in the population-based Carolina Breast Cancer Study (CBCS). Proc Am Soc Clin Oncol 2004;22(14 Suppl):9510 (abstract).

(49) Fu SW, Schwartz A, Stevenson H, Pinzone JJ, Davenport GJ, Orenstein JM, et al. Correlation of expression of BP1, a homeobox gene, with estrogen receptor status in breast cancer. Breast Cancer Res Treat 2003;5:R82–7.

(50) Berg PE, Fu SW, Pinzone JJ, Man Y-G. Expression of BP1, a homeobox gene, correlates with breast cancer aggressiveness. Breast Can Res Treat 2003;21:41 (abstract).

(51) Olopade OI, Ikpatt OF, Dignam JJ, Khramtsov Z, Tetriakova M, Grushko T, et al. "Intrinsic Gene Expression" subtypes correlated with grade and morphimetrics parameters reveal a high proportion of aggressive basal-like tumors among black women of African ancestry. Proc Am Soc Clin Oncol 2004;23:9509 (abstract).

(52) Ademuyiwa FO, Olopade OI. Racial differences in genetic factors associated with breast cancer. Cancer Metastasis Rev 2003;22:47–53.[CrossRef][ISI][Medline]

(53) Porter PL, Lund MJ, Lin MG, Yuan X, Liff JM, Flagg EW, et al. Racial differences in the expression of cell cycle–regulatory proteins in breast carcinoma. Cancer 2004;100:2533–42.[CrossRef][Medline]

Manuscript received August 20, 2004; revised January 4, 2005; accepted January 12, 2005.


This article has been cited by other articles in HighWire Press-hosted journals:


Correspondence about this Article

             
Copyright © 2005 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement