The Influence of Socioeconomic Status on Racial/Ethnic Disparities among the ER/PR/HER2 Breast Cancer Subtypes

Background. The eight ER/PR/HER2 breast cancer subtypes vary widely in demographic and clinicopathologic characteristics and survival. This study assesses the contribution of SES to the risk of mortality for blacks, Hispanics, Asian/Pacific Islanders, and American Indians when compared with white women for each ER/PR/HER2 subtype. Methods. We identified 143,184 cases of first primary female invasive breast cancer from the California Cancer Registry between 2000 and 2012. The risk of mortality was computed for each race/ethnicity within each ER/PR/HER2 subtype. Models were adjusted for tumor grade, year of diagnosis, and age. SES was added to a second set of models. Analyses were conducted separately for each stage. Results. Race/ethnicity did not contribute to the risk of mortality for any subtype in stage 1 when adjusted for SES. In stages 2, 3, and 4, race/ethnicity was associated with risk of mortality and adjustment for SES changed the risk only in some subtypes. SES reduced the risk of mortality by over 45% for American Indians with stage 2 ER+/PR+/HER2− cancer, but it decreased the risk of mortality for blacks with stage 2 triple negative cancer by less than 4%. Conclusions. Racial/ethnic disparities do not exist in all ER/PR/HER2 subtypes and, in general, SES modestly alters these disparities.

The relationship between race/ethnicity and SES is complicated and it remains difficult to completely unravel their respective roles in breast cancer outcomes. This conundrum is evident from the conflicting results of studies investigating racial/ethnic disparities in cancer. Some have shown comparable outcomes after adjustment for sociodemographic factors if patients have equal access to healthcare [10,[15][16][17][18][19]. Others have shown that racial disparities persist even after adjusting for SES and despite equal access to healthcare [20][21][22]. Further, some studies have found that low SES, not race/ethnicity, was associated with poorer outcomes [23][24][25].
A factor that is seldom addressed in the research of race/ ethnicity and SES in breast cancer disparities are the breast cancer tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). These tumor markers are well known to clinicians, readily available, inexpensive, reproducible, reliable, and recorded in most tumor registries. Although these tumor markers have demonstrated wide variability in incidence and survival, most disparities research considers breast cancer as a single disease [4,26].
O'Malley and colleagues explored the role of SES on racial/ethnic differences in breast cancer survival when adjusted for clinical variables including ER and PR status but not HER2 status and found that black women continued to have slight but significantly poorer survival when compared with white women [27]. This study prompts the question of whether racial disparities in breast cancer vary by ER/PR/HER2.
The objective of this study is to examine the contribution of SES to racial disparities in breast cancer mortality by assessing the risk of mortality for African American, Hispanic, Asian/Pacific Islanders, and American Indians within each of the ER/PR/HER2 subtypes.  [30]. This SES variable is an index that uses education, employment characteristics, median household income, proportion of the population living 200% below the Federal Poverty Level, median rent, and median housing value of census tract of residence for case and denominator population. A principal component analysis was used to identify quintiles of SES ranging from 1 (the lowest) to 5 (the highest) [31]. This area based SES measure has been used in many studies utilizing cancer registry data [32][33][34][35][36].
2.3. Race/Ethnicity. Race/ethnicity was classified into 5 mutually exclusive categories: non-Hispanic white, African American/black, Hispanic, American Indian or Alaskan native, and Asian/Pacific Islander. Race/ethnicity was based on the information obtained from the medical record, which was derived from patient self-identification, assumptions based on personal appearance, or inferences based on the race/ethnicity of the parents, birthplace, surname, or maiden name. Hispanic ethnicity was based on the information from the medical record and computerized comparisons to the 1980 US census list of Hispanic surnames. Patients identified as Hispanic on the medical record or patients identified as white, black, or of unknown race with a Hispanic surname were classified as Hispanic.

Statistical Analysis.
Kaplan-Meier survival analysis and the Log-Rank test were used to assess differences in survival among the ER/PR/HER2 subtypes. Cox Proportional Hazards modeling was used to compute the risk of mortality for each race/ethnicity when compared with white women for each ER/PR/HER2 subtype except the ER−/PR+/HER2− and ER−/PR+/HER2+ subtypes. These subtypes lacked sufficient cases.
The first models adjusted race/ethnicity for tumor grade, year of diagnosis, and age. Tumor size was not included because of its high correlation with AJCC stage. SES was added to the second set of models. Analyses were conducted separately for each AJCC stage because of the differences in prognosis of patients diagnosed in different stages.
Hazard ratios (HRs) and 95% confidence intervals (CI) were computed for all models and represented the risk of mortality for each race/ethnicity relative to white women with the same stage and ER/PR/HER2 subtype. The HRs were only interpreted when the Wald 2 for race/ethnicity was statistically significant ( < 0.05). All analyses were conducted using SPSS 21.0 [39].
This research study involved analysis of existing data from the CCR without subject identifiers or intervention. Therefore, the study was categorized as exempt from institutional review board oversight. Table 1 displays the demographic and tumor characteristics of each of the race/ethnicities included in the study. Median follow-up time was 54 months with a maximum of 155 months. The ER+/PR+/HER2− subtype was the predominant subtype and represented 58.1% of all cases followed by the triple negative subtype at 12.8%. The ER-positive subtypes represented almost 80% of all cases, but there was wide variation by race/ethnicity.

Results
Blacks were the only race/ethnicity where fewer than 50% of cases were the ER+/PR+/HER2− subtype, but they had the highest percent of triple negative cases. Asian/Pacific Islanders were least likely to have the triple negative subtype but made up a higher proportion of the ER−/PR−/HER2+ subtype than any other race/ethnicity.
Whites and Asian/Pacific Islanders were more likely to be in the highest SES and diagnosed in stage 1 and blacks and Hispanics in the lowest SES. American Indians and blacks were more likely to be diagnosed in stage 4. Table 2 and Figure 1 demonstrate that all of the ERpositive subtypes had better 5-year survival than the ERnegative subtypes, and the ER+/PR+/HER2− subtype had the best overall survival, statistically significantly better than all other subtypes ( < 0.001). The triple negative subtype had the worst overall survival followed by the ER−/PR−/HER2+ subtype.
The heterogeneity of the HER2-positive subtypes and the influence of ER-positivity were evident with the ER+/ PR+/HER2+ subtype having 92.0% survival contrasting with the ER−/PR−/HER2+ subtype having an 81.1% survival. The importance of PR status was noted when comparing the subtypes that differ only by its presence or absence.
Cox Proportional Hazards models revealed that the contribution of SES to the survival disparities in race/ethnicity

Discussion
This study has shown that the contribution of SES to racial/ ethnic disparities varies considerably for each of the ER/ PR/HER2 subtypes.
To our knowledge, this is the first study to address the contribution of SES to racial disparities in breast cancer within stage of disease and the individual ER/PR/HER2 subtypes.
In stage 1, there are no racial/ethnic disparities for any subtype when controlling for SES which suggests that innate biological differences among the ethnicities, at least for this stage, appear unlikely consistent with previous research [17,18,23,57]. In contrast, others found a black/white disparity even after adjusting for SES and other variables [22,27].
In stages 2, 3, and 4, race/ethnicity is associated with risk of mortality, and adjustment with SES changed this risk only in some subtypes. The most extreme case is where SES reduced the risk of mortality by over 45% for American Indians with the ER+/PR+/HER2− subtype in stage 2. However, for stage 2 triple negative cases, SES decreased the risk of mortality for blacks by less than 4%. Asian/Pacific Islanders have traditionally been found to have equal or better survival than whites [5,58,59]. This advantage is not as apparent when stratified by stage and subtype.
These results provide further evidence for the heterogeneity of breast cancer and emphasize the use of the eight ER/PR/HER2 subtypes. The variation in racial disparities is particularly evident in the higher stages of disease, and, as stated in our prior research, it is unknown if tumor or host factors play a role in advanced stages of disease or if there is an element of racial/ethnic discrimination in receipt of more aggressive cancer treatments [57].
Our findings might suggest that there is progress in the elimination of disparities in breast cancer survival. However, our descriptive data and previous research project a completely different picture [26]. In most instances, white women present with favorable tumor and demographic conditions and black women with unfavorable conditions. White women are more likely to present in stage 1 with small, grade 1 ER+/PR+/HER2− subtype tumors and reside in the highest SES strata. Conversely, black women have the lowest proportion of ER+/PR+/HER2− cases and present at later stages with higher grade tumors and are in the lowest SES strata. Black women are also more likely to present with ER-negative breast cancer, especially the triple negative subtype. Although younger age or premenopausal status is an important risk factor for the triple negative subtype in white women, African ancestry may be more important in black women [45,[60][61][62]. These differences continue to impact racial/ethnic disparities, especially the black/white disparity, and it appears that little has changed over time [63,64].
The limitations of population-based cancer registry investigations, including missing data, especially ER, PR, and HER2, lack of central pathology review, and comorbid conditions have been described in our prior publications [32,33,38,57]. The determination of race/ethnicity can be problematic, arbitrary, and subject to error [57,65]. Accurate and precise treatment information was not available from the registry. Although it has been suggested that suboptimal use of adjuvant treatments may explain differences in outcomes [6,[66][67][68][69][70], others have reported little or no racial/ethnic differences with regard to chemotherapy administration [71][72][73]. The CCR does not have the ability to obtain individual level SES so our measure of SES was at the neighborhood level rather than the individual level. However, this measure of SES has been used in many studies that utilize cancer registry data [33,34,38,74,75] and many have commented on the usefulness of composite SES measures [24,[76][77][78][79][80]. Nevertheless, nondifferential misclassification of cases by SES was possible, which would bias the results toward the null.
The strengths of this study include the large number of cases reported to the statewide cancer registry from an ethnically diverse population, maximum follow-up of almost 13 years, and use of the individual ER/PR/HER2 subtypes.
In conclusion, we have shown that, in the state of California, racial/ethnic disparities in breast cancer survival do not exist for all eight ER/PR/HER2 subtypes. Further, the contribution of SES to racial/ethnic disparities varies by ER/ PR/HER2 subtype and stage at diagnosis, and, in most instances, it is quite modest. Continued research is warranted in genetic, societal, and lifestyle factors which are associated with poor breast cancer survival.

Disclaimer
The collection of cancer incidence data used in this study was supported by the