Breast Cancer Mortality among Asian-American Women in California: Variation according to Ethnicity and Tumor Subtype

Breast cancer is a heterogeneous disease characterized by gene expression patterns or differential expression of the tumor markers, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [1, 2, 3]. Breast cancer subtypes, either defined molecularly or exclusively by ER, PR, and HER2, have different outcomes, responses to treatment, and racial/ethnic distribution [1, 2, 3, 4]; therefore, it appears logical to incorporate these subtypes into survival studies.

Asian-American women have generally been noted to have equal or better breast cancer survival rates than non-Hispanic white women [5] but many studies use the generic term "Asian" or combine all Asians into the aggregate "Asian/Pacific Islander" (API) category, a term commonly used in epidemiologic research [6, 7, 8, 9]. Trinh et al. [10] demonstrated the distinction of Asian subgroups in a study examining cancer-specific mortality between whites and Asian-Americans in the United States. While Japanese women and those classified as "other Asians" had a lower risk of breast cancer mortality, all of the other surveyed Asian ethnicities had a survival rate comparable to that of white women.

Among the Asian ethnicities, there is marked variability in the demographics and clinicopathological features of breast cancer. Prior research in California has shown that Southeast Asians, Filipino, and Korean women were more likely than white women to have the ER+/PR+/HER2+ subtype, while Chinese, Pacific Islander, and Filipino women were less likely to have the triple-negative subtype [11].

It is unknown whether there is similar variability in mortality among the Asian ethnicities within the ER/PR/HER2 subtypes. The objectives of this study were to assess the risk of mortality of seven subgroups of Asian-Americans within the ER/PR/HER2 subtypes and determine whether the risk of mortality for the aggregate API category is reflective of the risk of all Asian ethnicities.

There were 90,930 cases with incomplete data for race/ethnicity, cause of death, AJCC stage, ER, PR, HER2, tumor grade, treatment, or SES (Table 1). All cases had information on age and year of diagnosis. The cases with incomplete data were evenly distributed among all ethnicities. HER2 was the variable missing from the largest percentage of cases. Prior to 2007, HER2 was not a mandatory variable, and in many instances, it was entered into the CCR in a text field so it was not always retrievable [24]. The final database for analysis contained 110,120 cases of Asian and white women with complete data.

Table 1
Number of cases with missing data for white and Asian Ethnicities in the California Cancer Registry 2000–2013

• Click for larger image
• Click for full table
• Download as Excel file

Table 2 displays the demographic and tumor characteristics of the cases with complete data that were included in the study. The median follow-up time was 60 months, with a maximum of 167 months. The most common Asian ethnicities were Filipino (29.0%), Chinese (22.3%), and SEA (22.8%). The Japanese and white women were very similar in age (p=0.887). White and Japanese women had clinicopathologic characteristics associated with better survival rates, including early diagnosis in stage 1, over 70 years of age, small grade 1 tumors, and ER+/PR+/HER2- subtype. White and Japanese women were also similarly distributed among the SES categories.

Table 2
Demographic and clinicopathologic characteristics of 110,120 non-Hispanic white and Asian cases with first primary female invasive breast cancer with complete data from the California Cancer Registry 2000–2013^*

• Click for larger image
• Click for full table
• Download as Excel file

Sixty-one percent of all cases were ER+/PR+/HER2- [3]. Only Koreans were found to have fewer than 50% of this tumor subtype. Women from the Indian Subcontinent and Korea were found to have a higher proportion of the triple negative subtype. Korean and Filipino women had the highest percentage of cases with the HER2 overexpressing subtypes [3, 25]. Filipino and Japanese women had the lowest percentage of the triple negative subtype while Japanese and white women had the lowest percentage of the HER2 overexpressing subtype.

The percentage of ER-positive cancers was 82.3% for whites and 78.8% for the API category. However, among the Asian ethnicities, this percentage varied from 72.3% (Koreans) to 84.0% (Japanese). The percentage of HER2-positive cancers was 16.9% for whites and 24.0% for the aggregate API category with a range of 18.1% for Japanese to 28.5% for Korean women. For white women, the ER-/PR-/HER2+ subtype represented 30.9% of all HER2-positive cancers, whereas for the API category, this subtype represented 36.9% of all HER2-positive cancers, ranging from a low of 27.8% (Japanese) to a high of 37.5% (Pacific Islanders). Chinese, Korean, and Filipino women had a similarly high percentage of the ER-/PR-/HER2+ subtype.

Figure 1 shows that differences in unadjusted breast cancer-specific survival rates between Asian and white women are related to both the ER/PR/HER2 tumor subtype and whether Asians were combined into one category or considered as ethnic subgroups. Filipino women (χ²=6.05; p=0.014) had significantly poorer survival rates and Southeast Asian (p=0.045) and Japanese (p=0.002) women had better survival rates than white women for the ER+/PR+/HER2- subtype (Figure 1A). Filipino (p=0.046), Japanese (p=0.006), and Chinese (p=0.045) women with the ER-/PR-/HER2+ subtype (Figure 1B) had better survival rates than whites. There were no differences in survival rates among the subgroups of Asians with the ER-/PR-/HER2- subtype (Figure 1C), but Asians had significantly better survival rates than whites (p=0.025) when the ethnic subgroups were combined into the aggregate API category (Figure 1D).

Figure 1
Unadjusted Kaplan-Meier breast cancer-specific survival analysis of the individual Asian ethnicities for the ER+/PR+/HER2– subtype (A), ER–/PR–/HER2+ subtype (B), and ER–/PR–/HER2– subtype (C). (D) This compares non-Hispanic white women with the aggregate Asian/Pacific Islander category for the ER–/PR–/HER2– subtype.
ER=estrogen receptor; PR=progesterone receptor; HER2=human epidermal growth factor receptor 2.

• Click for larger image
• Download as PowerPoint slide

Table 3 presents the HRs that compare the risk of mortality for the individual Asian ethnicities and the aggregate Asian/Pacific Islander category with non-Hispanic white women for each of the ER/PR/HER2 subtypes. The stage×race/ethnicity interaction was not statistically significant. Blank spaces in the table indicate that ethnicity was not a statistically significant risk factor for mortality within a subtype.

Table 3
Breast cancer specific mortality (HR) for seven Asian subgroups and the aggregate Asian/Pacific Islander category^*

• Click for larger image
• Click for full table
• Download as Excel file

When all Asian subtypes were combined, Southeast Asian, Japanese, and Filipino women, as well as the aggregate API category, had a lower risk of mortality when compared with whites (Table 3). The individual subtypes, ER-/PR+/HER2- and ER-/PR+/HER+ were excluded from multivariable analysis due to an insufficient number of cases. For the ER+/PR+/HER2- subtype, only Southeast Asian and Japanese women had a lower risk of mortality, when compared with whites, and the aggregate API category showed a 17% lower risk of mortality. For the ER+/PR-/HER2- subtype, Southeast Asian, Filipino women and the aggregate API category had a lower risk of mortality than whites. For the ER-/PR-/HER2- and ER+/PR+/HER2+ subtypes, Asian ethnicity was associated with a risk of mortality only when using the aggregate API category. For ER-/PR-/HER2+ subtype, Japanese, Filipino, as well as the API category, had a lower risk of mortality. Ethnicity was not a significant factor for risk of mortality for women with the ER+/PR-/HER2+ subtype.

The rapid recent growth in the Asian-American population in the United States has sparked considerable interest in breast cancer incidence and mortality [26]. In the present investigation, a population-based study of 110,120 women illustrates the demographic and tumor characteristic variation among the Asian ethnicities. Additionally, this study also demonstrates the wide variation in breast cancer mortality among women of Asian ethnicity. Japanese women, more than any other Asian ethnicity, are strikingly similar to white women with regard to clinicopathologic features.

Our findings show that variation in breast cancer survival rates among Asians depends on how both breast cancer and the Asian ethnicities are defined, similar to previous research showing that these two factors are also important in determining the risk of having a specific ER/PR/HER2 breast cancer subtype. For example, women from the Indian Subcontinent have been shown to have an increased probability of the triple negative subtype [11]. However, the current findings suggest that their risk of breast cancer-specific mortality is no worse than that of white women.

We showed that when all tumor subtypes are combined, the HRs of breast cancer-specific mortality for the aggregate API category would indicate a 17% lower risk of mortality. However, analysis of the regional Asian ethnicities showed that this is true only for Southeast Asian, Japanese, and Filipino women. Similarly, although the HRs for the triple negative and HER2-overexpressing subtypes would indicate a 16% and 21% lower risk of mortality, respectively, for the aggregate API category, the impact of breast cancer heterogeneity becomes evident when the individual Asian ethnicities are examined. For the triple negative subtype, no individual Asian ethnicity was found to have a lower risk of mortality and only Japanese and Filipino women had a lower risk of mortality for the HER2-overexpressing subtype.

Our results are similar to those of Trinh et al. [10] who found a 29% lower breast cancer mortality rate for the Japanese and a 39% lower mortality rate for "other Asians," compared to white women when breast cancer was considered as a single disease. However, our results suggest that Japanese women have no survival advantage over whites for the triple negative subtype. Warner et al. [16] assessed the racial disparities of breast cancer in 17,268 women, including 533 Asians, using a surrogate for the molecular classification. Although not a population-based investigation, they also reported that racial disparities vary by tumor subtype. These studies illustrate that the definitions of both race/ethnicity and breast cancer type are important. To our knowledge, this is the first study to consider how breast cancer mortality varies between individual Asian ethnicities and the ER/PR/HER2 subtypes.

We acknowledge the limitations of this retrospective, population-based cancer registry investigation. Histologic grading of cancers as well as tests for ER, PR, and HER2 were performed by a wide variety of laboratories without central review. Incomplete data, especially a lack of classification by ER, PR, and HER2 markers, is common and was described in our previous publications [3, 4, 27].

Some may question our exclusive use of ER/PR/HER2 tumor markers for characterization. However, in the absence of gene expression profiling, breast cancer subtypes, as expressed by ER, PR, and HER2, are a reasonable substitute for a molecular classification. These tumor markers are well known to clinicians, reliable, inexpensive, easy to interpret, and recorded in cancer registries.

The determination of race/ethnicity can be problematic, arbitrary, and subject to error. The birthplace of women was not always available, so this information was not included. There may be differences in the survival rates of United State versus foreign-born Asian women [9]. Our measure of SES was at the neighborhood level rather than the individual level, but similar composite measures have been shown to be quite useful for epidemiologic research and the impact of neighborhood demographics should not be ignored [4, 28].

We recognize that our treatment information is quite generic and lacking in chemotherapy specifics. Lastly, we have no information about any individual's reproductive history, diet, or lifestyle factors that may influence the breast cancer subtype and ultimately affect survival [29, 30].

Despite these shortcomings, this study is valuable because of the large number of cases of Asian-Americans with breast cancer, which allowed the use of the ER/PR/HER2 tumor marker subtypes and individual Asian subgroups for multivariable analysis. Separate analysis of these Asian ethnic subgroups rather than using an aggregate category of Asian/Pacific Islander, as required in smaller studies, revealed important ethnic differences.

In summary, breast cancer-specific mortality among Asian-American women varies according to their Asian ethnicity and breast cancer subtype. The all-inclusive Asian/Pacific Islander category is inconsistently reflective of breast cancer-specific mortality.