Using recent data about HER2-defined breast cancer occurrence in the large, diverse population of California, we found no evidence for a black–white crossover in breast cancer incidence for any of the four major molecular subtypes of breast cancer. Compared with white women, black women had higher rates of triple-negative breast cancer at all ages and lower rates of HR+/HER2− breast cancer after age 35 years. The black–white crossover in breast cancer incidence occurred only when all breast cancer subtypes are combined. Our data also demonstrate substantial racial and ethnic variation in the age-specific occurrence of breast cancer subtypes, especially the triple-negative form.
The HER2 status of tumors has only recently become information that is routinely collected as part of breast cancer registration and surveillance because HER2 expression has only recently become a standard part of breast cancer pathological assessment (16
) . Previous studies of breast cancer occurrence that differentiated tumors according to ER status revealed important clues about the contribution of tumor estrogen sensitivity to the observed deceleration of increasing age-specific incidence around the age of menopause (30
). Now, with population-based data regarding HER2-defined breast cancer subtypes, we are able to expand our understanding of the divergent occurrence of breast cancer subtypes by age and by race and ethnicity.
Our findings are consistent with those of Carey et al. (14
), who described higher occurrence of triple-negative breast cancer in black vs white premenopausal women, and of Chlebowski et al. (18
), who reported that black women were five times more likely than white women to have high-grade, ER-negative cancers; both groups invoked possible genetic causes for these differences based on studies of black breast cancer patients in Africa (31
). Our findings are also consistent with previous cancer registry–based studies of women that found higher overall incidences of triple-negative breast cancer among black women and of HR+
breast cancers among white women compared with women of other racial and ethnic groups (5
) as well as other epidemiological and clinical suggestions that these two subtypes are etiologically and biologically distinct (34–36
In 2008, Anderson et al. (1
) used a structured quantitative approach to show in SEER data that the black–white crossover in overall breast cancer incidence persisted across time and birth cohort; they concluded that the most likely explanation for the crossover involved biological heterogeneity of subtypes between black and white women. Other authors have pointed to the role of different racial and ethnic prevalence of risk factors, including reproductive history and other factors associated with socioeconomic status (4
), or ethnic variations in the magnitude of risk associated with particular exposures (eg, use of postmenopausal hormone therapy, parity, and body mass index [BMI]) (1
). Still other interpretations hypothesize novel, ethnically disparate causes, such as environmental exposures or susceptibility genes (18
). Although some ethnic disparities in both mammographic screening and BRCA1
gene mutation testing have been reported (41
), it is unlikely that these occur at levels sufficient to explain the black–white crossover in breast cancer incidence as reported in previous studies. After synthesizing the previous literature with our new observations, we suggest that the observed crossover mainly reflects racial and ethnic differences in the age-specific incidences of triple-negative breast cancer (higher in black women) and HR+
breast cancer (higher in white women, particularly those older than 35 years).
Several epidemiological studies have examined risk factors for specific breast cancer subtypes using datasets large enough to provide adequate statistical power for detecting differences among breast cancer subtypes. In a recent pooled analysis of 34 observational studies from the Breast Cancer Association Consortium (BCAC) (17
), reproductive risk factors (age at menarche, parity, and age at birth of first child) and BMI were associated with the risk of ER+
breast tumors but not with the risk of triple-negative breast cancer. In fact, a pooled analysis of the 12 eligible BCAC studies that had data on tumor HER2 status did not find an association between the risk of triple-negative breast cancer and any of the other risk factors that are typically considered when studying breast cancer as a single entity, with the exception of family history, which was positively associated with triple-negative and other breast cancer subtypes (17
). However, even that large pooled analysis did not have sufficient statistical power to examine associations between BMI or parity and the risk of triple-negative breast cancer specifically in black women. In a smaller study (36
), adjustment for BMI and age did not fully explain the elevated risk of triple-negative breast cancer among black women compared with white women. The consistently higher incidence of triple-negative breast cancer among black women compared with white women at all ages suggests that black women are more susceptible to triple-negative breast cancer (43
) than white, Hispanic, or Asian women. Indeed, our data show that the most marked racial and ethnic differences in incidence occur for triple-negative breast cancer, making this subtype worthy of particular scrutiny in genomic or other studies. Certainly, genetic or other nonenvironmental factors remain important candidates for explaining racial and ethnic differences in the incidence of specific molecular subtypes of breast cancer. Recent studies of the BRCA1
breast cancer susceptibility genes suggest that although mutation carrier prevalence is comparable among ethnic groups, there is substantial ethnic variation in the spectrum of mutations (44
Our analysis adds to the evidence suggesting that middle-aged Asian women have higher risks of HER2-overexpressing tumors compared with white women (33
). A previous analysis of California data showed that incidence of HER2-overexpressing tumors was higher among Korean, Filipina, Vietnamese, and Chinese women than among white women (45
). A pooled analysis of 13 BCAC studies found that BMI, parity, and age at birth of first child were associated with the risk of HER2-overexpressing tumors (17
), but it is uncertain whether these associations could explain higher incidence of HER2-overexpressing tumors among Asian populations. Although in this analysis we were not able to further stratify rates for Asian women by nativity or acculturation, previous analyses have shown that both factors affect overall incidence rates of breast cancer among Asian women (46
). Future epidemiological studies of molecular subtypes of breast cancer among Asian or Hispanic women should examine occurrence separately by ethnic subgroup and nativity.
This study has several strengths. We took advantage of some of the first population-based data for which ER, PR, and HER2 status are sufficiently complete to classify the four major current molecular subtypes of breast cancer. Moreover, the California data offer a large sample size and diversity for examining age-specific patterns in racial and ethnic groups and are generally representative of data in the larger SEER program.
However, this study, like all cancer registry–based analyses, was limited by some degree of missing data on these biomarkers, by the nonstandardized assessment of biomarker subtype as reported in individual pathology reports constituting the basis for cancer registry abstraction, and by the lack of detailed individual-level information on breast cancer risk factors. Although we cannot speak to the full set of risk factors for specific subtypes, we can confirm the suspicions of previous authors (1
) that the differential occurrence of etiologically distinct entities, namely triple-negative breast cancer and HR+
breast cancer, is responsible for the black–white difference in the age-specific incidence of breast cancer. For no subtype did we observe the black–white crossover in incidence that appears when breast cancer is analyzed as a single entity (ie, without regard to subtype), which suggests that the high rates of triple-negative breast cancer among black women at younger ages and the high rates of HR+
breast cancers among white women at older ages are the major contributors to the black–white crossover.
Future studies of racial and ethnic differences in breast cancer occurrence should examine molecular subtypes separately. As further molecular technological advances are made to characterize breast tumors in more meaningful ways, these discoveries should guide treatment options and, it is hoped, will lead to success in reducing the mortality and survival disparities for triple-negative and other aggressive forms of breast cancer that now disproportionately affect younger women.