In this national registry study conducted in a real-world setting of patients with HER2-positive MBC, black patients were found to have more adverse prognostic factors compared with white patients, including the greater BMI and a higher proportion of ER/PR-negative tumors. These differences in prognostic factors may have contributed to the observed decrease in PFS following first-line therapy (unadjusted median: 7.0 months [95 % CI 5.7–8.2] vs. 10.2 months [95 % CI 9.3–11.2]), and OS (unadjusted median: 27.1 months [95 % CI 21.3–32.1] vs. 37.3 months [95 % CI 34.6–41.1]) in black patients compared with white patients. Multivariate analyses confirmed that, after adjustment for differences in prognostic factors, black patients had a 30 % greater risk of disease progression in the first-line setting compared with white patients, as well as a 30 % increase in risk of death.
Black patients in this study had a higher prevalence of obesity and diabetes; both metabolic disorders have independently been associated with breast cancers that exhibit aggressive biological characteristics and have poor prognoses [15
]. Obesity and diabetes share similar biological mechanisms for their associations with breast cancer. In addition, in line with current population-based, epidemiologic data [16
], black patients in this study had a higher rate of underlying CVD at baseline compared with white patients and were more likely to present with de novo stage IV MBC or recurrent stage IV MBC within 12 months of initial stage I–III diagnosis. However, black patients consistently demonstrated poorer outcomes, even after adjusting for differences in BMI, the prevalence of underlying CVD between black and white patients, and stage at initial diagnosis.
The unexplained poorer outcomes in black patients with HER2-positive MBC, despite controlling for prognostic factors, suggest that other influences, in particular those underlying tumor and host biology, may play a role in the etiology and health outcomes of patients with HER2-positive breast cancer. One illustration of this can be observed in patients with tumors that are hormone receptor-negative, which are associated with poorer prognosis compared with hormone receptor-positive tumors [18
]. Consistent with the findings in registHER, data from the large, population-based Surveillance, Epidemiology, and End Results (SEER) database have shown that African American breast cancer patients are more likely to have ER/PR-negative tumors than European American [19
] and non-Hispanic white breast cancer patients [20
Interestingly, while black patients in the registHER cohort of HER2-positive patients were more likely to have ER/PR-negative disease compared with white patients, there was a trend toward worse outcomes in black patients within both the ER/PR-positive and ER/PR-negative subsets. While the literature on this finding is limited, an early-stage analysis from a recent, large, randomized trial population treated with anthracycline- and taxane-containing chemotherapy found that racial differences in outcome were observed primarily in the ER-positive group but not in the ER-negative or HER2-positive groups [21
There is evidence demonstrating that there are racial/ethnic differences in breast cancer molecular subtypes in addition to HER2-positive disease, as well as gene alterations, which have been associated with breast cancer outcomes. TNBC, which is associated with poor prognosis, an aggressive and early pattern of metastases, and limited therapeutic options [22
], occurs at a higher rate in indigenous African women [3
], as well as in African American women [2
], compared with white women. In a recently completed sequence analysis of 434 breast cancers in Nigerian patients, high frequencies of BRCA1
mutations were found (7.1 and 3.9 %, respectively), and 16 different BRCA1
mutations were detected [25
]. Alterations in p53 were significantly more common in African American women than in white women (odds ratio, 4.00; 95 % CI 1.77–9.01) in a study of 247 tumor samples, even after adjustment for disease stage at diagnosis and other prognostic factors [26
]. In 141 tumor tissue samples analyzed from 72 African American and 69 Latina women with breast cancer, more than 70 % of the patients with HER2-positive disease had elevated Akt levels, a level higher than reported for other ethnic groups in most studies [27
Given the increased prevalence of poor prognosis molecular subtypes and genetic alterations in black women with breast cancer, and the unexplained unfavorable outcomes in black patients in registHER, the current hypothesis-generating descriptive study suggests that expanded research into the role of the biology of HER2-positive MBC across race/ethnicity may provide an improved understanding of the etiology of these observations and could identify possible new targets for therapy.
To determine if racial disparities were evident for trastuzumab-associated cardiac safety events in registHER, reported cardiac safety events were compared in white and black patients treated with trastuzumab. Because the number of events in the analysis was small, results should be interpreted with caution. The incidence of cardiac safety events (collected via predefined checkboxes and physician subjective opinion) was slightly greater in black patients than white patients (10.9 vs. 7.9 %, respectively), as was the incidence of congestive heart failure (4.2 vs. 1.6 %, respectively). The contributing factors to this modest difference are unknown, but they are likely to include a higher incidence of hypertension that requires treatment in black vs. white patients, as it is known to be a risk factor for trastuzumab-induced cardiac toxicity [28
]. Additional research is needed to investigate risk factors for cardiac toxicity by race among patients receiving trastuzumab.
The fact that socioeconomic data were not collected in registHER, and therefore data could not be adjusted for socioeconomic status in this analysis, is a weakness of the study. Socioeconomic factors like account for some proportion of breast cancer outcome disparities, but a majority of pooled and population-based studies show a persistence of survival differences in black patients and white patients after adjustment for socioeconomic factors [7
]. Interestingly, despite the observed increase in breast cancer mortality in African American breast cancer patients, these patients are more likely to experience delays in completion of adjuvant chemotherapy, are more likely to receive potentially inappropriate and substandard healthcare, are less likely to undergo preventive cancer screening, and are less likely to participate in clinical trials [7
In addition to the lack of socioeconomic data in registHER, an inherent limitation of this study is possible “confounding by indication” because of the nonrandomized, observational nature of the registHER study. The analysis may also include possible residual confounding due to the inability to control for prior treatments, treatment compliance, tumor size, menopausal status, and New York Heart Association Functional Classification. CVD and cardiovascular safety data were collected via predefined checkboxes and physicians subjective opinion rather than via validated methods. Also, the overall findings should be interpreted with caution due to the small number of events. Limited information was collected for cause of death (options included only “cancer” and “other”) and was missing for 32/538 deaths (>5 % of deaths) in the registHER cohort (n = 1,001), which precluded the calculation of breast cancer-specific mortality rates in this study.