African American patients with breast, prostate, or ovarian cancer who were treated on phase III SWOG trials had statistically significantly worse overall survival than white patients. These results are important given all patients had uniform therapy and follow-up parameters, with adjustment for stage, socioeconomic factors, and known prognostic variables. Of note, these cancers are all sex specific. Racial differences in survival of this magnitude were not observed in patients with the non–sex-specific solid tumors (colon and lung cancer) or in patients with any hematologic malignancy examined.
Worse survival for African American women with breast cancer has been reported by the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry (14
), the Department of Defense database (15
), large single-institution studies (16
), and literature-based meta-analyses (17
). However, most of these sources had limited information on treatment, which was usually not standardized and often heterogeneous. Other analyses that evaluated outcomes in cooperative group analyses often did have complete treatment data but yielded conflicting results (18
). These studies reported that African American and white patients enrolled in selected National Surgical Adjuvant Breast and Bowel Project or Cancer and Leukemia Group B cooperative group trials did not differ in breast cancer mortality after controlling for prognostic factors. However, the small number of African American patients within smaller study samples may have obscured a difference. We found that, after controlling for stage, demographics, socioeconomic variables, tumor characteristics, and treatment factors, this disparity existed among both premenopausal and postmenopausal women who were diagnosed with early-stage breast cancer.
This racial disparity in survival among patients with early-stage breast cancer occurred in patients with both endocrine-responsive and nonresponsive tumors. African American women with breast cancer, especially those who are premenopausal, have a higher incidence of biologically more aggressive cancers with a basal-like subtype or that were triple negative (ie, lacking receptors for estrogen, progesterone, and HER2-neu). Several authors have stated that the predominance of this subtype among African Americans most likely explains previously reported racial disparities in survival outcomes (6
). To address this issue, we analyzed survival by race within hormone receptor status subgroups (), although HER2-neu data were not collected in the older trials in our database. Given the statistically significant adverse outcome for African Americans within the hormone receptor–positive group (as well as the hormone receptor–negative group), and the known widening of the disparity in survival over time since the 1980s, the triple-negative biology theory cannot be the sole explanation for the difference in breast cancer outcomes by race. Our results suggest that there are other causes for the disparity when the treatment type and ER status are similar by race (along with the other factors in the breast cancer dataset).
We observed that African American men with advanced prostate cancer who were treated uniformly on phase III clinical trials had a higher mortality rate (HR for death = 1.19, 95% CI = 1.05 to 1.35; P
= .008), after adjustment for all other available factors. Age-adjusted mortality rates reported by the SEER national registry consistently demonstrated that African American men have a death rate that is double that of white men (22
). Two studies (23
) reported that even after controlling for the effects of age, preoperative serum prostate-specific antigen level, pathological grade, and stage, the racial disparity in progression-free survival persists among men diagnosed with clinically localized prostate cancer. The disparity in outcome also occurs among men with androgen-independent metastatic prostate cancer. In a single-institution study (25
), African American race was the only independent predictor of time to prostate-specific antigen progression, indicating that biological and genetic differences underlie this disparity. Some have speculated that the racial disparity in survival among men with local or regional prostate cancer was explained by socioeconomic factors. For example, Du et al. (10
) reported that lower socioeconomic status appeared to be one of the major barriers to achieving comparable outcomes for men with prostate cancer. However, our analysis demonstrated that the disparity in prostate cancer survival persisted despite adjusting for income and education.
We observed an increase in mortality (HR = 1.65, 95% CI = 1.21 to 2.24; P
= .002) among African American women with ovarian cancer in our population who were treated uniformly on phase III clinical trials after adjustment for all available factors. A previous study (26
) reported that African American patients had more advanced disease and were less likely to undergo cancer-specific surgery than white women, but after adjusting for prognostic factors, African American women still had an increased risk of death from any cause (HR = 1.30, 95% CI = 1.20 to 1.40; P
< .001). This disparity in survival was even observed in equal-access care systems, such as Kaiser Permanente (27
). In our analysis, which is to our knowledge the only one designed to additionally adjust for treatment-related factors, the disparity persisted.
No deficit in survival was observed for African American patients with nonmetastatic colon cancer in our treatment-controlled dataset. In a previous report (28
), African Americans were more likely to die of colon cancer than whites, probably because African Americans were more often diagnosed with advanced-stage disease. However, survival differences were also reported within each stage of disease. These findings may be explained by degree of delivery of adjuvant systemic therapy, in that African American patients are less likely than white patients to be treated with adjuvant chemotherapy (29
). However, the National Surgical Adjuvant Breast and Bowel Project reported (5
) a pooled database analysis in which African Americans experienced a statistically significantly greater risk of death, despite uniform use of adjuvant chemotherapy. It is possible that our smaller colon cancer analysis was underpowered to detect a survival difference or that, with modern treatments for colon cancer, disparities in outcome was reversed.
There are several limitations to our analysis. First, although use of clinical trial data implicitly controls for many treatment and access to care issues, it is possible that cancers of non–African American patients were more likely to be screen detected, especially in the adjuvant breast cancer setting, resulting in possible lead-time bias. Unfortunately, data on patients whose breast cancer was detected by screening and those whose breast cancer was detected clinically were not available. African Americans with pre- or postmenopausal breast cancer were less likely to be diagnosed with tumors smaller than 2 cm in diameter, but incorporation of three categories for tumor size (<2, 2–5, or >5 cm) had little impact on the strength of the survival differences by race. Furthermore, adjustment for the stronger prognostic factor of axillary lymph node status did not lessen the degree of breast cancer survival disparity. Consequently, lead-time bias cannot fully, or even in large part, explain our observations. Second, some of the overall survival differences observed between African American patients and patients of other ethnic or racial groups may be related to noncancer health and comorbid disease disparities, although why this effect would be more dominant in breast, ovarian, and prostate cancers than in other types of cancer is unclear. However, patients who participate in clinical trials may be more compliant and healthier in general than patients who are not eligible or refuse to participate in clinical trials (31
). This so-called healthy subject effect might diminish the potential influence of noncancer disparities in survival. Nevertheless, to address this concern, we performed approximate cause-specific survival analyses () (32
). These analyses found little change in regression estimates by race, indicating that non–cancer-related deaths were similar between the racial groups and thus were not the explanation for the survival disparity. Cause-specific analyses rely on the assumption that the cancer outcome of interest is independent of other outcomes, so our analysis of cancer-specific survival must be viewed with caution, especially because the cause of death was estimated rather than explicitly identified.
Another limitation to our analysis was our inability to assess adherence to the oral adjuvant hormonal therapies prescribed in the protocols in detail. There may be differential rates of adherence to hormonal therapy, with African American women with breast cancer on average being less likely to complete a full 5-year course of treatment (33
). This aspect might also explain the prostate cancer findings but most likely not the disparities in hormone receptor–negative breast cancer or in ovarian cancer. An additional limitation pertained to a concern that chemotherapy delivery and dosing may be substandard in African Americans. We conducted an in-depth analysis of two trials from the breast cancer database and found that, after adjustments for baseline white blood cell counts, body surface area, treatment quality, and treatment delivered (relative dose intensity), the disparity in survival outcome by race persisted (34
). These factors were not independently associated with increased mortality. We were not, however, able to control for specific comorbid conditions that were not otherwise precluded by study eligibility criteria, are known to be more prevalent in African Americans, and are associated with reduced overall survival. Differential distribution of comorbid conditions may have also influenced the overall survival disparity that we observed, but as discussed above, there did not appear to be a difference in the rate of non–cancer-related deaths by race.
A provocative aspect of our analysis was that African American patients had statistically significantly worse survival in the sex-specific cancers (breast, ovarian, and prostate) but not in the other cancers examined, which include the major tumor types diagnosed in the United States. Although there are other non–sex-specific cancers that were not included in this analysis and that may also show disparities, one explanation for our findings might be that there are hormonal factors that contribute to the aggressiveness of some cancers that differ by race. Another possibility is that inherited genetic differences across races, especially in single-nucleotide polymorphisms, exist in the way resistance to therapy develops in these tumors and/or in how standard doses of drugs are activated and metabolized. Racial and ethnic variations in single-nucleotide polymorphisms for CYP2D6, UGT1A1, and SULT1A have been reported, which may account for differences in both risk and outcome (35
). Female sex has been found to be independently associated with favorable survival in lung cancer (39
). It is postulated that hormonal influences including estradiol levels and single-nucleotide polymorphisms that differ by sex, along with pharmacogenetic differences in drug metabolism, explains this observation (40
). More research is clearly needed regarding interactions among treatment, sex, race, and survival.
We report the first comprehensive analysis, to our knowledge, from a large, unique cohort of patients who were treated on SWOG clinical trials that demonstrate racial disparities in survival persist for patients with breast, prostate, and ovarian cancer after controlling for prognostic, treatment, and socioeconomic factors. The randomized clinical trial setting used in this analysis ensured similarity in disease stage, eligibility requirements, and treatment plan and allowed adjustment for all other potential prognostic factors. Our findings suggest that unrecognized interactions of tumor biological, hormonal, and/or inherited host factors must be contributing to differential survival outcomes by race in sex-specific malignancies.