Race Free State Assignment Hazard Ratio

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Abstract

Background

The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy.

Methods

The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline- and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided.

Results

Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P < .001) and a higher body mass index (median: 31.7 vs 27.4 kg/m 2 ; P < .001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor–positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor–positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival ( P = .027) but not for overall survival ( P = .086).

Conclusion

Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor–positive breast cancer.

CONTEXT AND CAVEATS

Prior knowledge

The increased disease recurrence and worse survival of black women with breast cancer have been attributed to various factors, including a higher incidence of more aggressive (ie, triple-negative) disease, disparities in care, and comorbidities.

Study design

A retrospective secondary analysis that compared the outcomes of black patients with those of nonblack patients in a large cohort of women with stage I–III breast cancer who participated in a randomized phase III trial that compared the efficacy of several taxane regimens.

Contribution

Among patients with stage I–III hormone receptor–positive breast cancer who were treated with standard chemohormonal therapy, black patients had worse disease-free and overall survival compared with nonblack patients.

Implication

Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor–positive breast cancer.

Limitations

The study was retrospective in nature, and the analysis was not prespecified in the original trial design. Black breast cancer patients differed from nonblack patients with respect to some characteristics. Data on adherence to endocrine therapy came from case reports.

From the Editors

Breast cancer is the most common cancer in women in the United States and the second leading cause of death ( 1 ). Black race is known to be associated with a worse prognosis in breast cancer ( 2 ) and in other hormone-dependent cancers, such as uterine and prostate cancers, but generally not in other cancer types ( 3 , 4 ). Multiple factors that may contribute to the worse outcomes for black women with breast cancer include their greater likelihood of having advanced-stage ( 5 ) or triple-negative (ie, tumors that lack expression of the estrogen receptor [ER], progesterone receptor [PR], and HER2/neu) ( 6 ) disease. Triple-negative disease is a surrogate for basal subtype of breast cancer, which has been associated with a poor prognosis ( 7 ). Other factors that are associated with poor prognosis in black women with breast cancer include poor adherence to chemotherapy ( 8 ) and endocrine therapy ( 9 ), increased number of comorbidities ( 10 ), and disparities in care ( 11–13 ). Black race has also been associated with worse outcomes in male breast cancer ( 14 ). Although breast cancer incidence and mortality have declined by approximately 35% in the United States since 1990, the mortality rates have declined less in black women, which has contributed to an approximately 35% higher breast cancer mortality rate for black women compared with other women ( 15 ). However, a widening racial gap has also been observed for women in the US Department of Defense health-care system, suggesting that factors other than disparities in care may be playing a role in contributing to inferior outcomes ( 16 ).

To disentangle the various factors that influence disease recurrence and survival of black women with breast cancer, we compared the outcomes of black patients with those of nonblack patients in a large cohort of women with stage I–III breast cancer who participated in a National Cancer Institute (NCI)–sponsored randomized phase III trial that compared the efficacy of several taxane regimens (trial E1199; http://Clinicaltrials.gov identifier: NCT00004125) ( 17 ).

Patients and Methods

Patient Selection and Treatment

Women who had operable adenocarcinoma of the breast with axillary lymph node metastases [tumor stage T1, T2, or T3; nodal stage N1 or N2, or high-risk node-negative disease (T2 or T3, N0) without distant metastases according to the American Joint Commission on Cancer, Fifth Edition ( 18 )] were eligible for the randomized trial. Participants were required to have normal cardiac, renal, hepatic, and bone marrow function and good performance status. Other details regarding trial eligibility, the treatment administered, and the results have been previously reported ( 17 ). Briefly, patients received four cycles of doxorubicin and cyclophosphamide given every 3 weeks, followed by paclitaxel or docetaxel given every 3 weeks for four cycles or weekly for 12 cycles. Patients with hormone receptor–positive tumors (defined as ER and/or PR positive) were required to take tamoxifen (20 mg daily) for 5 years (or an aromatase inhibitor if there was a contraindication to tamoxifen therapy); the protocol was amended to allow switching from tamoxifen to an aromatase inhibitor after switching to an aromatase inhibitor was shown to be an effective alternative to tamoxifen alone ( 19 ). All patients received standardized care as stipulated by the trial. Information provided by the local institution was self-reported race and ethnicity at the time of registration in accordance with National Institute of Health guidelines used for NCI-sponsored trials ( http://grants.nih.gov/grants/guide/notice-files/not-od-01-053.html ).

Statistical Analysis

The disease-free and overall survival rates over time were estimated using Kaplan–Meier method, and the breast cancer–specific survival rates were estimated as 1 minus the cumulative incidence of breast cancer–specific death. Disease-free survival was defined as the time from randomization to disease recurrence, diagnosis of contralateral breast cancer, or death from any cause, whichever occurred first. Overall survival was defined as the time from randomization to death from any cause. Breast cancer–specific survival was defined as time from randomization to death from breast cancer. Patients whose cause of death was unknown but had breast cancer recurrence before death were also coded as death from breast cancer. Patients who died of other causes were censored at the date of death. Univariate and multivariable Cox proportional hazards models were used to estimate the unadjusted and adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The covariates in the multivariable Cox proportional hazards models included race (black vs nonblack), body mass index (BMI) at registration (≥30 vs <30 kg/m 2 ), age at registration (<50 vs ≥50 y), number of positive lymph nodes at registration (0 [referent] vs 1–3 vs ≥4), pathological tumor size at registration (≤2 vs >2 cm), most extensive surgical procedure at registration (breast-sparing procedure vs mastectomy), and hormone therapy on the study (tamoxifen alone vs aromatase inhibitor with or without tamoxifen [referent] vs no endocrine therapy or unknown). Hormone therapy was coded as a time-varying variable (patients started endocrine therapy at different time after registration in E1199), and all other variables were coded as time-fixed variables. The assumption of proportional hazards was checked by testing the statistical significance of interaction between covariates and time (in log scale) in Cox models. The proportional hazards assumption for all covariates was met for disease-free survival (based on P > .05 for the covariate-by-time interaction term in the Cox models, indicating that the HRs for the covariate do not change with time), whereas for overall survival and breast cancer–specific survival, the proportional hazards assumption for obesity only was not. Hence, sensitivity analysis was conducted by fitting separate Cox regression models for obese and nonobese patients. The results showed a slight change in hazard ratios for race but no change in the results of the statistical significance test (HR for race was somewhat higher for obese patients [overall survival: HR = 1.09; breast cancer–specific survival: HR = 1.22] and somewhat smaller for nonobese patients [overall survival: HR = 2.53; breast cancer–specific survival: HR = 2.78]). Overall, the model fit the data well. For the breast cancer–specific survival outcome, in addition to the cause-specific hazard analysis based on the multivariable Cox proportional hazard models, we also performed subdistribution hazards analysis for competing risks to adjust for comorbidities that compete with death from breast cancer. Patient characteristics were compared by the Fisher exact test for categorical variables and the two-sample Wilcoxon rank-sum test for continuous variables. Adverse events (defined by NCI Common Toxicity Criteria, version 2.0, available at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf ) were compared by the Fisher exact test. All P values are two-sided, and P values less than or equal to .05 were considered statistically significant. The median follow-up for surviving patients was 95 months (range = 0–119 months), at which time there were 1252 disease-free survival events, 904 deaths, and 704 breast cancer–specific survival events; the breast cancer–specific survival events included 577 patients who were coded by the treating institutions as having died of breast cancer (64% of all deaths) and 127 patients who had a breast cancer recurrence and whose deaths were coded by the treating institutions as due to an unknown cause (14% of all deaths). Other deaths included 119 patients who were coded as having died of other causes (13% of all deaths) and 81 patients who were coded as having died of an unknown cause and who did not have breast cancer recurrence (9% of all deaths). The median time from breast cancer recurrence to death was 15.2 for those coded as having died of breast cancer and 12.4 months for those coded as having died of an unknown cause after a breast cancer recurrence.

Results

Patient Characteristics

Of the 5052 patients enrolled on the study between October 1999 and January 2002, 4817 were included in this analysis, of whom 405 (8.4%) self-reported as being black or African American; 235 patients were not included in this analysis because they were ineligible for reasons described in the original report (n = 102) or were enrolled via the NCI Expanded Participation Project and had missing treatment and toxicity data (n = 133).

Table 1 presents the characteristics of black and nonblack patients included in this analysis. Compared with nonblack patients, black patients had statistically significantly higher rates of triple-negative disease (31.9% vs 17.2%; P < .001) and HER2-positive disease (24.7% vs 19.3%; P = .045) and larger tumors ( P = .020) but less extensive nodal involvement ( P < .001). Compared with nonblack patients, black patients were younger at trial enrollment (median age: 48 vs 51 years, P < .001), had a higher BMI (median BMI: 31.7 vs 27.4 kg/m 2 ; P < .001), and were more likely to be obese (BMI ≥30 kg/m 2 : 57.8% vs 34.2%;

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