Affiliations of authors: D. Hershman (Department of Medicine and the Herbert Irving Comprehensive Cancer Center), K. Alexis (Department of Medicine), College of Physicians and Surgeons, M. Weinberg, Z. Rosner (Department of Epidemiology), A. Troxel (Departments of Epidemiology and Biostatistics), Mailman School of Public Health, V. R. Grann, A. I. Neugut, Department of Medicine, College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; A. Tiersten, Department of Medicine, New York University, New York.
Correspondence to: Dawn Hershman, MD, MS, New York-Presbyterian Hospital, 161 Ft. Washington Ave., Rm. 1068, New York, NY 10032 (e-mail: dlh23{at}columbia.edu).
ABSTRACT
Disparities in breast cancer survival have been observed between African American and white women. There are also known differences in mean baseline white blood cell (WBC) count among racial and ethnic groups. If the WBC count falls below conventionally defined treatment thresholds for patients undergoing adjuvant chemotherapy, reduced doses or treatment delays may occur, which could lead to race-based differences in treatment duration. We used the tumor registry at Columbia-Presbyterian Medical Center to identify 1178 women with newly diagnosed stage I and II breast cancer from whom we collected base-line information for 73 African American women and 126 age- and tumor stagematched white women. Of these women, 43 African American and 93 white women underwent adjuvant chemotherapy. African American women had statistically significantly lower WBC counts than white women at diagnosis (6.2 x 109/L for African American women versus 7.4 x 109/L for white women, difference = 1.2, 95% confidence interval [CI] = 0.2 to 1.2; P = .02) and after treatment (5.3 x 109/L for African American women versus 6.4 x 109/L for white women, difference = 1.1, 95% CI = 0.2 to 2.5; P = .03). Overall, African American women required a statistically significantly longer duration of treatment than white women (19 weeks versus 15 weeks, respectively, difference = 4 weeks, 95% CI = 0.5 to 7.2 weeks; P = .03). The lower baseline WBC counts and longer duration of treatment for early-stage breast cancer in African American women compared with those in white women result in lower dose intensity of treatment for African American women, possibly contributing to observed racial differences in breast cancer survival.
African American women can have white blood cell (WBC) counts that are on average 25%40% lower than those of women of European-American ancestry (4). Up to 50% of individuals of African ancestry have baseline WBC counts lower than 4.0 x 109/L and absolute neutrophil counts (ANCs) lower than 2.5 x 109/L. The lower baseline ANC in these otherwise healthy individuals has been labeled ethnic neutropenia; however, these lower counts are likely a normal variant. The reason(s) for the lower baseline WBC counts in individuals of African ancestry is unclear, and most investigators have accepted the hypothesis of genetic differences (5). The mechanism by which baseline WBC counts and ANCs are lower in these individuals is thought to be due to a difference in the release of mature granulocytes from bone marrow storage pools (6) or to an altered bone marrow reserve (7,8). Differences in bone marrow reserve or in marrow response to growth factors may cause African American patients with breast cancer to have delayed WBC count recovery in response to cytotoxic chemotherapy.
We hypothesized that African American women with breast cancer may be more likely than white women with breast cancer to have lower WBC counts, both at baseline and as a result of chemotherapy, and that their WBC counts would return to conventionally defined thresholds for re-treatment less rapidly than those of white women. If this hypothesis is correct, the lower WBC count would prevent physicians from treating African American women for the prescribed treatment schedule and at the full dose intensity, perhaps contributing to the observed racial disparities in survival between these groups of patients. Hence, to test this hypothesis, we conducted a study of African American and white women with early-stage breast cancer and compared WBC counts and treatment duration.
After obtaining approval from the human subjects committee, we identified 2723 women at Columbia-Presbyterian Medical Center (New York, NY) who were newly diagnosed with breast cancer between January 1, 1996, and December 31, 2000. From that group, we identified 1178 women with stage I or II breast cancer (excluding patients with ductal carcinoma in situ) of whom 73 were recorded in the hospitals clinical information system as being of African ancestry. Each African American patient was matched for age (±5 years) and tumor stage with two white patients who also had early-stage breast cancer (n = 126). Of these patients, 43 African American women and 93 white women had undergone adjuvant chemotherapy treatment. Billing records were used to determine which patients received chemotherapy, the chemotherapeutic agents used, and the dates of treatment. Complete blood count information at the time of diagnosis and prior to each treatment was obtained from the hospitals clinical information system. Basic demographic information was obtained from the tumor registry.
Statistical analyses for baseline characteristics and within group measures were performed using SAS software (version 6.12; SAS Institute, Cary, NC). Continuous variables, such as WBC counts and treatment duration, were compared between groups using Students t test. Dichotomous variables were compared using chi-square tests. Analyses were also adjusted for matching factors (i.e., patient age and tumor stage). However, because the results of the adjusted analyses were comparable to those of the unadjusted analyses, we present the simpler analysis in the interest of clarity. All statistical tests were two-sided, and statistical significance was accepted at a P value of .05.
The African American women (n = 73) and the white women (n = 126) did not differ statistically significantly in mean age, mean tumor size, disease stage distribution [as determined by the American Joint Committee on Cancer (AJCC) staging system (9)], hormone receptor status, lymph node positivity, rate of lymphovascular invasion, or tumor grade [as determined by the modified ScarffBloomRichardson grading system (10)] (Table 1).
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Because the ANC is used to determine the time of re-treatment and the subsequent doses of most chemotherapy regimens (11), patients who have low ANCs at baseline are subject to more frequent delays in treatment and dose reductions (12). Hence, African American women (who have lower ANCs than white women) who receive adjuvant chemotherapy may have larger declines in their WBC counts to below conventionally defined treatment thresholds, leading to reduced doses of chemotherapy regimens or treatment delays. This lower dose intensity may compromise the efficacy of adjuvant chemotherapy regimens and could perhaps contribute to the observed disparities in survival between African American patients and white patients.
Interestingly, one study (13) has suggested that breast cancer patients with lower baseline ANCs may in fact be at increased risk for treatment delays. Of the 60 patients with breast cancer who were studied, 22 had neutropenia (i.e., a baseline ANC3000). The patients with and without neutropenia were heterogeneous in terms of age, stage of disease, and treatment received. In the group of patients with baseline ANCs of less than 3000, subsequent treatment cycles were delayed three times more frequently (29 versus nine events; P<.05) than in the group of patients with ANCs greater than 3000. The sample was too small, however, for definitive analysis of the effects of race or ANC on the incidence of neutropenic fever. Differential use of growth factors between racial groups may also influence dose intensity; however, the use of growth factors in these patients was not reported and therefore could not be adjusted for in the analysis (13).
After controlling for other factors such as age, a low baseline WBC count is one of the strongest predictors of febrile neutropenia and of a relative dose intensity of less than 85% (14). In the majority of patients in whom dose intensity was not achieved, appropriate dose intensity could be achieved if adequate supportive care, such as growth factors, was added to the regimen (14).
Because both low dose intensity and treatment delays decrease breast cancer survival, the racial differences in treatment duration we observed could contribute to a suboptimal outcome for African American women. In a retrospective review of 12 clinical trials of adjuvant anthracycline-based chemotherapy, both dose intensity and total dose were important prognostic factors in the outcomes of patients with lymph nodepositive breast cancer and were associated with increases in relapse-free survival (15,16). These findings have been validated in both randomized clinical trials (1719) and in a population-based study (20). The importance of doseresponse was introduced in a trial by the Cancer and Leukemia Group B in which low-dose, moderate-dose, and high-dose chemotherapy were tested in women with stage II breast cancer (18,19). At a median follow-up of 9 years, disease-free and overall survival for patients on the moderate- and high-dose regimens were superior to the survival outcomes of patients on the low-dose regimen (19). The initial report of that trial (18) concluded that the dose of chemotherapy used to treat breast cancer should not be reduced or delayed if maximal benefit is to be achieved.
In summary, we found that African American women who have early-stage breast cancer had lower baseline WBC counts and longer duration of adjuvant chemotherapy treatment than white women who have early-stage breast cancer, matched for age and tumor stage. Because of the retrospective nature of this study, we were unable to exclude a role for other behavioral or biologic factors, such as access to care, socioeconomic status, or other treatment-related toxicities, in the observed increase in treatment duration. This difference in dose intensity may contribute to the observed disparities in survival between African American women and white women with breast cancer. We are presently undertaking a larger study to confirm these findings and to determine if the conventionally defined treatment threshold for the WBC count is appropriate for patients with lower baseline WBC counts.
NOTES
Supported in part by the Avon Products Foundation and the Jean Sindab Fund. Dr. Hershman was the recipient of a National Cancer Institute (NCI)funded postdoctoral fellowship (T32 CA09529) and is currently the recipient of an American Society of Clinical Oncology Career Development Award and a K07 Award from the NCI (CA95597). Dr. Neugut is the recipient of a K05 Award (CA89155).
We thank Dr. Karen Antman (Department of Medicine and the Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY) for her critical review of this manuscript.
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Manuscript received April 8, 2003; revised August 6, 2003; accepted August 15, 2003.
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