BRIEF COMMUNICATION

Ethnic Neutropenia and Treatment Delay in African American Women Undergoing Chemotherapy for Early-Stage Breast Cancer

Dawn Hershman, Mitchell Weinberg, Zachary Rosner, Karenza Alexis, Amy Tiersten, Victor R. Grann, Andrea Troxel, Alfred I. Neugut

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 stage–matched 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.


Despite lower breast cancer incidence, African American women have a worse prognosis from breast cancer than white women, even when the stage at diagnosis is equivalent (1,2). The reasons for this disparity are probably multifactorial, including socioeconomic, sociocultural, and biologic factors. Interestingly, unfavorable biologic parameters, such as negative estrogen receptor status, high nuclear grade, and high S-phase fraction, are more common in breast cancers in African American women than in white women (2,3).

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 hospital’s 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 hospital’s 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 Student’s 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 Scarff–Bloom–Richardson grading system (10)] (Table 1Go).


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Table 1. Age and tumor characteristics of study patients according to race*
 
African American women who had received adjuvant chemotherapy had statistically significantly lower WBC counts than white women, both at baseline (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) (Fig. 1Go). The baseline WBC count did not differ between African American women who received adjuvant chemotherapy (n = 43) and those who did not (n = 30) (data not shown). The mean percentage decrease in WBC count from baseline to the conclusion of treatment was similar for each of the ethnic groups (Fig. 1Go).



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Fig. 1. White blood cell counts for patients with early-stage breast cancer undergoing adjuvant chemotherapy by race. Data are presented as means (95% confidence intervals) for white women (n = 93; open bars) and for African American women (n = 43; shaded bars). There was a statistically significant difference in mean white blood cell counts between the white women and the African American women at baseline (P = .02) and at the end of treatment (P = .03).

 
In addition, African American women received adjuvant chemotherapy for a statistically significantly longer duration than white women (19 weeks versus 15 weeks, respectively, difference = 4 weeks, 95% CI = 0.5 to 7.2 weeks; P = .03). A longer duration of treatment was observed for each of the common adjuvant chemotherapy regimens, but the difference was not statistically significant within each of the chemotherapy groups (Fig. 2Go), probably because the statistical power to analyze each of the adjuvant chemotherapy regimens was limited by the small sample size in each subset.



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Fig. 2. Duration of adjuvant chemotherapy treatment for patients with early-stage breast cancer by race according to chemotherapy type. Data are presented as means (95% confidence intervals) for white women (n = 93; open bars) and for African American women (n = 43; shaded bars). Any Rx = all chemotherapy types combined; A = doxorubicin; C = cyclophosphamide; T = taxane; M = methotrexate; F = 5-fluorouracil. AC>T = four cycles of AC followed by four cycles of T. There was a statistically significant difference in mean duration of adjuvant chemotherapy treatment between the white women and the African American women for all chemotherapy types combined (P = .03) but not for the individual chemotherapy types.

 
Thus, our study confirmed the presence of lower baseline WBC counts in African American women with early-stage breast cancer than in white women with early-stage breast cancer, matched for age and tumor stage; this difference in WBC count persisted through the completion of adjuvant chemotherapy treatment. We also found that the duration of treatment with chemotherapy for African American women was statistically significantly longer than that for white women.

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 ANC<=3000). 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 node–positive 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 dose–response 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.

REFERENCES

1 Clegg LX, Li FP, Hankey BF, Chu K, Edwards BK. Cancer survival among US whites and minorities: a SEER (Surveillance, Epidemiology, and End Results) Program population-based study. Arch Intern Med 2002;162:1985–93.[Abstract/Free Full Text]

2 Joslyn SA, West MM. Racial differences in breast carcinoma survival. Cancer 2000;88:114–23.[CrossRef][ISI][Medline]

3 Elledge RM, Clark GM, Chamness GC, Osborne CK. Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States. J Natl Cancer Inst 1994;86:705–12.[Abstract]

4 Bain BJ. Ethnic and sex differences in the total and differential white cell count and platelet count. J Clin Pathol 1996;49:664–6.[Abstract]

5 Shoenfeld Y, Weinberger A, Avishar R, Zamir R, Gazit E, Joshua H, et al. Familial leukopenia among Yemenite Jews. Isr J Med Sci 1978;14:1271–4.[ISI][Medline]

6 Mason BA, Lessin L, Schechter GP. Marrow granulocyte reserves in black Americans. Hydrocortisone-induced granulocytosis in the "benign" neutropenia of the black. Am J Med 1979;67:201–5.[ISI][Medline]

7 Phillips D, Rezvani K, Bain BJ. Exercise induced mobilisation of the marginated granulocyte pool in the investigation of ethnic neutropenia. J Clin Pathol 2000;53:481–3.[Abstract/Free Full Text]

8 Bain BJ, Phillips D, Thomson K, Richardson D, Gabriel I. Investigation of the effect of marathon running on leucocyte counts of subjects of different ethnic origins: relevance to the aetiology of ethnic neutropenia. Br J Haematol 2000;108:483–7.[CrossRef][ISI][Medline]

9 Beahrs OH, Henson DE, Hutter RV, Kennedy BJ. Manual for staging of cancer. 4th ed. Philadelphia (PA): J.B. Lippincott; 1992. p. 164.

10 Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer. Br J Cancer 1957;11:359–77.[ISI]

11 Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328:1323–32.[Free Full Text]

12 Silber JH, Fridman M, DiPaola RS, Erder MH, Pauly MV, Fox KR. First-cycle blood counts and subsequent neutropenia, dose reduction, or delay in early-stage breast cancer therapy. J Clin Oncol 1998;16:2392–400.[Abstract]

13 Lerma P, Besa E, Klease C, Joseph R, Ozer H. Benign neutropenia patients are subjected to frequent treatment delays when current treatment guidelines are used [abstract 1627]. Proc ASCO 1999;18:422a.

14 Lyman GH. A predictive model for neutropenia associated with cancer chemotherapy. Pharmacotherapy 2000;20:104S–11S.[ISI][Medline]

15 Hryniuk W. Importance of chemotherapy scheduling: pieces of the puzzle. Cancer Invest 1999;17:545–6.[ISI][Medline]

16 Hryniuk W. Re: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 1999;91:1425.[Free Full Text]

17 Pronzato P, Campora E, Amoroso D, Bertelli G, Botto F, Conte PF, et al. Impact of administration-related factors on outcome of adjuvant chemotherapy for primary breast cancer. Am J Clin Oncol 1989;12:481–5.[ISI][Medline]

18 Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330:1253–9.[Abstract/Free Full Text]

19 Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 1998;90:1205–11.[Abstract/Free Full Text]

20 Ottevanger PB, De Mulder PH, Grol RP, Van Lier H, Beex LV. Effects of quality of treatment on prognosis in primary breast cancer patients treated in daily practice. Anticancer Res 2002;22:459–65.[ISI][Medline]

Manuscript received April 8, 2003; revised August 6, 2003; accepted August 15, 2003.


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