© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 36-43,
2001
© 2001 Oxford University Press
Efficacy of Systemic Adjuvant Therapy for Breast Cancer in African-American and Caucasian Women
Affiliations of author: Biostatistical Center, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, and Department of Health Studies, University of Chicago, IL
Correspondence to: James J. Dignam, Ph.D., Department of Health Studies, 5841 South Maryland Ave., MC 2007, University of Chicago, Chicago, IL 60637 (e-mail: jdignam{at}health.bsd.uchicago.edu).
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ABSTRACT |
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Observed variations in breast cancer survival by racial/ethnic background have been attributed to many factors, including differences in clinical and pathologic disease features at diagnosis and economic resource inequities that may affect treatment access and quality. In this report, we examine outcomes for African-American and Caucasian breast cancer patients participating in selected randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine whether prognosis or efficacy of systemic adjuvant therapy differed between these groups. Randomized clinical trials offer the advantages of a similar disease stage and a uniform treatment plan for all participants. Patients from four NSABP trials enrolling patients from 1982 through 1994 with axillary lymph node-negative disease (543 African-American and 7582 Caucasian) and three trials enrolling patients from 1984 through 1991 with axillary lymph node-positive disease (548 African-American and 4986 Caucasian) were included. Disease-free survival (DFS), which was defined as time on study free of breast cancer recurrence, second primary cancer, or death preceding these events, and survival risk ratios (RRs) with two-sided 95% confidence intervals (CIs) for African-Americans versus Caucasians were computed from Cox proportional hazards models that included relevant prognostic covariates. Treatment benefits for the therapies evaluated in these trials were estimated separately for African-Americans and for Caucasians. Among patients with lymph node-negative disease, African-Americans had similar DFS rates to Caucasians (African-American/Caucasian RR = 1.06, 95% CI = 0.92 to 1.23) but had modestly greater mortality rates (RR = 1.21, 95% CI = 1.01 to 1.46). Among lymph node-positive patients, DFS was similar (RR = 1.04, 95% CI = 0.93 to 1.17) and survival was again less favorable for African-Americans (RR = 1.18 95% CI = 1.03 to 1.34). Survival excluding deaths most likely attributable to causes other than cancer was similar between African-Americans and Caucasians (RR = 1.08 [95% CI = 0.88 to 1.33] for lymph node-negative patients and RR = 1.09 [95% CI = 0.96 to 1.25] for lymph node-positive patients). Among lymph node-negative and lymph node-positive patients, African-Americans and Caucasians realized comparable benefit from either the addition of chemotherapy or tamoxifen to surgery alone or the addition of chemotherapy to tamoxifen. In summary, African-American women and Caucasian women who were diagnosed at a comparable disease stage and were similarly treated tended to experience similar breast cancer prognosis. However, a mortality deficit persisted for African-American women relative to Caucasian women, which may be in part due to greater mortality from noncancer causes among African-Americans. Benefit from systemic adjuvant therapy for recurrence and mortality reduction was comparable between African-Americans and Caucasians. This study and investigations in other health-care settings suggest that African-American women and Caucasian women with breast cancer derive a similar benefit from systemic adjuvant therapy when it is administered in accordance with their clinical and pathologic disease presentation.
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INTRODUCTION |
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Differences in breast cancer survival among racial/ethnic groups have been noted in many studies, as well as in national cancer statistics summaries (1,2). Numerous factors have been implicated as sources of these differences, including disease characteristics at diagnosis, economic resource inequities and other social factors, and disparities in treatment access and (possibly) efficacy. Asian-Americans tend to have lower incidence of breast cancer than do Caucasians, and they also have a superior prognosis, in part because of earlier stage at diagnosis and favorable disease features (3,4). Women of Hispanic origin are more frequently diagnosed at a later stage and more often exhibit other less favorable disease features relative to non-Hispanic Caucasians (3,5–7). American Indian women more often are diagnosed at a later stage and have poorer survival rates than do both Hispanics and Caucasians (7,8). The most extensively investigated disparity in breast cancer prognosis is that between African-Americans and Caucasians. There is general consensus that African-American women are more often diagnosed at a later stage, have larger tumors with less favorable characteristics, and may suffer barriers to quality care, resulting in poorer survival [for review, see (9)].
The existence of cancer outcome disparities between race groups despite improvements in diagnosis and treatment over recent decades is considered by most to be largely a consequence of personal and institutional resource limitations in specific racial/ethnic communities rather than of any intrinsic aspect of race itself, although cultural and social factors associated with ethnicity may also play a role (10–14 [for review, see (15)]. In circumstances where resource disparities are absent, cancer-screening participation, disease stage at diagnosis, treatment, and subsequent outcomes are similar regardless of race, suggesting economic inequity as a major explanatory factor in outcome disparities (16–21).
To evaluate the role of disease stage at diagnosis and subsequent treatment in reducing outcome disparities among patients of different race backgrounds, we examined breast cancer prognosis among African-American and Caucasian women participating in randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP). The randomized clinical trials provide a setting for a comparison of outcomes among women diagnosed at the same disease stage and treated uniformly according to a prescribed protocol. In this study, we address 1) whether outcomes among African-American and Caucasian women included in these trials are more similar than those observed in the population at large and whether specific demographic, clinical, and biologic factors might explain any differences observed and 2) whether there is evidence of differential efficacy of systemic adjuvant therapy between African-Americans and Caucasians. Previous studies from the NSABP and others have found outcomes among Caucasians and African-Americans to be more comparable in clinical trials and other equal-care settings than those that have been observed in population-based studies (9,21–26).
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PATIENTS AND METHODS |
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Trials and Patients Included
The NSABP is a National Cancer Institute-sponsored cooperative clinical trials group evaluating treatments for breast and colorectal cancers. The group is headquartered in Pittsburgh, PA, and participating institutions enroll patients throughout North America. Beginning in the early 1980s, a series of trials were conducted among patients with operable breast cancer and axillary lymph nodes that were pathologically negative for tumor cells. In 1981, NSABP Protocol B-13 was opened for patients with lymph node-negative disease and estrogen receptor (ER)-negative tumors (<10 fmol/mg cytosol protein) and compared surgery alone with surgery followed by sequential methotrexate and 5-fluorouracil (M
F). Concurrently, NSABP Protocol B-14 enrolled lymph node-negative women with ER-positive breast tumors (
10 fmol) and compared long-term tamoxifen (5 years) with placebo after surgery. Following results from these trials indicating an advantage for active treatment, two trials for this same class of patients were initiated in 1988: Protocol B-19 compared MF with conventional cyclophosphamide (C), methotrexate (M), and 5-fluorouracil (F) (CMF) among those patients with ER-negative tumors. Protocol B-20 compared the addition of MF or CMF with tamoxifen among patients with ER-positive tumors.
During the 1980s, continuing developments in the treatment of patients with axillary lymph node-positive breast cancer led to several trials evaluating the utility of the doxorubicin (Adriamycin)–cyclophosphamide (AC) chemotherapy regimen. From 1984 through 1989, NSABP Protocols B-15 and B-16 accrued patients with operable breast tumors and positive axillary lymph nodes. Eligible patients for Protocol B-15 were those under 50 years of age and those aged 50–59 years with progesterone receptor (PgR)-negative tumors (<10 fmol). These patients were randomly assigned to receive conventional CMF, AC for four courses, or AC followed by CMF. Protocol B-16 enrolled patients aged 50–59 years with PgR-positive tumors and all patients aged 60–70 years. These patients were randomly assigned to receive either tamoxifen alone or tamoxifen and AC (additional treatment arms using L-phenylalanine mustard (L-PAM) were included in comparisons of race but omitted from evaluation of treatment efficacy in African-Americans and Caucasians, since this agent is no longer in use). Protocol B-22, which accrued patients from 1989 through 1991, evaluated increased and intensified doses of C in the AC regimen.
Patients from these trials were excluded from this analysis if they had either no follow-up information or unknown clinical or pathologic tumor size or if their axillary lymph node status did not match the protocol entry criteria for the trial to which the patient was enrolled. The proportion of patients with no follow-up (<1% of patients in any one trial), missing tumor size, or incorrect lymph node status did not differ significantly by race. From the trials for lymph node-negative breast cancer, 543 African-American, 7582 Caucasian, and 456 patients of other or unknown race were included in this analysis. Among patients included from the trials for lymph node-positive breast cancer, there were 548 African-Americans, 4986 Caucasians, and 317 patients of other or unknown race. Because this latter group is heterogeneous with regard to race, we do not provide specific inference about women in this category. Outcomes and characteristics for these women as a group were similar to those of Caucasians. African-Americans constituted 9%–11% of patients from individual trials in which patients with ER-negative tumors were enrolled (B-13 and B-19), in which younger and PgR-negative patients were enrolled (B-15), or in which ER was not an entry criterion (B-22). In trials that enrolled ER-positive (B-14 and B-20) or predominantly ER-positive (B-16) patients, African-Americans constituted 5%–6% of all patients enrolled, reflecting the lower incidence of ER-positive tumors observed among African-Americans in the population of breast cancer patients (5,27,28).
Further study design details and major findings from these trials have been presented previously (29–34). Results in this study reflect data reported to the NSABP data coordinating center as of December 31, 1999. Follow-up is administratively censored at 12 years for all studies.
Endpoints and Statistical Methods
Frequency distributions for selected characteristics were compared by using chi-square and exact tests. Two-sample t tests and appropriate nonparametric counterparts were used to compare means or medians of continuous distributions. Time-dependent endpoints were 1) disease-free survival (DFS) time, defined as time from surgery until breast cancer recurrence, new primary cancer, or death before recurrence or new primary cancer; 2) recurrence-free survival (RFS) time, which is defined as time until breast cancer recurrence, with other events treated as censored observations; and 3) survival time, which is defined as time from surgery until death from any cause.
The Cox proportional hazards model was used to compute risk ratios for African-Americans relative to Caucasians for each of the failure endpoints. Other potentially confounding covariates were included in these models. Evidence of a differential benefit for treatment according to race was tested by including cross-product terms representing the race x treatment interaction and testing the significance of these terms via likelihood ratio methods. Treatment comparisons were conducted separately for African-Americans and Caucasians irrespective of statistical significance of the interaction to illustrate the direction, magnitude, and variability of the treatment effect estimates within these groups. Analyses of treatment efficacy were confined to the individual trials. Analyses of differences between African-Americans and Caucasians were conducted 1) within individual trials, 2) combined across trials according to ER status, and 3) combined overall. All confidence intervals (CIs) shown are based on a two-sided 0.05 test criterion.
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RESULTS |
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Characteristics of African-Americans and Caucasians With Breast Cancer
Characteristics at diagnosis were compared for African-American and Caucasian patients separately by lymph node and ER status (not shown). Characteristics were somewhat less favorable for African-Americans compared with Caucasians but did not differ as greatly as was reported in population-based studies, since patients were similar with respect to disease stage within each trial. Among patients with lymph node-negative disease, the median age at diagnosis was 1 (ER-negative patients) to 3 (ER-positive patients) years less for African-Americans. African-Americans had tumors that averaged about one-half centimeter larger than those of Caucasians. Among lymph node-positive patients, African-Americans again tended to be 1–3 years younger at diagnosis and had larger tumors than their Caucasian counterparts, while the number of lymph nodes positive for tumor cells did not differ between African-Americans and Caucasians.
Outcomes for African-Americans Relative to Caucasians
Risk ratios (RRs), which represent the failure hazard ratio of African-Americans to Caucasians, taking into account other prognostic covariates (age, tumor size, and treatment), were computed for patients from trials for lymph node-negative patients (Fig. 1
. DFS was similar and did not differ significantly in individual trials or overall. ER-negative African-American and Caucasian patients had similar DFS (African-American/Caucasian RR = 1.07; 95% CI = 0.84 to 1.35), as did those with ER positive tumors (RR = 1.05; 95% CI = 0.87 to 1.27). Recurrence-free survival results were similar (not shown). African-American patients consistently showed a modestly increased mortality risk (Fig. 1; ER-negative RR = 1.30 [95% CI = 0.98 to 1.73]; ER-positive RR = 1.17 [95% CI = 0.92 to 1.49]. For all patients combined, there was a 21% excess risk of mortality for African-Americans (RR = 1.21; 95% CI = 1.01 to 1.46).
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RRs from the lymph node-positive trials are shown in Fig. 2
. DFS was similar for those with both ER-negative (RR = 1.02; 95% CI = 0.88 to 1.18) and ER-positive (RR = 1.09; 95% CI = 0.90 to 1.32) tumors. Results for RFS were similar (not shown). African-American patients again had higher mortality risk (Fig. 2; ER-negative RR = 1.06 [95% CI = 0.90 to 1.25]; ER-positive RR = 1.46 [95% CI = 1.18 to 1.80]) and an 18% excess mortality risk overall (RR = 1.18; 95% CI = 1.03 to 1.34).
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Because mortality differences persisted despite similar outcomes with respect to breast cancer recurrence, we compared survival, treating deaths before documented breast cancer recurrence or second primary cancer as censored observations. These deaths are usually attributed to causes other than cancer (although patients with inadequately documented breast cancer recurrence may also be included in this category), and there were marginally more African-American women with these events in every study examined. Mortality outcomes did not differ significantly between African-Americans and Caucasians after these events were censored (RR = 1.08 [95% CI = 0.88 to 1.33] for lymph node-negative patients; RR = 1.09 [95% CI = 0.96 to 1.25] for lymph node-positive patients).
Treatment Efficacy Estimates
The proportional hazards models were used to evaluate whether there was a differential treatment response between African-Americans and Caucasians by adding model terms representing the interaction effect and evaluating these terms via likelihood ratio tests. In no case was a statistically significant interaction between race and treatment found.
To illustrate the potential magnitude of treatment efficacy among African-Americans and Caucasians, treatment comparisons were conducted separately in each group. These comparisons were confined to the individual trials (e.g., not among patients aggregated over trials) to avoid temporal or other biases that might be introduced from comparisons of treatment groups from different trials. Note that each of these comparisons is tantamount to a randomized trial comparison within race group, since patients entering the trials are randomly assigned equally irrespectively of race and since relevant covariates are balanced by treatment arm. For lymph node-negative patients, the addition of chemotherapy to surgery alone among ER-negative patients (B-13) resulted in an approximate 33% reduction in DFS events (Table 1. The advantage of CMF over the MF regimen among ER-negative patients (B-19) was apparent among Caucasians, while outcomes for African-Americans appeared to be similar with either treatment (a formal interaction test was not significant). For ER-positive patients, the addition of tamoxifen to surgery (B-14) conferred a benefit of roughly a 25%–35% reduction in events for both African-Americans and Caucasians. For the addition of chemotherapy to tamoxifen among ER-positive patients (B-20), both African-Americans and Caucasians benefited with respect to reduction in DFS events (Table 1. Results for survival were largely similar to those for DFS but with less precision in estimates because of the relatively good survival prognosis among lymph node-negative patients (not shown).
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Treatment efficacy comparisons for lymph node-positive patients were also similar between African-Americans and Caucasians (Table 2
. The AC regimen was found to be at least as efficacious as the conventional CMF regimen both overall and among African-Americans or Caucasians (B-15). The addition of AC to tamoxifen in older and largely ER-positive patients (B-16) was beneficial in both African-Americans and Caucasians. Increased and increased/intensified dose of cyclophosphamide in the AC regimen (B-22) did not improve outcomes overall or among Caucasians, and there was no evidence that African-Americans in particular benefited from this regimen (Table 2. Results for survival were similar (not shown).
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DISCUSSION |
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A number of studies (21,25,26 have found that, when disease stage and treatment are comparable, breast cancer prognosis for African-Americans and Caucasians is similar. Similarly, when disease stage and important socioeconomic variables, which are highly correlated with care access and quality, are comparable, breast cancer outcomes for African-Americans and Caucasians are similar (17,19). Residual differences noted in many studies (5,27,28,35 may be caused by disease features other than stage, such as lack of hormone receptors and presence of necrosis, that could impart increased recurrence risk for African-American women. Other, yet unidentified factors may also contribute to poorer outcomes for patients of specific racial/ethnic background. Most likely, these would be confined to additional tumor-specific features that may be more prevalent in some race groups, as have been identified previously.
Data presented here from a series of randomized clinical trials conducted during the last 20 years provide a unique opportunity to compare outcomes for patients with similar disease receiving the same care and, furthermore, offer an opportunity to evaluate treatment benefit among African-Americans, albeit with a smaller than desirable sample size, under random treatment assignment—the recognized "gold standard" for therapy development. Some drawbacks of clinical trial databases include both a lack of socioeconomic data that might be relevant to this question and the small number of women of many race groups. Even if proportionally representative sampling is achieved, then an approximate 9 to 1 ratio of Caucasians to African-Americans will be enrolled. Women of other ethnicity backgrounds have even less representation in actual numbers.
Main findings from this recent survey of trials consistently indicated equivalent DFS and RFS outcomes for African-Americans and Caucasians within trials and over studies, combined. However, a mortality deficit for African-American women was consistently seen, with an approximate 21% excess risk of mortality among lymph node-negative African-American patients and a 17% excess risk of mortality among lymph node-positive African-American patients. These deficits would translate to an absolute deficit in 5-year mortality, a commonly referenced landmark measurement in cancer survival, of 1.0%–2.0% for good-prognosis patients (e.g., those who are ER positive and lymph node negative), and of 4.0%–5.0% for patients with a less favorable disease (e.g., ER-negative, lymph node-positive patients). The Survival, Epidemiology, and End Results (SEER)1 program reports absolute differences in 5-year relative survival (survival corrected for age- and race-specific life expectancy) of 8% for localized disease and 14% for regional breast cancer (2). Chu et al. (36 studied recent trends in SEER breast cancer mortality among African-Americans and Caucasians, finding that mortality for African-American women leveled off in the middle 1980s for most age groups but has not, as yet, shown the decrease seen among Caucasian women. They speculate that this may be because of a delay in benefit from treatment advances and early detection rather than because of any intrinsic features of breast cancer in African-Americans. The differences in mortality between African-Americans and Caucasians seen among NSABP clinical trial participants who experienced comparable treatment are smaller than those reported in this population-based sample but are, nonetheless, important and warrants further investigation.
Previous results from patients participating in randomized clinical trials have also found generally similar outcomes among different race groups. The Cancer and Leukemia Group B compared characteristics and outcomes for African-Americans and non-African-Americans (Caucasians and others) participating in a trial of adjuvant chemotherapy for lymph node-positive breast cancer (22). The authors found African-Americans to be younger at diagnosis and to have larger tumors that were more often ER negative. Excess risk of death among African-Americans relative to non-African-Americans was reduced from 35% to 14% after taking into account these prognostic factor differences. Excess risk of DFS events for African-Americans was reduced from 24% to 7%. Analyses of patients participating in randomized trials of the Southwest Oncology Group and the Eastern Cooperative Oncology Group also found comparable outcomes between African-Americans and Caucasians (23,24).
Treatment benefits in the trials that we examined here appeared to be commensurate in African-American patients to those of Caucasians. Evidence of differential treatment effects (e.g., interaction between race and treatment group) was not apparent, although such analyses are hindered by low statistical power and, in any case, should be interpreted conservatively (37,38). Both African-American and Caucasian lymph node-negative patients benefited from the addition of chemotherapy or tamoxifen to surgery. Major trial findings among lymph node-positive patients were also similar between African-Americans and Caucasians. These findings are further supported by a recent study (39 of contralateral breast cancer incidence among patients (1212 African-American and 12 932 Caucasian) participating in any of nine NSABP trials evaluating treatment for ductal carcinoma in situ, stage I, or stage II breast cancer. In that study, patients who received tamoxifen, either as the primary test question in a trial or incidental to other trial requirements (e.g., some trials mandated tamoxifen for all patients 50 years of age), were compared with patients who did not receive tamoxifen with respect to contralateral breast cancer incidence. Both African-American and Caucasian patients receiving tamoxifen experienced an approximate 40% reduction in contralateral breast cancer relative to those who did not receive tamoxifen, a result comparable to that observed in NSABP B-14 (30 and the Breast Cancer Prevention Trial (40). While it has been clearly demonstrated that African-American women are more frequently younger at diagnosis and have less favorable tumor characteristics and thus, based on these characteristics, may more frequently qualify as candidates for systemic chemotherapy, it appears that their response to treatment is similar to that of the majority population on which these treatments have been largely developed. The prospect of sufficient racial homogeneity, at least among African-Americans, to result in profound differences in treatment response strictly on the basis of race once known prognostic disease features are accounted for seems to be diminishing, based on results of clinical and genetic epidemiologic studies (41–43).
Observational retrospective studies evaluating outcomes in equal-access health-care systems also suggest equal outcomes among African-American and Caucasian patient populations (21,25,26 or identify additional factors, such as socioeconomic status, that explain remaining outcome differences (44). Results of these studies indirectly provide evidence that, for patients treated in accordance with recommendations for their clinical and pathologic disease presentation, outcomes and extent of benefit among African-Americans and Caucasians are comparable, as seen in clinical trials. Studies of treatment patterns in these settings can also serve to evaluate the extent to which current treatment guidelines are observed in certain patient populations. In some cases, treatment was in accordance with recommended guidelines (45; in contrast, in others, treatment for older and African-American patients did not as frequently adhere to recognized standards (10,14).
The modest mortality deficit noted in these trials is consistent with that seen in other equal-care settings, where breast cancer-specific outcomes were comparable but mortality lagged for African-American women (46,47). In our studies, we speculate that differential background mortality may play a role, particularly in stage I disease, where breast cancer-specific survival prognosis is high. Data from the National Center for Health Statistics (48 indicate a deficit in life expectancy of about 6 years for African-American women, relative to Caucasian women. Even when early mortality is removed, for instance, by examining years of life left for women surviving to 50 years, there remains a shortage of nearly 3 years for African-American women. To what extent these influences might be reflected in comparisons of long-term mortality in clinical trials is unclear. Other studies (49,50 among cancer patients have suggested a significant influence of coexisting diseases on outcomes in terms of both death from competing causes and interference with effective cancer treatment. In the NSABP trials examined for this study, there was a consistent small excess of deaths in the absence of documented recurrence or second primary cancer among African-Americans, suggesting greater mortality from other causes. This was particularly apparent in the trials both among lymph node-negative patients, where breast cancer prognosis is more favorable and, thus, mortality from other causes is more prevalent, and among lymph node-positive patients with ER-positive tumors, who, in these studies, tended to be older and, thus, prone to greater mortality from other causes in addition to breast cancer. When these "death, no evidence of breast cancer" events were considered censored observations in survival comparisons, the excess risk of mortality for African-Americans was reduced to roughly 8%. Detailed, reliable cause of death information would need to be obtained to fully address this question, since studies (51,52 have indicated problems with using reported cause of death information from clinical trials without careful review. After this information has been obtained, the contribution of non-cancer deaths to observed mortality differences in these trials could be evaluated further. A second possible source of survival differences despite equal time to recurrence is shorter time to death following recurrence among African-Americans, as has been suggested in one study (46). This explanation merits further investigation and will require that that site of recurrence and other factors such as therapy following recurrence be considered. However, it seems unlikely that second-line therapy differences would be a major source of mortality disparities in the randomized clinical trial setting for the same reasons stated earlier.
In summary, African-American and Caucasian women diagnosed at comparable disease stage and appropriately treated tend to experience similar breast cancer prognosis. From the clinical trial data and studies from equal-care settings, it may be indirectly inferred that treatment benefits are comparable across race groups. However, important clinical and pathologic disease characteristics may place certain women at increased risk of poor outcome and warrant continued study of how and why these characteristics may be related to race. Clearly, more comprehensive studies of the growing U.S. populations of women of Asian and Hispanic heritage, as well as the increasingly urban American Indian population, are needed. While the demographic constitution of National Cancer Institute-sponsored clinical trials has been found to be generally representative of the incident cancer burden in the population for the major race classes studied (53), increased racial/ethnic diversity in clinical trial participation is desirable. More diverse participation will provide justification for extrapolating from trial results to the population as a whole, ensure dissemination of quality care in accordance with current treatment guidelines, and provide the necessary data for future investigations of the role of race in breast cancer prognosis and optimal treatment.
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NOTES |
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Supported by Public Health Service grant U10CA69651 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. 
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