Although African American women have a lower incidence of. Histologic Grade, Stage, and Survival in Breast Carcinoma

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1 908 Histologic Grade, Stage, and Survival in Breast Carcinoma Comparison of African American and Caucasian Women Donald Earl Henson, M.D. 1 Kenneth C. Chu, Ph.D. 2 Paul H. Levine, M.D. 3 1 Department of Pathology, Office of Cancer Prevention and Control, The George Washington University Cancer Institute, Washington, DC. 2 Center to Reduce Cancer Health Disparities, National Cancer Institute, Bethesda, Maryland. 3 Department of Epidemiology and Biostatistics, The George Washington University School of Public Health and Health Services, Washington, DC. Supported by the Komen Foundation. Address for reprints: Donald Earl Henson, M.D., Department of Pathology, The George Washington University Medical Center, Ross Hall, Room 502, 2300 I Street, NW, Washington DC, 20037; Fax: (202) ; patdeh@gwumc.edu Received March 13, 2003; revision received May 1, 2003; accepted May 7, The opinions expressed herein do not necessarily reflect the views of the National Cancer Institute or the U. S. Government. *This article is a US Government work and, as such, is in the public domain in the United States of America. BACKGROUND. African American women have lower breast carcinoma survival rates than do Caucasian women. African American women often present with advanced-stage disease and more aggressive tumors as shown by histologic and laboratory-based prognostic factors. Aggressive tumor behavior may be responsible, at least in part, for the advanced stage and reduced survival rates. METHODS. The authors investigated the correlation between survival and histologic grade, stage of disease, and tumor size for both African American and Caucasian women who were younger than age 50 years and age 50 years and older. The authors also investigated the distribution of grade within each stage group and the distribution of grade by tumor size. African American and Caucasian women were matched by stage, tumor size, and histologic grade. Survival was represented by 6-year breast carcinoma specific survival rates. RESULTS. Compared with Caucasian women, African American women, regardless of age, had proportionally more Grade III tumors and fewer Grade I and II tumors for all stages combined and for each individual stage group. Similarly, matched for tumor size, African American women had more Grade III tumors and fewer Grade I and II tumors compared with Caucasian women, except for tumors smaller than 1.0 cm. For nearly all combinations of stage and grade regardless of age, the 6-year breast carcinoma specific survival rate was lower for African American women than for Caucasian women, although it did not always reach statistical significance. CONCLUSIONS. Compared with Caucasian women, African American women, regardless of age, presented with proportionally more aggressive tumors for each stage of disease and for each tumor size above 1.0 cm as revealed by the histologic grade. Higher histologic grade may be a significant contributing factor to survival disadvantage for African American women. Cancer 2003;98: Published 2003 by the American Cancer Society.* KEYWORDS: breast carcinoma, race, survival, histologic grade, stage, tumor size, African American women, Caucasian women. Although African American women have a lower incidence of breast carcinoma than Caucasian women (100.2 cases per 100,000 and cases per 100,000, respectively), African American women have a less favorable outcome than Caucasian women stage for stage. According to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the 5-year survival rates, all stages combined, for African American and Caucasian women are 69.0% and 84.4%, respectively. 1 Further evidence for this survival disadvantage is based on institutional studies of racial differences in outcome. 2,3 Published 2003 by the American Cancer Society* DOI /cncr.11558

2 Racial Differences in Histologic Grade/Henson et al. 909 FIGURE 1. Comparison of the proportional distribution of histologic grade for Caucasian women (white bars) and African American women (blue bars) younger than age 50 years, for all stages combined and for each stage. Patients were staged according to the American Joint Committee on Cancer TNM classification. Socioeconomic status (SES), lack of access to medical care, less utilization of screening, variations in treatment, comorbid conditions, lack of compliance with treatment recommendations, and late stage presentation have all been offered as explanations for the lower survival rates among African American women. 4 8 Although SES, even more than race, is considered by many the most important predictor of outcome, 5,9,10 studies continue to show that African American women present with more aggressive breast tumor types compared with Caucasian women In the current study, we investigated histologic grade as it relates to stage of disease, tumor size, and survival between African American and Caucasian women using data from the SEER program. The results indicate that aggressive tumor behavior as revealed by histologic grade should also be taken into account in studies on disparity. MATERIALS AND METHODS Data were obtained from the SEER program for the period January 1992 to December SEER covers 11 geographic areas: Atlanta, GA; Connecticut; Detroit, MI; Hawaii; Iowa; Los Angeles, CA; New Mexico; San Francisco Oakland, CA; San Jose Monterey, CA; Seattle Puget Sound; and Utah. These areas include approximately 12% of the U.S. population and represent national demographic patterns. Population based from inception, SEER has accrued data since 1973 in most survey areas through regional and statewide tumor registries. 1 Six-year cause-specific survival rates were calculated using death certificate data that listed breast carcinoma as the underlying cause of death. These disease-specific survival rates and standard errors were calculated for African American and Caucasian women using the SEER Public Use CD-ROM, 1973

3 910 CANCER September 1, 2003 / Volume 98 / Number 5 FIGURE 2. Comparison of the proportional distribution of histologic grade for Caucasian women (white bars) and African American women (blue bars) age 50 years and older, for all stages combined and for each stage grouping. Patients were staged according to the American Joint Committee on Cancer TNM classification. 1999, with its SEER*Stat 4.2 computer program. In situ cases (Stage 0) were excluded from the analysis. The number of cases recorded for each combination of grade and stage is listed in Tables 1 4. In the current study, Caucasian is used synonymously with white. All other racial/ethnic groups were omitted except for African American women. Staging was based on the TNM classification as published by the American Joint Committee on Cancer (AJCC) with four stages (Stages I IV). 14 Stage IV survival rates could not be determined for each grade for African American women. Histologic grade and tumor size were recorded from pathology reports. There were 4 categories for tumor size (i.e., 1.0 cm, cm, cm, and 5.1 cm, which corresponds to AJCC staging). To evaluate the effect of age, the study population was divided into 2 groups (younger than age 50 years and age 50 years and older). Methods for the statistical analyses of differences in stage distributions and differences in survival rates between Caucasian and African American women have been reported. 15 Corrections for multiple comparisons were used. RESULTS Distribution of Histologic Grade by American Joint Committee on Cancer Stage Figure 1 compares the grade distribution for African American and Caucasian women (younger than age 50 years) for Stages I IV combined, and for each individual stage, excluding cases of unknown grade. In general, Caucasian women had proportionally more Grade I and II tumors whereas African American women had a higher proportion of Grade III tumors for all stages combined and for each stage group. Figure 2 shows the distribution of grade for women

4 Racial Differences in Histologic Grade/Henson et al. 911 TABLE 1 Comparison of 6-Year Breast Carcinoma Survival Rates by Race, Grade, and American Joint Committee on Cancer Stage for Women Younger than Age 50 Years No. of patients 6-yr survival rate No. of White Black White Black Black/White survival rate difference AJCC Stages I IV Grade I IV 20, a Grade I Grade II a Grade III a Grade IV Unknown AJCC Stage I Grade I IV a Grade I Grade II Grade III Grade IV Unknown AJCC Stage II Grade I IV a Grade I Grade II a Grade III a Grade IV Unknown AJCC Stage III Grade I IV a Grade I Grade II Grade III a Grade IV Unknown AJCC Stage IV Grade I IV a Grade I 13 4 na na Grade II Grade III a Grade IV na na Unknown AJCC: American Joint Committee on Cancer; na: not available. a P value (two-sided) 0.01 (0.05/5). (age 50 years and older) for Stages I IV combined and for each stage. Again, African American women had proportionally more Grade III tumors and proportionally fewer Grade I and II tumors than Caucasian women did. For all stages combined (Figs. 1, 2), African American women had a significantly higher proportion of Grade III tumors than Caucasian women in both age groups. For Caucasian women younger than age 50 years, the proportion of Grade III tumors was significantly higher than the proportion of Grade II tumors. In contrast, for Caucasian women age 50 years and older, the proportion of Grade III tumors was significantly less than the proportion of Grade II tumors. However, this pattern was not seen among African American women. Among African American women age 50 years and older, the proportion of Grade III tumors was significantly higher than the proportion of Grade II tumors. Stage, Histologic Grade, and Survival For each combination of grade and stage, the 6-year disease-specific survival rate for African American

5 912 CANCER September 1, 2003 / Volume 98 / Number 5 TABLE 2 Comparison of 6-Year Breast Carcinoma Survival Rates by Race, Grade, and American Joint Committee on Cancer Stage for Women Age 50 Years and Older No. of patients 6-yr survival rate White Black White Black Black/White survival rate difference AJCC Stages I IV Grade I IV 58, a Grade I 11, a Grade II 26, a Grade III 19, a Grade IV Unknown 14, AJCC Stage I Grade I IV 31, a Grade I Grade II 14, a Grade III Grade IV a Unknown AJCC Stage II Grade I IV 21, a Grade I Grade II a Grade III a Grade IV Unknown AJCC Stage III Grade I IV a Grade I a Grade II Grade III Grade IV na na Unknown AJCC Stage IV Grade I IV Grade I na na Grade II Grade III Grade IV na na Unknown AJCC: American Joint Committee on Cancer; na: not available. a P value (two-sided) 0.01 (0.05/5). women younger than age 50 years was consistently lower than that for Caucasian women (Table 1). Although this observation did not reach statistical significance for every combination of grade and stage, it was observed in 11 of the 14 combinations that were analyzed (Table 1). The difference in survival was significantly smaller for African American women for Grade II and III tumors in Stages I IV combined (Table 1). It also was significantly smaller for all grades and stages combined (Table 1). African American women had significantly lower survival rates for Grade II and III tumors in Stage II, Grade III tumors in Stage III, and for Grade III tumors in Stage IV. For each combination of grade and stage, the 6-year disease-specific survival rate for African American women age 50 years and older was consistently lower than that for Caucasian women (Table 2). This difference did not reach statistical significance for every combination of grade and stage, but it was observed in 12 of the 13 combinations that were analyzed (Table 2). The difference in survival was significantly less for African American women for Grade II tumors in Stage I, for Grade II and III tumors in Stage II, and for Grade I tumors in Stage III (Table 2). It was also significant for all grades and stages combined.

6 Racial Differences in Histologic Grade/Henson et al. 913 FIGURE 3. Comparison of the proportional distribution of histologic grade for Caucasian women (white bars) and African American women (blue bars) younger than age 50 years, according to the size of the primary tumor. FIGURE 4. Comparison of the proportional distribution of histologic grade for Caucasian women (white bars) and African American women (blue bars) age 50 years and older, according to the size of the primary tumor. Distribution of Histologic Grade by Tumor Size The distribution of grade evaluated in correlation to tumor size is shown in Figures 3 and 4. For every size except tumors smaller than 1.0 cm, African American women had significantly more Grade III tumors in both age groups than did Caucasian women. Figures 3 and 4 also indicate that grade increases with tumor size in both African American and Caucasian women, regardless of age. For instance, for tumor size cm in women younger than age 50 years, 42% and 57% of Caucasian and African American women, respectively, had Grade III tumors. For tumor sizes 5.1 cm or larger, 63% of Caucasian women had Grade III tumors, compared with 78% of African American women. A similar observation was made for women age 50 years and older. Tumor Size, Histologic Grade, and Survival Tables 3 and 4 show, respectively, the 6-year breast carcinoma specific survival rates for each combination of tumor size and grade for women younger than

7 914 CANCER September 1, 2003 / Volume 98 / Number 5 TABLE 3 Comparison of 6-Year Breast Carcinoma Survival Rates by Race, Grade, and Tumor Size for Women Younger than Age 50 Years No. of patients 6-yr survival rate White Black Whites Blacks Black/White survival rate difference Tumor size 1.0 cm Grade I IV Grade I Grade II Grade III Grade IV na na Unknown Tumor size cm Grade I IV a Grade I Grade II a Grade III a Grade IV Unknown Tumor size cm Grade I IV a Grade I Grade II Grade III a Grade IV Unknown Tumor size 5.1 cm Grade I IV a Grade I Grade II Grade III a Grade IV Unknown na: not available. a P value (two-sided) (0.05/4). age 50 years and for women age 50 years and older. For all but 1 combination of size and grade (Grade IV, cm) in women younger than age 50 years, African American women had a less favorable outcome. DISCUSSION It has been known for years that histologic grade is correlated with survival in women with breast carcinoma. Greenough, 16 who defined three grades based on his analysis of eight histologic variables, reported the first studies in These variables included cell size, glandular formation, epithelial secretion, nuclear size, hyperchromatism, variation in size of the cell and nucleus, and mitotic activity. Since then, many investigators have confirmed the observations of Greenough Clinical trials and population studies have further confirmed the utility of grade as a prognostic factor The SEER data show that African American women have a less favorable 6-year causespecific survival than Caucasian women for nearly every combination of stage and grade, regardless of age. Although these differences did not reach statistical significance for most combinations, they were observed in 11 of the 14 combinations of stage and grade in women younger than age 50 years and in 13 of 14 combinations in women age 50 years and older. These results indicate that breast carcinoma survival rates for African American women are not only less favorable for all stages, they are also less favorable for nearly all combinations of stage and grade. For all stages, African American women, regardless of age, presented with proportionally more Grade III and fewer Grade I or II tumors compared with Caucasian women. This finding indicates that histologic grade, which is a reflection of aggressive tumors, may be an important factor in racial/ethnic disparity. Socioeconomic factors, access to care, less utilization

8 Racial Differences in Histologic Grade/Henson et al. 915 TABLE 4 Comparison of 6-Year Breast Carcinoma Survival Rates by Race, Grade, and Tumor Size for Women Age 50 Years and Older No. of patients 6-yr survival rate White Black White Black Black/White survival rate difference Tumor size 1.0 cm Grade I IV 15, a Grade I Grade II Grade III a Grade IV Unknown Tumor size cm Grade I IV 22, a Grade I Grade II 11, a Grade III Grade IV Unknown Tumor size cm Grade I IV 15, a Grade I Grade II Grade III a Grade IV Unknown Tumor size 5.1 cm Grade I IV a Grade I na na Grade II Grade III Grade IV na na Unknown na: not available. a P value (two-sided) (0.05/4). of screening, treatment differences, and late-stage presentation have been proposed as major causes of disparity. However, the results of the current study suggest that histologic grade also needs to be considered. Grade is evaluated at time of diagnosis and therefore reflects events occurring in the tumor before discovery and treatment. In malignant tumors, grade often correlates with aggressive behavior because higher-grade tumors usually show higher mitotic rates and, by definition, less differentiation. Previous studies have revealed that African American women are more likely to present with estrogen receptor negative tumors, higher S-phase fractions, and higher mitotic activity 12,13 factors usually associated with a less favorable outcome and more aggressive disease. These factors also correlate with higher-grade tumors. When the patterns of grade distribution were considered for all stages combined (Figs. 1, 2), differences were observed between African American women and Caucasian women. Combining stage groups merges all cases into a single group and enables an evaluation of the distribution of grade alone in the study population. For Caucasian women age 50 years and older, the proportion of Grade III tumors was significantly lower than the proportion of Grade II tumors, which differs from the finding for women younger than age 50 years. However, for African American women in both age groups, the proportion of Grade III tumors was significantly higher than the proportion of Grade II tumors. It probably is premature to speculate on the reasons for these different patterns, but they reflect the grade distribution in all stages. Similarly, for each tumor size, African American women consistently had reduced survival compared with Caucasian women. Although tumor size is part of the definition of stage, the data corroborate the reduced survival by stage in African American women. Additional comments should be made. Because

9 916 CANCER September 1, 2003 / Volume 98 / Number 5 the SEER data are derived from widely different areas of the country, pathology practice patterns (including the assignment of grade) will vary in these geographic areas. The assessment of grade is subjective and is a function of education and practice experience, which varies among institutions. However, despite these variations and lack of standardized grading criteria, the black-white differences in outcome were consistent within the combinations of stage and grade. Improved grading systems, such as the Nottingham Combined Histological Grade, have been recommended. 23 The Nottingham system not only provides uniform and quantitative data, it also provides measurements of differentiation, nuclear grade, and mitotic count, which are important parameters in the assessment of tumor aggressiveness. Published studies have shown that survival rates for Grade III and IV tumors are not statistically different. 24 As a result, most pathologists use only three grades for breast carcinoma, combining grades III IV. For this reason, the term grades III IV often is used in the literature to indicate that some pathologists still use Grade IV. Nonetheless, the data clearly indicate that African American women have a less favorable grade distribution at diagnosis for all stages compared with Caucasian women, even when Grade III and Grade IV tumors were combined. Whereas low SES and/or lack of screening may account for late-stage disease and larger tumor size at presentation, it is not so obvious that low SES or lack of screening accounts for the higher-grade tumors seen in African American women compared with Caucasian women. Although all pathologists will agree that high tumor grade indicates a more aggressive type of tumor, grade and other prognostic factors have not been considered a function of delayed diagnosis or lack of screening in contrast to stage and tumor size. Others have observed a higher proportion of Grade III IV breast tumors among African American women compared with Caucasian women. 11,12,25 27 Our data not only confirm these observations but also indicate that higher-grade tumors are found in all stages of breast carcinoma among African American women. For this reason, efforts to detect early-stage disease through screening, although improving survival, may not eliminate the survival disparity because of the higher-grade disease already present in Stage I and II among African American women. REFERENCES 1. Ries LAG, Eisner MP, Kosary CL, et al. SEER cancer statistics review, Bethesda: National Cancer Institute, Siegel R, Blacklow B, Schwartz A. 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