Abstract
Purpose
To evaluate the influence of race/ethnicity and tumor subtype in pathological complete response (pCR) following treatment with neoadjuvant chemotherapy.
Methods
2074 patients diagnosed with breast cancer between 1994 and 2008, treated with neoadjuvant anthracycline- and taxane-based chemotherapy, were included. pCR was defined as no residual invasive cancer in the breast and axilla. Kaplan-Meier product-limit was used to calculate survival outcomes. Cox proportional hazards models were fitted to determine the relationship of patient and tumor variables with outcome.
Results
Median age was 50 years, 14.6% patients were black, 15.2% Hispanic, 64.3% White, and 5.9% other race. There were no differences in pCR rates among race/ethnicity: (12.3% in black, 14.2% in Hispanics, 12.3% in whites and 11.5% in others, p=.788). Lack of pCR, breast cancer subtype, grade 3 tumors, and lymphovascular invasion were associated with worse RFS and OS (p≤.0001). Differences in RFS by race/ethnicity were seen in the patients with hormone receptor-positive disease, p=.007. In multivariate analysis, Hispanics had improved RFS (HR, 95% CI 0.69; 0.49-0.97) and OS (HR, 95% CI 0.63; 0.41-0.97); blacks had a trend to worse outcomes (RFS:HR, 95% CI 1.28; 0.97-1.68, OS:HR, 1.32; 95% CI; 0.97-1.81) when compared to whites.
Conclusions
In this cohort of patients, race/ethnicity was not significantly associated with pCR rates. In a multivariate analysis we observed improved outcomes in Hispanics and a trend towards worse outcomes in black patients, when compared to whites. Further research is needed to explore the potential differences in biology and outcomes.
Keywords: neoadjuvant chemotherapy, breast cancer, race, pathological complete response
Background
Breast cancer is the second most common cause of cancer death among women in the United States. In 2009 over 194,280 new cases will be diagnosed and is estimated that 40,610 deaths will occur1. Despite the reduction in mortality rates across all ethnic groups over time, clear survival disparities exist between women of different racial groups. Reports obtained from the Surveillance, Epidemiology, and End Results (SEER) Program show higher age-adjusted mortality rates for black women compared with white women, this disparity is present among women over and under age 50 years old 2. Several social, economical and biological factors have been extensively studied to explain the observed racial disparities 3-6. Compared to whites, young black women have higher incidence of triple-negative tumors, which could provide in part, the biological explanation of the poor prognosis seen in this group of patients 5, 7-9. Less information is available about Hispanics, but compared to whites, they appear to be more likely to have high grade cancers, triple-receptor negative disease, larger tumors and a greater number of positive lymph nodes at diagnosis 7, 10-12.
Neoadjuvant systemic therapy (NST), is the standard approach to treat women with locally advanced and inflammatory breast cancer, and is now being used in patients with earlier stage disease. By down-staging tumors; NST probably improves available surgical options while concurrently allowing for in vivo assessment of chemo-sensitivity. Furthermore, attaining a pathological complete response (pCR) following NST has been shown by a number of investigators to be a surrogate marker for improved long-term outcome, possibly due to the eradication of distant micrometastatic residual disease 13-19. A retrospective study from our institution demonstrated a survival benefit for patients who achieved a pCR compared with those that did not, regardless of hormone receptor status 20. Unfortunately, NST using conventional anthracyline and/or taxane-based regimens, results in pCR rates of only 8-31% 15, 17, 21, 22.
The purpose of this study was to determine the associations between race/ethnicity, pathological complete response (pCR), and survival outcomes following treatment with anthracycline and taxane-based neoadjuvant chemotherapy. We also aimed to explore whether differences in pCR according to race were present among the different tumor subtypes. The interaction between race/ethnicity and pCR, according to relapse free survival (RFS) or overall survival (OS) was also evaluated.
Methods
Patient Population
Patients treated with NST were identified in a prospectively maintained data base in the Breast Medical Oncology Department at The University of Texas, M. D. Anderson Cancer Center. Two thousand and seventy four female patients diagnosed withinvasive primary breast cancer between 1994 and 2008 and treated with anthracycline- and taxane-based NST were included. We excluded patients with metastatic disease at diagnosis, bilateral breast cancer, or males. The variables recorded included patient demographics (race, age, menopausal status), tumor characteristics (histology, grade, lymphovascular invasion, ER, PR and Her2 status), clinical stage at diagnosis (based on the criteria proposed by the American Joint Committee on Cancer Criteria version VI 23), type of surgery, pathological stage, and recurrence and survival information Race information was self-reported based on data derived from forms completed by the patient on her first visit to our institution. The race/ethnicity groups evaluated were white, black, Hispanic, and other. All pathology specimens were reviewed by dedicated breast pathologists at M.D. Anderson. Histologic type and grade were defined according to the WHO classification system 24 and modified Black’s nuclear grade system 25, respectively. All surgical breast and axillary lymph node specimens were reviewed centrally by dedicated breast pathologists to identify the presence or absence of residual disease. pCR was defined as no residual invasive cancer in both the breast and the axillary lymph nodes.
Treatment
All patients were treated with a multidisciplinary approach and they received NST with an anthracycline and taxane-based regimen. Taxanes administered included paclitaxel 175-250mg/m2 intravenously (IV) on day 1 every 21 days for four cycles; paclitaxel 80 mg/m2 weekly for 12 doses; or docetaxel 100mg/m2 IV on day 1 every 3 weeks for four cycles. Anthracycline regimens included 3 to 6 cycles of one of the following: fluorouracil 500mg/m2, epirubicin 100mg/m2 and cyclophosphamide 500mg/m2 IV on day 1, every 3 weeks; fluorouracil 500mg/m2 on days 1 and 4, epirubicin 75mg/m2 and cyclophosphamide 500mg/m2 IV on day 1, every 3 weeks (FEC 75); fluorouracil 500 mg/m2 IV on days 1 and 4, doxorubicin 50mg/m2 IV by continuous infusion over 72 hours and cyclophosphamide 500mg/m2 on day 1 every 3 weeks; or doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 IV on day 1, every 3 weeks. From the 468 patients with HER2-neu positive tumors, 55.6% (n=260) received neoadjuvant trastuzumab, 4mg/kg on day 1 followed by 2mg/kg weekly during 24 weeks, this regimen was given in combination with paclitaxel (225mg/m2 every 3 weeks or 80mg/m2 weekly) followed by FEC 75. In order to account for the effect of time in the selection of systemic therapy, we evaluated the distribution of the included patients according to their race/ethnicity by year of inclusion. After NST, all patients underwent definitive surgery. The decision for or against breast conserving surgery was made based on recommendation made by the multidisciplinary team and patient preferences. The Institution Review Board of The University of Texas, M. D. Anderson Cancer Center approved the study.
Statistical Analysis and Outcome Measures
We computed descriptive statistics. Patient characteristics were compared by pCR status and by race/ethnicity groups with a chi-square test or Wilcoxon’s rank sum test as appropriate. OS was calculated from the date of neoadjuvant chemotherapy response assessment (time of surgery) to the date of death or last follow-up. RFS was calculated from the date of neoadjuvant chemotherapy response assessment (time of surgery) to the date of first local or distant metastasis or last follow-up. Patients who died before experiencing a disease recurrence were considered censored at their date of death in the analysis of RFS.
Survival outcomes were estimated according to the Kaplan-Meier product limit method,and groups were compared with the log-rank test. Cox proportional hazards models were built to evaluate the association of pCR, race/ethnicity, and the interaction between the two, with survival outcomes after adjustment for other patient and disease characteristics. All variables that were significantly associated with race/ethnicity, pCR and/or overall survival (p<0.05) were considered for inclusion in the multivariable model. Test for interaction between race/ethnicity and pCR was evaluated in a model that included each of the survival outcomes. Age at diagnosis as a continuous variable, rather than menopausal status, was retained in the final model due to its clinical significance rather than statistical significance. Model selection was based on a backwards selection procedure where all variables of interest were included in a full model, and then variables were retained according to their two sided p-values (p< 0.05).
We also considered the effect of race/ethnicity on pCR rates and survival outcomes within the three different breast cancer subtypes defined by receptor status: hormone receptor positive (estrogen receptor or progesterone receptor positive and HER2-negative), HER2-positive (regardless of hormone receptor status), and triple receptor negative (hormone receptor and HER2 negative). Final model included breast cancer subtype, age at diagnosis, nuclear grade, lymphovascular invasion and stage. P-values less than 0.05 were considered statistically significant; all tests were two-sided. All analyses were performed using R 2.7.2 and SAS version 9.1, Cary (NC).
Results
Two thousand and seventy four patients were included, median age was 50 years (range 21-83). Three hundred and two (14.6%) patients were black, 316 (15.2%) Hispanic, 1334 (64.3%) white, and 122 (5.9%) of other race. Patients who were black or white tended to be post menopausal and have older age at diagnosis (p<0.0001), compared to those who were Hispanic or other race. Patients who were black tended to have higher clinical stage (p=0.004) and higher nuclear grade (p=0.0001), as well as triple receptor negative disease more frequently (p=0.003). Patient characteristics by race/ethnicity group are shown in Table 1.
Table 1.
Patient and Tumor Characteristics According to Race/Ethnicity
| Black | Hispanic | White | Other | P-Value | |||||
|---|---|---|---|---|---|---|---|---|---|
| N (302) | % | N (316) | % | N (1334) |
% | N (122) | % | ||
| Age at Diagnosis | |||||||||
| Median | 50 | -- | 47 | -- | 51 | -- | 47.5 | -- | <0.0001 |
| Menopausal Status | |||||||||
| Premenopausal | 124 | 41.06% | 172 | 54.43% | 534 | 40.03% | 72 | 59.02% | |
| Peri or Post | 175 | 57.95% | 141 | 44.62% | 794 | 59.52% | 50 | 40.98% | <0.0001 |
| Histology | |||||||||
| Ductal | 270 | 89.40% | 267 | 86.13% | 1078 | 80.81% | 107 | 87.70% | |
| Other | 32 | 10.60% | 43 | 13.87% | 256 | 19.19% | 15 | 12.30% | 0.0006 |
| Clinical Stage | |||||||||
| I | 7 | 2.32% | 9 | 2.85% | 63 | 4.72% | 1 | 0.82% | |
| II | 153 | 50.66% | 188 | 59.49% | 774 | 58.02% | 78 | 63.93% | |
| III | 142 | 47.02% | 119 | 37.66% | 497 | 37.26% | 43 | 35.25% | 0.004 |
| Nuclear Grade | |||||||||
| I | 2 | 0.66% | 7 | 2.22% | 57 | 4.27% | 4 | 3.28% | |
| II | 70 | 23.18% | 96 | 30.38% | 433 | 32.46% | 39 | 31.97% | |
| III | 218 | 72.19% | 210 | 66.46% | 803 | 60.19% | 79 | 64.75% | 0.0001 |
| Lymphovascular invasion | |||||||||
| Present | 78 | 25.83% | 85 | 26.90% | 370 | 27.74% | 28 | 22.95% | |
| Absent | 198 | 65.56% | 224 | 70.89% | 919 | 68.89% | 90 | 73.77% | 0.706 |
| Breast Cancer Subtype | |||||||||
| HER2 Positive | 59 | 19.54% | 80 | 25.32% | 297 | 22.26% | 32 | 26.23% | |
| Hormone Receptor | |||||||||
| Positive | 130 | 43.05% | 139 | 43.99% | 659 | 49.40% | 60 | 49.18% | |
| Triple Receptor Negative | 101 | 33.44% | 72 | 22.78% | 292 | 21.89% | 25 | 20.49% | 0.003 |
Two hundred sixty patients (12.5%) achieved a pCR. Compared to patients who did not achieved a pCR, those who did, tended to have higher nuclear grade disease (p<0.0001), no lymphovascular invasion (p<0.0001), and tumors that were HER2-positive or triple receptor negative (p<0.0001). There were no differences in pCR rates among racial/ethnic groups, 12.3% in black, 14.2% in Hispanics, 12.3% in whites and 11.5% in others (p=.788). When patients were stratified by tumor subtype, Hispanics seem to have higher pCR rates compared to whites, but this difference did not achieve statistical significance. Race/ethnicity was not significantly associated with obtaining a pCR within any of the receptor subgroups. pCR rates according to race and breast cancer subgroup are shown in Table 2.
Table 2.
Pathological complete response, and 5-year survival estimates by breast cancer subtype and race/ethnicity
| Pathological-Complete Response | Recurrence-Free Survival | Overall Survival | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Yes N (%) |
No N (%) |
P- value |
N Events |
5 Year Estimate |
95% Confidence Interval |
P- Value |
N Events |
5 Year Estimate |
95% Confidence Interval |
P- Value |
|
| All tumor subtypes | |||||||||||
| All | 260 (12.5) | 1814 (87.5) | 438 | 70.8 | (68.3, 73.5) | 327 | 75.7 | (73.1, 78.4) | |||
| Black | 37 (12.3) | 265 (87.7) | 90 | 60.2 | (53.0, 68.3) | 77 | 57.0 | (48.8, 66.5) | |||
| Hispanic | 45 (14.2) | 271 (85.8) | 52 | 75.8 | (69.6, 82.5) | 38 | 78.0 | (72.0, 86.5) | |||
| White | 164 (12.3) | 1170 (87.7) | 276 | 71.7 | (68.6, 74.9) | 201 | 78.9 | (75.1, 81.2) | |||
| Other | 14 (11.5) | 108 (88.5) | 0.788 | 20 | 75.7 | (66.1, 86.7) | <0.001 | 11 | 83.8 | (74.0, 94.8) | <0.001 |
| HER2 Positive | |||||||||||
| All | 106 (22.6) | 362 (77.4) | 99 | 70.6% | (65.3, 76.4) | 64 | 79.9% | (75.0, 85.0) | |||
| Black | 14 (23.7) | 45(76.3) | 17 | 60.0% | (45.5, 79.1) | 16 | 61.4% | (44.8, 84.0) | |||
| Hispanic | 20 (25.0) | 60 (75.0) | 13 | 74.9% | (61.8, 90.7) | 8 | 84.8% | (75.1, 95.6) | |||
| White | 63 (21.2) | 234 (78.8) | 65 | 70.6% | (64.3, 77.7) | 38 | 80.7% | (74.8, 87.1) | |||
| Other | 9 (28.1) | 23 (71.9) | 0.756 | 4 | 80.5% | (64.5, 100) | 0.157 | 2 | 95.8% | (88.2, 100) | 0.001 |
| Hormone Receptor Positive | |||||||||||
| All | 49 (5) | 939 (95.0) | 142 | 78.7% | (75.3, 82.2) | 95 | 83.90 | (80.5, 87.5) | |||
| Black | 6 (4.6) | 124 (95.4) | 27 | 70.2% | (60.0, 82.1) | 23 | 64.0% | (51.7, 79.3) | |||
| Hispanic | 8 (5.8) | 131 (95.2) | 11 | 86.1% | (78.4, 94.6) | 8 | 88.1% | (78.8, 98.5) | |||
| White | 35 (5.3) | 624 (94.7) | 97 | 78.6% | (74.6, 82.9) | 57 | 87.2% | (83.6, 91.0) | |||
| Other | 0 (0) | 60 (100) | 0.318 | 7 | 82.6% | (70.4, 96.9) | 0.007 | 7 | 74.0% | (58.0, 94.4) | <00001 |
| Triple Receptor Negative | |||||||||||
| All | 95 (19.4) | 395 (80.6) | 152 | 59.8% | (54.3, 65.9) | 134 | 57.8% | (51.8, 64.4) | |||
| Black | 17 (16.8) | 84 (83.2) | 39 | 51.2% | (38.7, 67.8) | 33 | 51.2% | (39.2, 67.0) | |||
| Hispanic | 15 (20.8) | 57 (79.2) | 17 | 68.4% | (55.1, 85.1) | 13 | 70.5% | (56.1, 88.5) | |||
| White | 59 (20.2) | 233 (79.8) | 88 | 60.2% | (53.4, 68.0) | 86 | 54.8% | (47.3, 63.5) | |||
| Other | 4 (16.0) | 21 (84.0) | 0.843 | 8 | 62.3% | (44.3, 87.6) | 0.151 | 2 | 91.3% | (80.5, 100) | 0.029 |
Median follow-up was 30 months (range 0–138 months). Among all patients, there were 438 recurrences (21.1%) and RFS at 5 years was 70.8% (95% CI 68.3%-73.5%). Fifty-seven patients died before experiencing a recurrence (35 whites, 9 Hispanic,12 black and 1 of other race). Patients who achieved pCR had longer RFS compared to patients who did not (91.44% versus 67.88% at the end of 5 years, p< 0.0001). 5-year unadjusted RFS estimates were 60.2% (95% CI 53.0-68.3) for blacks, 75.8% (95% CI 69.6-82.5) for Hispanics, 71.7% (95% CI 68.6-74.9) for whites and 75.7% (95% CI 66.1-86.7) for others, (p<.0001). pCR was associated with improved RFS regardless of race/ethnicity subgroup, and there was no evidence of an interaction between race/ethnicity and pCR. Figure 1 shows RFS by pCR groups for each of the race/ethnicity subgroups, and Table 2 shows RFS estimates. When looking at RFS rates by race, according to breast cancer subtype, no difference was seen between patients with HER2-positive tumors or with triple receptor negative tumors. However, amongst patients with hormone receptor-positive tumors the estimated percentage of patients alive and relapse free (RFS) at 5 years was lower for black patients (70.2%; 95% CI 60.0-82.1), compared with Hispanics (86.1%; 95%CI 78.4-94.6), whites (78.6%; 95% CI 74.6-82.9) and other (82.6%; 95% CI 70.4-96.9), p=0.007. In addition, amongst all patients, age older than 50 years (p=0.009), peri/postmenopausal status (p=0.019), hormone receptor positive disease (p<0.0001), early clinical stage (p<0.0001), low tumor grade (p<0.0001), and absence of lymphovascular invasion (p<0.0001) were associated with improved RFS.
Figure 1.
RFS and OS by pCR according to race/ethnicity.
There were a total of 327 deaths and overall survival at 5 years was 75.7% (95% CI 73.1%-78.4%). The results were similar to RFS except that menopausal status and age at diagnosis did not retain statistical significance. Table 2 shows the 5-year OS estimates. Patients who achieved pCR had better survival compared to those who did not (93.6% versus 73.21% at 5 years, p < 0.0001). The unadjusted 5-year OS estimates were 57% (95% CI 48.8-66.5) for blacks, 78% (95% CI 72.0-86.5) for Hispanics, 79%(95% CI 75.1-81.2) for whites and 84% (95% CI 74.0-94.8) for others, p<.0001. Figure 1 shows OS curves by pCR for each of the race/ethnicity subgroups, inspection of the curves indicates no interaction between pCR and race/ethnicity. When looking at OS by race according to breast cancer subtype, we observed that black patients had decreased crude rates of OS when compared to other races/ethnicities. Amongst patients with HER2-positive tumors, 5 year-OS rates were 61.4% (95% CI 44.8-84.0) in black, 84.8% (95% CI 75.1-95.6) in Hispanics, 80.7% (95% CI 74.8-87.1) in whites and 95.8% (95% CI 88.2-100) in other (p=0.001). The 5-year OS rates for patients with hormone receptor-positive tumors were 64.0% (95% CI 51.7-79.3) for blacks, 88.1%(95% CI 78.5-98.5) in Hispanics, 87.2% (95% CI 83.6-91.0) in whites and 74.0% (95% CI 58.0-94.4) in other races (p<0.0001). Amongst women with triple negative breast cancer the crude survival rates were 51.2% (95% CI 39.2-67.0) in blacks, 70.5% (95% CI 56.1-88.5) in Hispanics, 54.8% (95% CI 47.3-63.5) in whites and 91.3% (95% CI 80.0-100) in others (p=0.029). In Figure 2 the RFS and OS rates by race for each triple receptor subgroups are shown.
Figure 2.
RFS and OS by tumor subtype and race/ethnicity.
Table 3 shows the results of the multivariable models for RFS and OS. The final models include terms for race/ethnicity, pCR, breast cancer subtype, age at diagnosis, nuclear grade, lymphovascular invasion and clinical stage. The interaction of pCR and race/ethnicity was not statistically significant for RFS (p= 0.53) or OS (p=0.73), so it was not included in the final models. After adjustments were made, patients who achieved a pCR had a significantly decreased risk of both relapse (HR 0.22; 95% CI 0.13-0.36) and death (HR 0.18; 95% CI 0.10-0.34) as compared to patients who did not achieve a pCR. Compared to white patients, Hispanic patients had a 31% reduction in the risk of disease recurrence (HR 0.69; 95% CI; 0.49-0.97), black patients had a 28% increase in the risk of disease recurrence but this difference did not reach statistical significance (HR 1.28; 95% CI 0.97-1.68). For OS, compared to white patients, Hispanics had a 37% reduction in the hazard of death (HR 0.63; 95% CI 0.41-0.97), and black patients had a trend towards increase in the risk of death (HR 1.32; 95% CI 0.97-1.81). Patients of other race/ethnicities had no significant difference with white patients for both RFS and OS. In order to evaluate whether the observed differences in outcome were significantly affected by the small sample size, we built a multivariable model including the 1814 patients that did not achieve a pCR. Compared to white patients, Hispanics tended to have a reduction in the risk of recurrence (HR: 0.73; 95% CI 0.52-1.04), black patients tended to have and increase in the risk of recurrence of the same magnitude as the observed for the cohort of patients that achieved a pCR (HR 1.32; 95% CI 1.00-1.75). For OS, using white patients as a reference category, similar estimates were seen, but they did not reach statistical significance. (HR 0.67; 9% CI 0.43-1.57 and HR 1.32: 95% CI 0.95-1.82).
Table 3.
Multivariable Cox Proportional Hazards Models*
| HR | Recurrence-Free Survival 95% Confidence Interval |
P-value | HR | Overall Survival 95% Confidence Interval |
P-Value | |
|---|---|---|---|---|---|---|
| Age at Diagnosis (Continuous) | 0.99 | (0.99, 1.00) | 0.3 | 1.01 | (0.99, 1.02) | 0.29 |
| RACE | ||||||
| White | 1 | 1 | ||||
| Black | 1.28 | (0.97, 1.68) | 0.084 | 1.32 | (0.97, 1.81) | 0.082 |
| Hispanic | 0.69 | (0.49, 0.97) | 0.034 | 0.63 | (0.41, 0.97) | 0.035 |
| Other | 1.00 | (0.62, 1.62) | 0.99 | 0.80 | (0.42, 1.52) | 0.5 |
| pCR | ||||||
| No | 1 | 1 | ||||
| Yes | 0.22 | (0.13, 0.36) | <0.0001 | 0.18 | (0.10, 0.34) | <0.0001 |
| Breast Cancer Subtype | ||||||
| HER2 Positive | 1 | 1 | ||||
| Hormone Receptor Positive | 0.67 | (0.50, 0.90) | 0.007 | 0.83 | (0.58, 1.20) | 0.33 |
| Triple Receptor Negative | 1.78 | (1.36, 2.34) | <0.0001 | 2.82 | (2.02, 3.95) | <0.0001 |
| Clinic Stage | ||||||
| I | 1 | 1 | ||||
| II | 1.45 | (0.68, 3.10) | 0.340 | 0.75 | (0.39, 1.44) | 0.38 |
| III | 3.32 | (1.55, 7.12) | 0.002 | 1.97 | (1.01, 3.80) | 0.045 |
| Lymphovascular Invasion | ||||||
| Absent | 1 | 1 | ||||
| Present | 1.85 | (1.48, 2.30) | <0.0001 | 1.52 | (1.17, 1.99) | 0.002 |
| Nuclear Grade | ||||||
| I&II | 1 | 1 | ||||
| III | 1.33 | (1.02, 1.75) | 0.037 | 1.79 | (1.26, 2.54) | 0.001 |
No differences in the type of chemotherapy or proportion of patients receiving neoadjuvant trastuzumab according to race/ethnicity were seen. In order to account for the effect of time in the selection of systemic therapy, we evaluated the distribution of the included patients according to their race/ethnicity by year of inclusion. No difference in the race/ethnicity inclusion, according to 5 year cohorts, was observed.
Discussion
The aim of this study was to describe the effect of race/ethnicity and survival outcomes in patients with breast cancer treated with anthracycline and taxane-based chemotherapy. In this large, single-institution study, we show that pCR rates are not related to race. We did not find a significant association between race/ethnicity and the likelihood of achieving a pCR. Furthermore, achieving a pCR had a similar association with survival outcomes in each of the race/ethnicity subgroups. Consistent with other reports 20, 26, we showed that regardless of race, patients who achieved a pCR following anthracycline and taxane-based NST, had better RFS and OS compared to patients who did not achieving a pCR.
After adjustment for patient and disease characteristics, we found that Hispanic patients had significantly better RFS and OS compared to patients in other race/ethnicity groups. Black patients tended to have worse RFS and OS compared to patients in other race/ethnicity groups, but such difference did not achieve statistical significance. It is important to mention that black patients tended to have disease characteristics associated with worse prognosis; interestingly, the largest survival differences amongst blacks were seen in the hormone receptor-positive group. Limited data are available with regard to outcomes in Hispanic patients, however in a large population-based study that included 124,934 breast cancer patients, Li et al. 27 found that after adjusting for stage, hormone receptor status and surgical and radiation treatments, Hispanics had similar mortality rates compared to non-Hispanic whites (HR 1.1; 95% CI 0.8-1.3). Contrary results were found in black patients who tended to have worse outcomes (HR 1.5; 95% CI 1.4-1.6). Recent data from the SEER program2, show that from 2002-2006, the age U.S. adjusted overall mortality rates from breast cancer are lower for Hispanics (15.5/100,000) and higher for blacks (33.0/100,000) when compared with whites (23.9/100,000), similar estimates were observed when only looking at the 17 SEER areas. The improved health outcomes observed in Hispanic populations is a phenomenon described and referred to as the Hispanic Paradox. This term specifically refers to the epidemiological finding that Hispanics in the U.S. paradoxically tend to have substantially better health outcomes than the average population in spite of what their aggregate socioeconomic indicators would predict 28-31. The factors responsible for this observation are poorly understood. Even if underclassification of outcomes, migration, and acculturation play a role, it seems that unrecognized biological, environmental, cultural, and lifestyle factors could be important to understand these differences 30-33.
Several studies have shown that black women tend to present with more advanced stages at diagnosis and also have disease characteristics associated with worse outcomes, however it is likely that the differences in outcomes that have been described are result not only of differences in biology, but also differences in the patterns of care, socioeconomic and life style factors as well as access to health insurance and medical coverage 3-6, 8, 34, 35. Woodward et al. 36 explored the effect of race on survival in patients treated at M. D. Anderson Cancer Center on prospective clinical trials where all patients received anthracycline-based chemotherapy. Despite uniform distribution of treatment, black patients were found to have poorer survival, with no differences found between Hispanics and whites. They suggested that maybe biologic differences play a major role to the poor survival observed among black patients with breast cancer. Contrary, Bradley et al4., used data from the Detroit SEER program linked to Medicaid records to evaluate the association between race, breast cancer outcomes and socioeconomic factors. They found that the association between race and outcomes lost statistical significance after controlling for Medicaid enrollment and poverty, suggesting, that maybe the differences seen are not solely to be explained by biology. When we looked at the unadjusted 5 year-RFS and 5 year-OS rates, we observed interesting differences in outcome according to race, based on the tumor type, however there results need to be interpreted carefully as baseline differences in known prognostic factors exist. Black patients with hormone receptor- positive disease had worse RFS and OS rates compared to whites, potentially reflecting differences in further access to health care or coverage for medications prescribed in the adjuvant setting (i.e. tamoxifen or aromatase inhibitors); that may affect compliance. Although less clear, another possible contributing factor is a different percentage of black patients being poor CYP2D6 metabolizers 37, 38. Despite our short follow-up, similar results were very recently reported as part of a large randomized study. Sparano et al.39 analyzed the effect of race and tumor subtype in outcome. They included participants of clinical trial E1199 (n=4950), patients were treated with adjuvant anthracycline and taxane-based chemotherapy. With a median follow up of 95 months, and after adjusting for potential confounders, the authors observed that black patients with hormone receptor positive disease had worse DFS and OS compared to whites (HR 1.82; 95% CI 1.36-2.44 and HR 1.82; 95% CI 1.18-2.78 respectively).
Dawood el at26, in a data base analysis from our institution, explored the effect of race in pCR among patients with triple negative tumors. Three-year RFS and three-year OS rates were similar for the black group, compared with white/other race group. After controlling for patient and tumor characteristics, race was not significantly associated with RFS (HR, 95% CI 1.08; 0.69-1.68) or OS (HR, 95% CI 1.08; 0.69-1.68). Also, similar to our own results, no significant differences were observed when racial groups were divided according to pCR. We believe this is a very important observation, as it suggests that among different races, pCR is an important surrogate marker of improved long-term outcome.
Contrary results have been reported by Balmanoukian et al 40. In a restrospective analysis of 38 patients with triple receptor negative tumors treated with NST (33 of them received anthracycline and taxane-based NST), differences in outcome were observed according to race. With a median follow-up of 2.1 years, survival curves show shorter RFS and OS (p=.045 and .028 respectively) for African American women compared with white/other women. This difference in results is likely related to small sample size, different patient populations and differences baseline characteristics potentially not accounted for in the multivariable analysis. The report by Balmanoukian 40 serves to highlight the fact that results of single-institution retrospective studies need confirmation from larger multi-institutional prospective studies.
To appreciate the findings of our study, some strengths and limitations need to be addressed. To the best of our knowledge this is the largest study evaluating the effect of race/ethnicity in pCR in patients treated with anthracycline and taxane-based NST. Despite the retrospective nature of our analysis, the data base that we used was prospectively maintained. All the patients were treated at M.D. Anderson Cancer Center; allowing us to state with confidence that patients were treated with standard chemotherapy in a similar way, irrespective of their race, reducing any potential bias derived from differences in treatment. Race was self-reported and the only groups identified in our data base are black, white, Hispanic and other; therefore it is possible that considerable heterogeneity exists within each group. It is possible that some differences in outcome, did not achieve statistical significance when the analyses were made according to race and breast cancer subtype because of the small numbers of patients that achieved a pCR. Additionally, this cohort of patients received homogeneous NST and surgical treatments, although differences in follow up or compliance with subsequent therapy were not addressed. The median follow-up on our study was 30 months, this is potentially a limited follow-up time for the patients with hormone receptor positive tumors. It is possible that with longer follow-up some differences become evident.
In conclusion, this study makes the important observation that in this cohort of patients, race was not significantly associated with pCR rates in patients receiving anthracycline- and taxane-based NST. In a multivariate analysis we observed a trend towards worse outcomes in black patients, and also improved 5-year RFS and OS in Hispanics when compared to whites. Our observations need to be confirmed in a larger prospective study. Several questions remain unanswered regarding outcome differences amongst Hispanics and black patients, further epidemiological and molecular characterization of the tumors is needed in order to explore the potential differences in biology and outcomes.
Aknowledgments
This work was funded by NIH K23 CA121994, and Komen for the Cure Catalytic Award for Ana M. Gonzalez-Angulo.
Footnotes
Disclaimers: The authors have no potential conflicts of interest.
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