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CA Cancer J Clin 2000;50:50-64
James J. Dignam, PhD
Abstract
This review explores factors potentially contributing to the disparity in survival
after breast cancer between African-American and Caucasian women in the United States. A
number of factors have been implicated as the cause of poorer survival for black women,
including clinical and pathologic features of the disease that are indicative of poor
prognosis, economic resource inequities, and differences in treatment access and efficacy.
The latter is explored in detail using data from the National Surgical Adjuvant Breast and
Bowel Project (NSABP), a nationwide multicenter clinical trials group for breast and
colorectal cancers.
Key studies into the disparity in breast cancer survival are reviewed according to
proposed principal determinants of poorer outcome for black women. Results among black and
white women participating in several randomized NSABP clinical trials are also presented.
Primary endpoints in those studies were clinical and pathologic disease characteristics at
study entry, time to disease progression or new cancers, and total survival time after
breast cancer diagnosis and treatment.
In most studies reported in the literature, the primary explanatory factor alone,
such as stage of disease at diagnosis, did not fully account for differences in outcome
between groups; when additional factors were taken into account, however, prognoses became
more similar. Results from the NSABP clinical trials similarly indicated that when stage
of disease and treatment were comparable, outcomes for blacks did not differ markedly from
those of whites.
In summary, black women, diagnosed at comparable disease stage as white women and
treated appropriately, tend to experience similar breast cancer prognoses and survival.
However, important clinical and pathologic disease characteristics may continue to place
certain women at increased risk of poorer outcome, and warrant continued study. The
opportunity for increased clinical trial participation by black women is encouraged. (CA
Cancer J Clin 2000;50:50-64.)
Introduction
Breast cancer is the most common malignancy among females in the United States. This
year, approximately 184,200 new cases of female breast cancer will be diagnosed, and more
than 40,000 deaths will be attributed to the disease.1 Although white
women have a higher incidence of breast cancer than blacks, mortality rates for black
women meet or exceed those of whites, indicating a poorer survival experience for black
women. Results from several large-scale cancer surveillance studies conducted over the
past few decades have confirmed this survival disadvantage.2-5
Data from the End Results Program of the National Cancer Institute found five-year
breast cancer survival rates adjusted for race and age-specific all-cause mortality
(called relative survival rates) of 47% for blacks and 64% for whites for the period
between 1960 and 1967, and 51% for blacks and 65% for whites between 1968 and 1973.2
Data from the Surveillance, Epidemiology, and End Results (SEER) program showed
improvement for both groups between 1973 and 1979, yet the survival deficit for blacks
remained.3
Figure 1
shows yearly age-adjusted breast cancer incidence and mortality rates for the period
from 1973 to 1996, reported by the SEER program.4 Rising incidence in
both groups and the greater incidence in whites over the period can be seen, as well as
equal or greater mortality for blacks from 1980 to 1994. The approximately 3% increase in
breast cancer mortality among all patients between 1980 and 1990 is in part due to an 18%
increase in mortality among blacks. Beginning in 1990, a trend towards declining mortality
overall and for white women is seen, as has been recently reported.5 It
should be noted, however, that mortality for black women has thus far largely remained
constant, with a small decline in mortality appearing after 1995.
This report presents historic and recent research concerning breast cancer prognosis
among black and white women, highlighting results from a large body of articles
investigating the complex web of clinical, pathologic, social, economic, and demographic
factors that may contribute to poorer outcomes for African-American women. Areas with
potential for intervention, such as early detection and adequate characterization of
disease stage and pathology, will be emphasized, and the role of clinical trials in
improving treatment for black women will be explained.
Research efforts towards understanding this problem will be described using data from
the National Surgical Adjuvant Breast and Bowel Project (NSABP), a large multicenter
clinical trials group that evaluates surgical, radiation, chemotherapy, and endocrine
treatments for breast and colorectal cancers.
Factors Implicated in Poorer Breast Cancer Prognosis Among Black Women
Factors potentially related to differential breast cancer prognosis for black and white
women are many and varied, and include clinical characteristics, biologic aspects of the
disease, socioeconomic status, and related health care factors. Historic and recent
literature regarding the influence of these factors on breast cancer survival for black
and white women are classified here into broad categories, although most studies
necessarily explore several factors concurrently.
Stage of Disease at Diagnosis
The stage of the primary breast cancer at diagnosis remains the foremost determinant of
ultimate outcome. Indeed, the benefit obtained from effective treatments is modest
compared with the predictive effect that disease stage has on prognosis. Patients with
metastatic breast cancer have a relatively poor prognosis, and even effective therapies
may add only months of life. In contrast, breast cancer that is confined to the breast and
axillary lymph nodes (node-positive breast cancer) is treatable in many cases, although
long-term prognosis for these patients is still markedly poorer than for women whose
disease is completely confined to the breast without evidence of lymph node involvement
(node-negative disease).
Data from many national surveys and health statistics sources have indicated that black
patients are more frequently diagnosed with a more advanced stage of breast cancer than
are white patients. Figure 2,
which is based on 1996 SEER program data, shows stage of disease at diagnosis and
indicates a greater proportion of higher-stage cases among black women.4
Numerous retrospective and prospective epidemiologic studies have confirmed this
observation.
The obvious question, therefore, is to what degree does difference in stage at
diagnosis alone account for poorer outcomes for black women? Secondary questions relate to
whether more advanced stage at diagnosis is wholly due to lack of access to or utilization
of health care resources—which would result in later detection of disease—or is due, in
part, to more aggressive forms of the disease being more common among black women.
Regardless of the reasons black women are more frequently diagnosed with later-stage
disease, many investigators have sought to determine whether outcomes are similar among
black and white patients of comparable stage. In most studies where black and white
patients with the same stage of breast cancer are compared, however, some residual
disparity in outcome remains and, for a given stage, black women more often exhibit
disease characteristics associated with poorer prognosis.6-11
In one of the largest studies that examined stage of disease at diagnosis, Natarajan
and colleagues used a portion of data from the 1982 American College of Surgeons National
Survey to analyze breast cancer survival by race.6 Data reported on
2,296 black and 24,265 white patients from 565 hospitals in a long-term survey, and on
1,571 black and 17,701 white patients in a short-term survey were included. Information
was obtained on demographic characteristics, disease stage and pathology, treatment, and
specific patient history, such as method of tumor discovery, menopausal status, use of
hormones, and family history.
Larger tumor size, greater nodal involvement, and estrogen receptor (ER)-negative
tumors occurred with greater frequency in black women. Outcomes for patients stratified by
nodal status showed significantly increased survival rates for whites. Race remained a
prognostic factor after taking into account stage, age, and tumor characteristics,
suggesting that black/white survival differences are only partially explained by
differences in stage and related factors.
A similar retrospective analysis of 2,322 white and 536 black patients, sampled from
female residents in metropolitan Atlanta with a diagnosis of breast cancer between 1978
and 1982, found that blacks were younger at diagnosis, had larger tumors, more nodal
involvement, and more advanced-stage disease.7 Among similarly treated
patients with advanced disease, survival rates for blacks were lower than for whites.
Among women with node-negative disease, blacks still had slightly lower survival rates.
More recent studies in women with early-stage disease have also demonstrated that
blacks with stageI disease had shorter times to recurrence and lower overall survival
rates than whites.8-10 Results from the National Cancer Institute's
Black/White Cancer Survival Study (BWCSS) indicated that among breast cancer patients from
three US metropolitan areas, stage at diagnosis only partially accounted for differences
in survival.11
A recent study using SEER data tracked breast cancer stage at diagnosis through the
1980s, finding a shift toward earlier stage at diagnosis, probably due to screening
efforts. Nevertheless, this trend differed by race, with black women remaining less likely
to be diagnosed at an early stage.12 A subsequent study examining
survival patterns showed that black women who were diagnosed at younger ages bore a higher
probability of dying of breast cancer within five years of the diagnosis. Since competing
causes of death are more prevalent at older ages, breast cancer takes its greatest
toll—in terms of years of life lost—on younger women. Several studies have demonstrated
that black women tend to be younger at diagnosis, and this study further illustrates
poorer outcomes for these women relative to whites of the same age.13
Like age, obesity has been identified as both a risk factor for breast cancer and a
contributing factor to poorer prognosis.14,15 In a recent study, obesity
was found to be more prevalent among black women with breast cancer, and was associated
with more advanced disease stage in both blacks and whites.16 These
findings were conjectured to be due to the effect of obesity on endogenous hormone levels,
which can also affect progression of the disease.17 Other potential
contributing factors have been suggested, such as greater difficulties in clinical
detection of breast disease in obese patients.
These and many other studies have shown that African-American women are more frequently
diagnosed with breast cancer at a more advanced stage, and that this stage difference is a
major factor in poorer prognosis for these women. It is also clear from most studies,
however, that some disparity exists after accounting for stage differences, and that
additional factors also contribute to outcome differences.
Disease Characteristics in Addition to Stage
In addition to disease stage, there are specific pathologic breast tumor
characteristics that may account for black/white differences in outcomes.
Hormone Receptors and Cell Differentiation
Among characteristics that differ in favor of whites are the presence of hormone
receptors on tumor cells and degree of cell differentiation. Estrogen receptors and
progesterone receptors, for example, are important both as independent indicators of
prognosis—with ER-negative tumors exhibiting more aggressive growth—and as a basis for
selecting treatment. Specifically, patients whose tumors are characterized as ER-positive
are candidates for the antiestrogen tamoxifen (or similar agents), while patients with
ER-negative tumors are often given chemotherapy.
Numerous studies have found differences in tumor ER- and progesterone-receptor (PR)
content between black and white patients, with black patients less frequently having ER-
and PR-positive tumors.6,10,17-20 A survey by the American College of
Surgeons found that 71% of whites had ER-positive tumors compared with only 58% of blacks.6
In a study of estrogen receptors, progesterone receptors, and pathologic features from
tissue samples of 146 black female breast cancer patients from Howard University Hospital,
poorly differentiated and ER-negative tumors were found more frequently than in the white
population at large.18
A comparison of estrogen and progesterone receptors among patients in Birmingham's
University Hospital found that blacks were significantly more likely to have ER- and
PR-negative tumors.19 Likewise, an analysis of participants in the NCI's
BWCSS found blacks significantly more likely to have tumor characteristics associated with
poor prognosis, such as lack of hormone receptors, high-grade nuclear atypia, and poorly
differentiated tumors, compared with whites with the same disease stage.20
A survey of tumor specimens submitted to the University of Texas again found that ER-
and PR-negative tumors with higher S-phase fraction were more common in black patients.17
And, one study has suggested that ER negativity is associated with a particularly high
risk for black patients, while for whites with ER-negative tumors and for all patients
with ER-positive tumors, outcomes were significantly more favorable.10
Results from these studies offer compelling evidence that other disease characteristics
contribute to poorer prognosis for black women, even when stage of disease is comparable.
However, comparability of stage and standard of treatment must be established before these
more subtle effects can be adequately evaluated.
Type and Quality of Screening/Treatment
Appropriate treatment for operable breast cancer, according to current recommendations
of consensus panels periodically convened by the National Institutes of Health or of
independent experts in the field, include surgery, with radiation therapy after
breast-conserving procedures, generally followed by some type of systemic treatment,
either hormonal therapy, chemotherapy, or a combination.21,22 In the
1980s, the recommendation for adjuvant therapy was first made for node-positive patients
only, and later was extended to node-negative patients with specific disease features. For
example, by the late 1980s, node-negative patients with ER-negative tumors were found to
benefit from chemotherapy while ER-positive patients were found to benefit from tamoxifen.
Two dimensions of the contribution of treatment to differences in prognosis can be
examined. First, some studies have investigated whether suitable care was provided
uniformly to black and white patients, including adequate diagnostic procedures and
therapy recommendations in accordance with national guidelines. Second, the question of
whether efficacy of established therapies differs by racial groups has been addressed, in
an attempt to identify a so-called treatment by race interaction.
With respect to treatment quality for breast cancer patients, McWhorter and Mayer23
investigated the relationship between race, treatment received, and survival using 36,905
cases from nine registries of the SEER program. Blacks were significantly less likely to
have received surgical treatment, which may have been partially due to the greater
prevalence of cases with inoperable, advanced disease. However, differences in treatment
persisted after adjustment for age, stage, and histology, possibly accounting for the
survival disadvantage in blacks noted in the SEER survey.
In a study evaluating quality of care for breast cancer patients among hospitals in
Illinois, late-stage diagnosis was more frequent in urban hospitals and among patients
with poor insurance coverage.24 More interesting was the observation
that omission of important diagnostic tests and radiation therapy was more frequent in
urban hospitals, suggesting a greater degree of nonstandard care in the urban facilities
examined. A prospective evaluation of treatment plans for stage II breast cancer patients
participating in the NCI's BWCSS found similar treatment recommendations for blacks and
whites, which were generally in accordance with national guidelines.25
However, a subsequent analysis of this same cohort revealed that certain aspects of care
differed according to factors such as age and race, with older and black patients less
frequently receiving treatment in accordance with recommended guidelines.26
Similar Care, Similar Outcomes
Studies in which comparable treatments were administered, such as in clinical trials or
single institution studies, tend to show similar outcomes between blacks and whites. A
recent study that followed 1,037 white and 481 African-American women who were uniformly
treated reported very similar outcomes, but continued to note that black women more
frequently had larger tumors and positive nodes, resulting in a small survival
disadvantage.27 Another study of black women treated for breast cancer
at the Cook County Hospital in Chicago found that node-negative patients treated
surgically had recurrence and mortality rates comparable to those published for white
patients treated elsewhere.28 In that study, black patients with
node-positive tumors who were treated with chemotherapy and/or tamoxifen achieved a degree
of benefit similar to that seen for white patients. A more recent study of blacks and
whites receiving comparable screening, treatment, and follow-up care through a large
metropolitan health maintenance organization showed similar breast cancer survival rates.29
Likewise, a large multicenter clinical trial evaluating chemotherapy for patients with
node-positive breast cancer found a similar benefit among black and white patients.30
Outcomes for black and white patients in NSABP clinical trials will be discussed later in
this report.
Access to Breast Cancer Screening
Some studies have specifically addressed the potential of improving access to breast
cancer screening to reduce disparity in outcomes. In a Health Insurance Plan of New York
study, participants were randomized to either a screening group where periodic
examinations were provided, or to a control group where patients received their usual care
with no particular emphasis on breast cancer screening.31 Five-year
relative survival rates indicated that mortality due to breast cancer was lower in the
screening group by nearly 40%, with white and black patients having roughly equal survival
rates. In the control group, however, mortality rates differed substantially by race.
In 1988, early results of a breast cancer screening program instituted in an urban
Chicago hospital showed a significant increase in the percentage of women receiving
mammograms, compared with the period prior to screening, when only 2% of the eligible
population received mammograms.32 Comparing early and late periods of
the breast screening implementation, a significant trend toward greater detection of
localized disease was seen. However, several issues remain to be resolved concerning
effective screening in this population, as recent studies have found differences in
mammographic screening rates that do not satisfactorily explain later-stage diagnosis
among African Americans.33,34 Similarly, delay in treatment-seeking or
delay in care caused by greater time from consultation to diagnosis and treatment
recommendation were not shown to be major contributing factors in stage differences
between blacks and whites.35,36 Regardless of the role of screening in
the past, as well as in time to detection, recent evidence shows significantly increased
mammography use rates in black women.37,38
Social and Economic Factors
In addition to treatment access, other economic and social factors related to health
status and health care utilization represent possible explanations for the disparity in
outcomes. A retrospective study of breast cancer patients treated at the Harlem Hospital
in New York City described a distinctly disadvantaged population compared with US blacks
nationwide and particularly compared with white patients.39
This dimension of the problem is most difficult to study, particularly in a
retrospective manner or from large databases, which record limited information beyond
disease status and ultimate outcome. Economic factors are often inferred from more general
information, such as census tract data. Detailed information about the health knowledge,
behaviors, and access to health care of individuals is not measured directly. Few studies
have directly ascertained factors related to poverty, education, delay in seeking and
accessing care, and fewer still have addressed factors related to social support and
coping.11,34,40
Two early studies that implicated socioeconomic status as a confounding factor in poor
survival for black women—one conducted among 4,618 white and 912 black patients treated
at the MD Anderson Cancer Center in Houston between 1949 and 1968, and the other from the
Medical College of Virginia among 515 white and 388 black breast cancer patients treated
between 1968 and 1977—found a strong association between race, low economic status, and
poor survival.41,42
Data from the Western Washington Cancer Surveillance System in Northwest Washington
state were used to study the effect of social class and race on breast cancer survival
among patients diagnosed between 1973 and 1983.43 Measures of
socioeconomic status, such as the percentage of individuals below the poverty level,
percentage of high school graduates, percentage of female-headed households, and other
indicators were developed for each patient's residence based on 1980 census block group
information. Results showed that race was not a predictor of survival after age, stage,
and social class indicator differences were taken into account.
In a similar study using 1990 census tract information to establish socioeconomic
measures for 1,132 white and 253 black patients with primary breast cancer diagnosed
between 1974 and 1985, socioeconomic status alone was highly predictive of survival and
disease-free survival, while race was not predictive after adjustment for socioeconomic
status and other factors.44
A 1986 study examined the relationships among income, stage at diagnosis, and race in
breast cancer cases reported to the New York State Cancer Registry between 1976 and 1981.45
A comparison of disease stage among 4,443 black and 47,198 white patients indicated that
blacks were more likely to present with regional or metastatic disease at time of
diagnosis. Black/white differences in disease stage by per capita income of the resident
county showed a significant association, with the disparity in stage being minimal among
women from higher income areas. A related study in 1990 that studied breast cancer in
higher income black women confirmed this association.46 Black women from
this higher income community were only about 1.15 times as likely as US whites to die from
breast cancer. Adjustment for age and other characteristics would be expected to further
reduce this rate.
Similar findings were obtained when data from the SEER program were examined according
to race and income status.47 A strong association between disease stage
at diagnosis and income level was noted, with black and white women of the same income
category having essentially similar stage distributions. A similar study conducted among
cases from the Connecticut Tumor Registry showed an association between socioeconomic
status—defined as percent high school graduates present in the relevant census tract—and
stage at diagnosis, and confirmed the finding that among women of higher socioeconomic
status, stage of disease at diagnosis was similar between blacks and whites.48
As might be expected, most indices of poverty are associated jointly with poor
prognosis and more advanced stage of disease at diagnosis, making it difficult to parse
out separate effects. These studies have drawn the anticipated conclusion that poverty
adversely affects cancer prognosis independently of racial status, and that economic and
resource equity would greatly contribute to an improved outcome for black women with
breast cancer. As Harold Freeman, MD, Chairman of the President's Cancer Panel, has noted,
race is largely a social rather than biologic construct in the US, and can serve as a weak
discriminant of outcome at best once its confounders are accounted for.49,50
Findings from NSABP Clinical Trials
NSABP studies, a series of multicenter randomized clinical trials administered by the
University of Pittsburgh since 1971, have evaluated many aspects of breast cancer
treatment, including surgical procedures, radiation therapy, chemotherapy, and endocrine
therapy. Findings from these studies have profoundly affected breast cancer care,
including the pioneering use of breast-conserving surgery and radiation (instead of
mastectomy) and the administration of adjuvant therapy across a spectrum of node-positive
and node-negative breast cancer patients both nationally and globally.
Using clinical trial data to assess differences in outcome among black and white
patients affords several advantages over other data sources. First, patients are
homogeneous with respect to disease stage at diagnosis, as defined in the protocol entry
criteria. Second, treatment is delivered in a uniform, quality-controlled manner. Third,
patients generally have minimal concurrent serious morbidity at study entry. Finally,
information about relevant features, such as estrogen content and size of the primary
tumor, allows consideration of important factors that contribute to prognosis. Such
studies also provide the opportunity to assess treatment efficacy among black patients
directly, albeit with a smaller than desirable sample, and to compare the magnitude of any
benefit with that seen among white patients. On the other hand, the use of clinical trial
data also involves some disadvantages, including a lack of detailed social and economic
data and the small numbers of African-American participants in many of the studies, as
well as the inherent danger in retrospectively examining trial results in patient subsets,
which may lead to spurious findings.51
Prognosis among Black and White Women in NSABP Surgical Trials
Protocol B-04: Radical versus Total Mastectomy
In the early 1970s, the NSABP conducted a trial (Protocol B-04) to evaluate different
surgical procedures for patients with breast cancer that may or may not have spread to the
axillary lymph nodes. The primary goal of the study was to determine whether there was any
additional benefit associated with radical mastectomy compared with total mastectomy,
which is a less extensive surgical procedure. The study also evaluated the role of
radiation therapy for node-negative patients who were treated with total rather than
radical mastectomy. Results of this study over the last 20 years continue to indicate no
difference in outcome between the less extensive and more extensive surgical procedures,
and have shown that radiation is effective in preventing local tumor recurrence.
Results of this trial were analyzed for differences in outcomes between the 191 black
and 442 white participants who had undergone radical mastectomy. This group was chosen
because information about nodal status, which was determined pathologically, was available
for these patients. Black patients were younger at diagnosis, had larger tumors, and were
more likely to have positive nodes. Moreover, pathologic features of tumors associated
with poor prognosis were found more frequently in black patients. For node-positive
patients, outcomes for black women were worse, with 45% surviving through five years,
compared with 61% of whites. Poorer prognostic factors for black patients accounted
partially for this difference, and the survival rate for blacks adjusted for prognostic
factor differences was within 10% of that for whites. Survival among node-negative
patients was similar for the two groups, with about 85% of both black and white patients
surviving for five years.
Protocol B-06: Lumpectomy + Radiation versus Total Mastectomy
In contrast, a subsequent NSABP study evaluating lumpectomy plus radiation compared
with total mastectomy (Protocol B-06) indicated a significantly poorer prognosis among
node-negative black women (74%) compared with white women (89%) at five years.9
Additional analyses indicated that tumors in black patients were more likely to exhibit
poor nuclear grade and other pathologic characteristics associated with less favorable
prognosis, and were less likely to be ER- and PR-positive. The somewhat contradictory
findings in these two surgical trials motivated a more detailed analysis of data from two
recent trials for node-negative breast cancer patients.
Prognosis Among Node-Negative Breast Cancer Patients Receiving Adjuvant Therapy
Until the late 1980s, patients with breast cancer that was completely confined to the
breast, with no evidence of spread to the lymph nodes, were considered to have
sufficiently good prognoses as to preclude the need for further therapy after surgery.
Results of clinical trials at the end of that decade, however, indicated that these
patients could benefit from additional systemic therapy.
Protocols B-13 and B-14: Surgery Alone versus Surgery + Chemotherapy or Tamoxifen
In 1982, two such trials were initiated by the NSABP. Protocol B-13, a trial for
patients with ER-negative tumors [<10 femtomoles(fmol)/mg cytosol protein], compared
surgical treatment alone with surgery plus 12 courses of sequential methotrexate and
fluorouracil (5-FU) (M*F). Protocol B-14 compared surgery plus placebo with surgery plus
long-term (five years) tamoxifen among patients with ER-positive tumors (>=10 fmol).
In 1996, results from these studies were analyzed to determine (1) whether there were
differences in prognoses between black and white patients, after controlling for
hormone-receptor status, treatment, and other pathologic and clinical factors; and (2)
whether blacks and whites similarly benefited from the systemic therapies administered.52
Endpoints for evaluation were overall survival (time to death from any cause) or
disease-free survival (time to breast cancer recurrence at any anatomic site; a new
primary cancer; or death from some other cause). Results from a total of 916 white and 108
black patients from Protocol B-13, and 3,709 white and 203 black patients from Protocol
B-14 were analyzed.
Examining patient characteristics at diagnosis, we found that among ER-negative
patients, black women more often had PR-negative tumors. Among ERpositive patients, blacks
were younger at diagnosis and had larger tumors. In both trials, blacks were more likely
to have been treated with total mastectomy than with lumpectomy and radiation.
When we looked at disease-free survival in ER-negative patients, 71% of blacks remained
event-free through five years, compared with 74% of white patients. Among ER-positive
patients, disease-free survival for blacks was comparable to that for whites, with 81% of
black patients and 80% of white patients remaining event-free at five years.
Survival for these patients was also similar. Among ER-negative patients, 83% of blacks
survived through five years, compared with 85% of whites. Among ER-positive patients, 93%
of blacks and 92% of whites were alive at five years. Estimated risk of breast cancer
recurrence or death, taking into account differences in tumor characteristics, was also
very similar.
Disease-free survival and survival by treatment group were estimated separately for
blacks and whites (Fig. 3).
Among patients with ER-negative tumors, five-year disease-free survival was 60%
for black patients treated with surgery alone and 80% for those receiving M*F. Among white
patients, five-year disease-free survival was 68% in the surgery-alone group and 76% for
M*F patients.
Among patients with ER-positive tumors, five-year disease-free survival was 79% for
blacks receiving placebo and 82% for blacks receiving tamoxifen. Among whites, 72% of
placebo patients and 83% of tamoxifen patients were event-free at five years. Results of
survival analyses by race and treatment group similarly showed an equal degree of
treatment benefit for black and white patients.
Results from Adjuvant Therapy Trials Involving Node-Positive Patients
Protocol B-09: Chemotherapy plus Tamoxifen
In 1987, we used data from an NSABP study (Protocol B-09) comparing the chemotherapy
drugs melphalan (L-PAM) plus 5-FU (PF) with L-PAM plus 5-FU and tamoxifen (PFT) to examine
survival outcomes for blacks and whites.53 One thousand forty-two (896
white, 146 black) stage II breast cancer patients accrued between 1977 and 1980 were
included. In the PF arm, unadjusted five-year survival rates were 52% for blacks and 68%
for whites, while in the PFT arm, 57% of blacks and 65% of whites were alive at five
years. Tumors tended to be larger among black patients, and ER-negative tumors were found
in 63% of black patients compared with 47% of white patients. Adjusted five-year survival
rates for blacks (57% for PF and 61% for PFT) were not significantly different from those
of whites, but still reflected slightly poorer survival after controlling for possible
confounding factors.
An examination of other chemotherapy trials for node-positive patients also indicated a
modest survival disadvantage for black patients, partially explained by baseline
characteristics associated with poorer prognosis. Where benefit was noted for a given
treatment regimen, black and white patients appeared to benefit equally over their
counterparts receiving the comparison regimen.
Discussion
Several studies have shown that when breast cancer stage of disease and treatment are
comparable, outcomes for African-American and white patients are largely similar.27-30
Likewise, when disease stage and socioeconomic status, which is correlated with quality of
care, are comparable, outcomes for black patients are greatly improved and resemble those
of whites.43,44,46 Residual differences noted in many studies may be due
to other factors, such as heterogeneity in disease features—which impart greater risk for
blacks, even after controlling for disease stage and treatment. Other, as yet unidentified
factors, may also contribute to poorer outcomes for some patients. Increasingly, however,
evidence from genetic epidemiology does not support the notion that there would be
sufficient racial homogeneity to expect profoundly distinct disease characteristics or
treatment response strictly on the basis of race.54
Results from our detailed study of node-negative breast cancer indicated that times to
disease recurrence and survival among blacks and whites in our clinical trials are
similar.52 Comparisons of treatment efficacy among blacks and whites
separately indicated that a similar benefit was achieved, particularly for ER-negative
patients. These results—combined with findings from other studies that support the
benefit of early breast cancer detection and show that black and white patients confined
to a similar stage and similarly treated have similar outcomes—suggest that early
detection, followed by appropriate therapy, could appreciably reduce the disparity in
outcome. On the other hand, comparisons of patient characteristics at diagnosis examined
in all of our studies confirm other findings that African-American women more frequently
have characteristics associated with poorer prognosis. Additionally, we noted small racial
disparities in outcome throughout the trials involving node-positive patients.
In the population at large, treatment quality remains an important concern with regard
to breast cancer prognosis for all women. Currently, treatment choice is made in
accordance with known indicators that place patients at particular risk, and so it is
vital that adequate clinical and pathologic characterization of the disease be performed
at diagnosis. It may be that more African-American women than white women of a given
disease stage will be found to be eligible for adjuvant chemotherapy, given our (as well
as those of others) observations that black women often have indicators of poor prognosis
at diagnosis. To reduce or eliminate differences in outcomes among these patients, it is
imperative that established therapies be uniformly delivered to all women in accordance
with their anticipated clinical prognoses.
We observed in our trials that, where either procedure was acceptable, black women were
much more likely to have received total mastectomy rather than lumpectomy with radiation
therapy. This finding may have many explanations, including lack of adequate radiation
therapy programs at institutions where black patients are treated; lack of resources,
time, and/or access to enable selection of radiation therapy as an option; preference on
the part of black patients; surgeon's preference; and numerous other factors.23,24,55,56
One study showed frequency of breast-conserving surgery to be related to higher income and
education, but not independently to race.54 While breast-conserving
surgery has been shown to be equivalent to more extensive procedures for managing breast
cancer, the lesser frequency of its use may be an indirect measure of other health care
indicators related to outcome, and requires further investigation.
At the time that the NSABP studies described in this report were accruing, no special
efforts were made to enhance participation of black patients. A tacit assumption when
examining black/white differences in these studies is that the randomized clinical trial
setting provides a degree of control for factors related to quality of care, since
treatment and follow-up care are carefully monitored.
In recent years, the NSABP and other clinical trial groups have undertaken programs to
increase participation of traditionally under-represented patients in randomized clinical
trials. Despite concerns about minority participation, a study of racial/ethnic
representation in NCI-funded clinical trials found participation of blacks and Hispanics
commensurate with their respective percentages in the general population.57
Nonetheless, changes mandated by Congress through the NIH Revitalization Act of 1993 have
brought about increased minority recruitment efforts at the NCI.58 Such
participation in randomized clinical trials may represent a way to offer better quality
care, while at the same time ensuring that study results can more appropriately be
generalized to the population of all women.
All federally funded clinical trials meet ethical standards that require that new
agents having potential benefit be compared against current standard therapy, so that
participants are assured of receiving the best proven therapy at a minimum, and may have
the opportunity to receive agents that are not available outside the clinical trial
setting. Quality assurance of treatment delivery is incorporated into the study design and
monitoring of such trials. A greater representation of African-American women in clinical
trials could serve both individual patients and the scientific community in its efforts to
answer the important public health question of why some women have poorer outcomes.
Despite these recommendations, there are often significant barriers to entry among
these women, including the failure of physicians to offer clinical trial participation and
reticence on the part of some patients, which is understandable given some of the
unfortunate historical events involving African-Americans and medical research in the US.59
Focused efforts by African-American scientists and community leaders will increase
awareness and lead to new approaches for improving this situation.60 In
addition to recruitment of minorities by clinical trial groups and other researchers,
investigators should continue to study—where feasible using existing databases—the
potential for increased risk of recurrence and death among black women with breast cancer.
Dr. Dignam is Research Assistant Professor in the Department of Biostatistics at the
Graduate School of Public Health, University of Pittsburgh, and Statistician, National
Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA.
References
1. Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer Statistics, 2000. CA Cancer J Clin
2000; 50:7-33.
2. Axtell LM, Myers MH: Contrasts in survival of black and white cancer patients,
1960-73. J Natl Cancer Inst 1978;60:1209-1215.
3. Young JL Jr, Ries LG, Pollack ES: Cancer patient survival among ethnic groups in the
United States. J Natl Cancer Inst 1984;73:341-352.
4. Ries LAG, Kosary CL, Hankey BF, et al. (eds): SEER Cancer Statistics Review
1973-1996. Bethesda, National Cancer Institute. Bethesda, MD, 1999.
5. Chu KC, Tarone RE, Kessler LG, et al: Recent trends in U.S. breast cancer incidence,
survival, and mortality rates. J Natl Cancer Inst 1997;88:1571-1579.
6. Natarajan N, Nemoto T, Mettlin C, et al: Race-related differences in breast cancer
patients: Results of the 1982 national survey of breast cancer by the American College of
Surgeons. Cancer 1985;56:1704-1709.
7. Bain RP, Greenberg RS, Whitaker JP: Racial differences in survival of women with
breast cancer. J Chron Dis 1986;39:631-642.
8. Pierce L, Fowble B, Solin LJ, et al: Conservative surgery and radiation therapy in
black women with early stage breast cancer. Cancer 1992;69:2831-2841.
9. Fisher ER, Redmond CK, Fisher B: Prognostic factors in NSABP studies of women with
node-negative invasive breast cancer. J Natl Cancer Inst Monogr 1992;11:151-158.
10. Crowe JP, Gordon NH, Hubay CA, et al: The interaction of estrogen receptor status
and race in predicting prognosis for stage I breast cancer patients. Surgery
1986;100:599-605.
11. Eley JW, Hill HA, Chen VW, et al: Racial differences in survival from breast
cancer: Results of the National Cancer Institute black/white cancer survival study. JAMA
1994;272:947-954.
12. Swanson GM, Ragheb NE, Lin CS, et al: Breast cancer among black and white women in
the 1980's: Changing patterns in the United States by race, age, and extent of disease.
Cancer 1993;72:788-798.
13. Swanson GM, Lin CS: Survival patterns among younger women with breast cancer: The
effects of age, race, stage, and treatment. J Natl Cancer Inst 1994;16:69-77.
14. Bernstein L, Ross RK: Endogenous hormones and breast cancer risk. Epidemiologic
Reviews 1993;15:48-65.
15. Coates RJ, Clark WS, Eley JW, et al: Race, nutritional status, and survival from
breast cancer. J Natl Cancer Inst 1990;82:1684-1692.
16. Jones BA, Stanislav KV, McCrea MG, et al: Severe obesity as an explanatory factor
for the black/white difference in stage at diagnosis of breast cancer. Am J Epidemiol
1997;146:394-404.
17. Elledge RM, Clark GM, Chamness GC, et al: 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.
18. Mohla S, Sampson CC, Khan T, et al: Estrogen and progesterone receptors in breast
cancer in black Americans. Cancer 1982;50:552-559.
19. Beverly LN, Flanders WD, Go RC, et al: A comparison of estrogen and progesterone
receptors in black and white breast cancer patients. Am J Public Health 1987;77:351-353.
20. Chen VW, Correa P, Kurman RJ, et al: Histological characteristics of breast
carcinoma in blacks and whites. Cancer Epidemiol Biomarkers 1994;3:127-135.
21. NIH Consensus Conference: Treatment of Early Stage Breast Cancer. JAMA
1991;265:391-395.
22. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International
consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst
1998;90:1601-1608.
23. McWhorter WP, Mayer WJ: Black/white differences in type of initial breast cancer
treatment and implications for survival. Am J Public Health 1987;77:1515-1517.
24. Hand R, Sener S, Imperato J, et al: Hospital variables associated with quality of
care for breast cancer patients. JAMA 1991;266:3429-3432.
25. Muss HB, Hunter CP, Wesley M, et al: Treatment plans for black and white women with
stage II node-positive breast cancer. Cancer 1992;70:2460-2467.
26. Breen N, Wesley MN, Merrill RM, et al: The relationship of socioeconomic status and
access to minimum expected therapy among female breast cancer patients in the National
Cancer Institute Black/White Cancer Survival Study. Ethn Dis 1999;9:111-125
27. Heimann R, Ferguson D, Powers C, et al: Race and clinical outcome in breast cancer
in a series with long-term follow-up evaluation. J Clin Oncol 1997;15:2329-2337.
28. Briele HA Jr, Walker MJ, Wild L, et al: Results of treatment of stage I-III breast
cancer in black Americans: The Cook County Hospital experience 1973-1987. Cancer
1990;65:1062-1071.
29. Yood MU, Johnson CC, Blount A, et al: Race and differences in breast cancer
survival in a managed care population. J Natl Cancer Inst 1999; 91:1487-1491
30. Roach M, Cirrincione C, Budman D, et al: Race and survival from breast cancer:
Based on Cancer and Leukemia Group B Trial 8541. Cancer J Sci Am 1997;3:107-112.
31. Shapiro S, Venet W, Strax P, et al: Prospects for eliminating racial differences in
breast cancer survival rates. Am J Public Health 1982;72:1142-1145.
32. Ansell DA, Dillard J, Rothenberg R, et al: Breast cancer screening in an urban
black population: A preliminary report. Cancer 1988;62:425-428.
33. Jones BA, Kasl SV, Curnen M, et al: Can mammography screening explain the race
difference in stage at diagnosis of breast cancer? Cancer 1995;75:2103-2113.
34. Hunter CP, Redmond CK, Chen VW, et al: Breast cancer: Factors associated with stage
at diagnosis in black and white women. Black/White Cancer Survival Study Group. J Natl
Cancer Inst 1993;85:112937.
35. Coates RJ, Bransfield DD, Wesley M, et al: Differences between black and white
women with breast cancer in time from symptom recognition to medical consultation.
Black/White Cancer Survival Study Group. J Natl Cancer Inst 1992;84:938-950.
36. Caplan LS, Helzlsouer KJ, Shapiro S, et al: System delay in breast cancer in whites
and blacks. Am J Epidemiol 1995;142:804812.
37. Frazier EL, Jiles RB, Mayberry R: Use of screening mammography and clinical breast
examination among black, Hispanic, and white women. Prev Med 1996;25:118-125.
38. Makuc DM, Breen N, Freid V: Low income, race, and the use of mammography. Health
Serv Res 1999;34:229-239.
39. Freeman HP, Wasfie TJ: Cancer of the breast in poor black women. Cancer
1989;63:2562-2569.
40. Reynolds P, Boyd PT, Blacklow RS, et al: The relationship between social ties and
survival among black and white breast cancer patients. Cancer Epidemiol Biomarkers
1994;3:253-259.
41. Vernon SW, Tilley BC, Neale AV, et al: Ethnicity, survival, and delay in seeking
treatment of breast cancer. Cancer 1982;53:1563-1571.
42. Dayal HH, Power RN, Chiu C: Race and socio-economic status in survival from breast
cancer. J Chron Dis 1982;35:675-683.
43. Basset MT, Krieger N: Social class and black-white differences in breast cancer
survival. Am J Public Health 1986;76:1400-1403.
44. Gordon NH, Crowe JP, Brumberg DJ, et al: Socioeconomic factors and race in breast
cancer recurrence and survival. Am J Epidemiol 1992;135:609-618.
45. Polednak AP: Breast cancer in black and white women in New York state. Cancer 1986;
58:807-815.
46. Polednak AP: Cancer mortality in a higher-income black population in New York
state. Cancer 1990;66:1654-1660.
47. Wells BL, Horm JW: Stage at diagnosis in breast cancer: Race and socioeconomic
factors. Am J Public Health 1992;82:1383-1385.
48. Farley TA, Flannery JT: Late-stage diagnosis of breast cancer in women of lower
socioeconomic status: Public health implications. Am J Public Health 1989;79:1508-1512.
49. Freeman HP: The meaning of race in cancer of the breast. Cancer J Sci Am
1997;3:76-77.
50. Freeman HP: Cancer in the socioeconomically disadvantaged. CA Cancer J Clin
1989;39:266-288.
51. Yusuf S, Wittes J, Probsfield J, Tyroler HA: Analysis and interpretation of
treatment effects in subgroups of patients in randomized clinical trials. J Am Stat Assn
1991;266:93-98.
52. Dignam J, Redmond CK, Fisher B, et al: Prognosis among African American women and
white women with lymph node-negative breast carcinoma: Results from two randomized trials
of the National Surgical Adjuvant Breast and Bowel Project. Cancer 1997;80:80-90.
53. Costantino JP, Redmond CK, Wickerham DL, et al: A comparison of survival between
white and black breast cancer patients: Results from NSABP B-09. Proc Am Soc Clin Onc
1987;6:230.
54. Owens K, Kin MC: Genetic views of human history. Science 1999;286:451-453.
55. Lazovich D, White E, Thomas DB, et al: Underutilization of breast-conserving
surgery with radiation therapy among women with stage I or II breast cancer. JAMA
1991;266:3433-3438.
56. Albain KS, Green SR, Lichter AS, et al: Influence of patient characteristics,
socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment
in women enrolled in adjuvant breast cancer studies: An analysis of two intergroup trials.
J Clin Oncol 1996;14:3009-3017.
57. Tejeda HA, Green SB, Trimble EL, et al: Representation of African-Americans,
Hispanics, and Whites in National Cancer Institute cancer treatment trials. J Natl Cancer
Inst 1996;88:812-816.
58. Watanabe ME: "Amid criticism, NCI tries to boost minority clinical-trial
recruitment." The Scientist (April 1) 1996;10:1,4-5.
59. Gamble VN: Under the shadow of Tuskegee: African-Americans and health care. Am J
Public Health 1997;87:1773-1778.
60. Brown KS: "Scientists, African American clergy join forces for trial
recruitment." The Scientist (February 17) 1997;11:1,10.
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