Abstract

BACKGROUND.
Tumor markers are becoming increasingly important in breast cancer research because
of their impact on prognosis, treatment, and survival, and because of their relation to
breast cancer subtypes. The triple-negative phenotype is important because of its
relation to the basal-like subtype of breast cancer.
METHODS.
Using the population-based California Cancer Registry data, we identified women
diagnosed with triple-negative breast cancer between 1999 and 2003. We examined
differences between triple-negative breast cancers compared with other breast cancers in
relation to age, race/ethnicity, socioeconomic status (SES), stage at diagnosis, tumor
grade, and relative survival.
RESULTS.
A total of 6370 women were identified as having triple-negative breast cancer and were
compared with the 44,704 women with other breast cancers. Women with triple-
negative breast cancers were significantly more likely to be under age 40 (odds ratio
[OR], 1.53), and non-Hispanic black (OR, 1.77) or Hispanic (OR, 1.23). Regardless of
stage at diagnosis, women with triple-negative breast cancers had poorer survival than
those with other breast cancers, and non-Hispanic black women with late-stage triple-
negative cancer had the poorest survival, with a 5-year relative survival of only 14%.
CONCLUSIONS.
Triple-negative breast cancers affect younger, non-Hispanic black and Hispanic women
in areas of low SES. The tumors were diagnosed at later stage and were more
aggressive, and these women had poorer survival regardless of stage. In addition, non-
Hispanic black women with late-stage triple-negative breast cancer had the poorest
survival of any comparable group. Cancer 2007. 2007 American Cancer Society.
Breast cancer is the most common cancer among
women in California, accounting for approximately
one-third of newly diagnosed cancers.1 Racial
disparities in breast cancer outcomes have been well
documented,27 with African American women having
a lower incidence of breast cancer compared with
whites but a higher overall mortality.2, 8 In California
the relative burden of invasive breast cancer varies by
age and by race/ethnicity. Thus, breast cancer
comprises nearly one-quarter (24.4%) of all new
invasive cancers in black women aged 20 to 29 years,
whereas it only represents 9.1% in non-Hispanic
whites. Similarly, average age-adjusted mortality rates
for African American women less than 50 years of age
are reported at 11.9 deaths per 100,000, or nearly twice
the rate in non-Hispanic whites (6.0 deaths per
100,000). Even after age 50, black women continue to
have the highest mortality rate.2
Determination of estrogen receptor (ER) status of
invasive breast carcinoma is useful as a prognostic and
predictive factor and has become standard practice in
the management of this neoplasm. ER positivity
predicts for response to endocrine therapy such as
antiestrogen (tamoxifen) administration or ovarian
suppression. Similarly, human epidermal growth factor
receptor 2 (HER2) positivity is useful for selecting
targeted therapy with monoclonal antibody
(trastuzumab) against HER2. Recently, microarray
profiling of invasive breast carcinoma has identified 5
distinct subtypes of morphologically similar breast
cancers (luminal A, luminal B, normal breast-like,
HER2-overexpressing, and basal-like).9 The basal-like
subtype, accounting for about 15% of breast cancer
cases and characterized by negativity for ER,
progesterone receptor (PR), and HER2, is associated
with aggressive histology, poor prognosis, and
unresponsiveness to the usual endocrine therapies,
shorter survival, and BRCA1-related breast cancer.9
12
Because basal-like breast cancers are ER-, PR-, and
HER2-negative, they are sometimes called triple-
negative, although it should be noted that only about
85% of triple-negative phenotypic breast cancers are
deemed to be basal-like when tested by appropriate
immunohistochemical means.13, 14 To help develop
treatment strategies for this subtype of breast cancer,
we undertook the present study to better characterize
the triple-negative phenotype with respect to age,
race/ethnicity, socioeconomic status, and survival.
MATERIALS AND METHODS
Case Identification
Data included in this study were identified using the
California Cancer Registry (CCR), a population-based
registry composed of 8 regional registries collecting
cancer incidence and mortality data for the entire
population of California. A state law passed in 1985
mandated the reporting of all newly diagnosed cancers
in California, and statewide implementation began
January 1, 1988. Cases are reported to the Cancer
Surveillance Section of the California Department of
Health Services from hospitals and any other facilities
providing care or therapy to cancer patients residing in
California.15
First primary cases of invasive, female breast cancer
(ICDO-3 sites C50.0-C50.9)16 diagnosed between
January 1, 1999, and December 31, 2003, and reported
to the CCR as of April 2006, are presented in these
analyses. A case was defined as triple-negative if ER,
PR, and HER2 were negative and the remaining breast
cancer cases, where tumor marker status was known,
were defined as other breast cancers.
The CCR requires the collection of tumor marker
information from the medical record on the status of
ER and PR for breast cancers diagnosed on or after
January 1, 1990, and the status of HER2 for breast
cancers diagnosed on or after January 1, 1999.15 ER
and PR status are recorded according to the
pathologist's interpretation of the assays. ER and PR
are considered negative if immunoperoxidase staining
of tumor cell nuclei is less than 5%. ER and PR status
can also be determined by examining cytosol protein.
ER is considered negative if there are fewer than 3
femtomoles per milligram of cytosol protein and PR is
considered negative if there are fewer than 5
femtomoles per milligram of cytosol protein.17 HER2
was assessed through immunohistochemistry (IHC) or
fluorescence in situ hybridization (FISH). IHC is
scored on a qualitative scale from 0 to 3+, based on
interpretation of staining intensity, with 0 and 1+
classified as negative, 2+ as borderline, and 3+ as
positive.18 FISH is scored on a quantitative scale with
less than 2 copies of the HER2 gene classified as
negative.19
Variables
Race/ethnicity was classified into 4 mutually exclusive
categories of Asian-Pacific Islander, Hispanic, non-
Hispanic black, and non-Hispanic white. Race/ethnicity
was based on information obtained from the medical
record, which can be derived from patient self-
identification, assumptions based on personal
appearance, or inferences based on the race/ethnicity of
the parents, birthplace, surname, or maiden name.
Hispanic ethnicity was based on information from the
medical record and computerized comparisons to the
1980 US census list of Hispanic surnames. Patients
identified as Hispanic on the medical record, or patients
identified as white, black, or of unknown race with a
Hispanic surname were classified as Hispanic. Cases
with unknown race/ethnicity, age, or sex were excluded
from these analyses.
Quintile of socioeconomic status (SES) was derived
from a principle component analysis using data from
the 2000 US census.20 SES was assigned at the census
block group level (2000 US census) and based on
address at time of initial diagnosis as reported in the
medical record.
Stage at diagnosis was collected from the patient's
medical record and coded according to the American
Joint Commission on Cancer (AJCC) Cancer Staging
Manual, 6th ed.21 The CCR collected Surveillance,
Epidemiology, and End Results (SEER) extent of
disease (EOD)22 for breast cancer cases diagnosed
from 1988 through December 2004. EOD was
converted to AJCC stage at diagnosis using SEER
guidelines.23 For logistic regression and survival
analyses, stage III and stage IV were combined owing
to small cell counts. Tumor grade was collected from
the medical record and coded according to ICDO-
3.16 Tumor size in millimeters was collected from the
medical record according to SEER EOD.22
Statistical Analysis
Proportions and 95% confidence intervals (CI) were
calculated for age, race, SES, and tumor characteristic
comparisons, including AJCC stage and tumor grade. T-
tests were used to detect differences in average age and
tumor size between the 2 breast cancer groups. Tests of
independent proportions were used to detect
differences for age group, race, SES, AJCC stage, and
tumor grade.24 Bivariate and multiple logistic
regression analyses were performed to calculate odds
ratios (OR) and 95% CIs for demographic differences
between triple-negative breast cancers and other breast
cancers. ORs from the multiple logistic regression were
adjusted for age, race, SES, AJCC stage, and tumor
grade. Counts and 5-year relative cumulative survival,
a type of overall survival, were calculated using
SEER*Stat 6.1.4. The actuarial method was used for
relative survival calculations. SAS (Cary, NC) 9.1.3
was used for logistic regression analyses.
RESULTS
Of the 92,358 women with first primary breast cancer
diagnosed between 1999 and 2003, 51,074 (55.3%)
were found to have the 3 markers and 41,284 (44.7%)
were missing 1 or more of the markers. We performed
2 sets of analyses, first comparing triple-negatives to
other breast cancers with known tumor marker status,
and second comparing triple-negatives to other breast
cancers including cases with at least 1 unknown tumor
marker. The bivariate and multivariate comparisons
were nearly identical, with no differences in statistical
significance with regard to median age, age groupings,
stage, race/ethnicity, SES, and overall relative 5-year
survival. Only those cases with known tumor marker
status were included in these analyses. The triple-
negative phenotype was observed in 6370 (12.5%) of
the eligible breast cancer cases, and the remaining
44,704 cases were classified as other breast cancers.
Table 1 shows the demographic characteristics of the
51,074 women with known tumor marker status. The
median age at diagnosis for the triple-negative group
was 54 years, significantly less than 60 years for the
other breast cancer group. Approximately 63% of
women with triple-negative breast cancer were
diagnosed before age 60, whereas fewer than half of
women with other breast cancer were diagnosed in that
age range. Although the majority of women with breast
cancer were non-Hispanic white, a smaller proportion
(62%) was observed among the triple-negative group
when compared with women with other breast cancers
(73%). The percent of non-Hispanic black women
among the triple-negative group was twice that of the
other breast cancer group (P < .001). The proportion of
Hispanic women in the triple-negative group was also
significantly higher than the proportion in the other
breast cancer group. No significant difference was
noted for Asian-Pacific Islanders. In addition, one-
quarter of non-Hispanic blacks (24.6%) were found to
have the triple-negative phenotype, whereas the percent
of non-Hispanic whites or Asian-Pacific Islanders with
triple-negative features was low, 10.8% and 11.7%,
respectively (data not shown). Hispanics were
intermediate at 17.2%.
Table 1. Characteristics of Invasive Breast Cancer Cases in Women in California With Known
Tumor Marker Status, 19992003
 Other breast cancers
Triple negative N = 6370
N = 44,704
Characteristics P*

No. (%) No. (%)

SES indicates socioeconomic status.

*
t-tests were used to test for differences in means for age and tumor size, and tests of independent proportions were used to test for differences
race, SES, stage, and grade.

Total 6370 44704

Age at diagnosis, median 54 60 <.001

<40 778 (12.2) 2534 (5.7) <.001

4049 1553 (24.4) 8359 (18.7) <.001

5059 1690 (26.5) 11,415 (25.5) .192

6064 1108 (17.4) 9616 (21.5) <.001

7079 817 (12.8) 8671 (19.4) <.001

80 424 (6.7) 4109 (9.2) .027

Race/ethnicity

Non-Hispanic white 3959 (62.2) 32,712 (73.2) <.001

 Other breast cancers
Triple negative N = 6370
N = 44,704
Characteristics P*

No. (%) No. (%)

Non-Hispanic black 636 (10.0) 1951 (4.4) <.001

Hispanic 1187 (18.6) 5714 (12.8) <.001

Asian/Pacific Islander 537 (8.4) 4043 (9.0) .319

Other 51 (0.8) 284 (0.6) .44

SES

SES 1, Low 830 (13.0) 4344 (9.7) <.001

SES 2 1180 (18.5) 6701 (15.0) <.001

SES 3 1345 (21.1) 8969 (20.1) .2

SES 4 1479 (23.2) 11,014 (24.6) .116

SES 5, High 1536 (24.1) 13,676 (30.6) <.001

Tumor size in mm, median 22 17 <.001

AJCC stage at diagnosis

 Other breast cancers
Triple negative N = 6370
N = 44,704
Characteristics P*

No. (%) No. (%)

Stage I 2088 (32.8) 20,439 (45.7) <.001

Stage II 3099 (48.6) 17,919 (40.1) <.001

Stage III 686 (10.8) 3016 (6.7) .001

Stage IV 248 (3.9) 1440 (3.2) <.001

Unknown 249 (3.9) 1887 (4.2) .409

Tumor grade

Well differentiated 195 (3.1) 10,091 (22.6) <.001

Moderately differentiated 1003 (15.7) 18,786 (42.0) <.001

Poorly differentiated 4526 (71.1) 11,825 (26.5) <.001

Undifferentiated 333 (5.2) 773 (1.7) .004

Unknown 313 (4.9) 3229 (7.2) .039

Among both groups of women the percent of all breast

cancers increased as SES increased, although women
with triple-negative breast cancer had a larger
proportion diagnosed in areas of low SES. Stage at
diagnosis was significantly different between the 2
groups, with the triple-negative patients presenting at a
more advanced stage. Median tumor size was
significantly larger for the triple-negative group (22
mm versus 17 mm, P < .001). The vast majority of
triple-negative breast cancers (76%) were classified as
poorly differentiated or undifferentiated, whereas only
28% of the other breast cancer group were so
categorized (P < .001).
Table 2 shows the adjusted ORs and 95% CIs from the
multiple logistic regression analyses for patient
demographics of triple-negative breast cancers
compared with other breast cancers. The odds of
having triple-negative breast cancer increased with
younger age, with women less than age 40 being 1.53
times more likely than 60 to 69-year-olds to be
diagnosed with triple-negative breast cancer. Non-
Hispanic black women were nearly twice as likely to be
diagnosed with triple-negative breast cancer when
compared with non-Hispanic whites, and Hispanic
women were slightly more likely to be diagnosed with
triple-negative breast cancer. Compared with women
living in areas of the highest quintile of SES, women
living in areas of lower SES were more likely to be
diagnosed with triple-negative breast cancer than other
breast cancers. However, women in the lowest level of
SES were only marginally significantly more likely to
be triple-negative.
Table 2. Adjusted Odds Ratios* and 95% Confidence Intervals for Patient Characteristics and
Triple-Negative Phenotype Among Women With Breast Cancer in California, 19992003
 No. (%) Adjusted odds ratio 95% CI

SES indicates socioeconomic status.

*
Adjusted for age, race, SES, AJCC stage, and tumor grade.

Age group at diagnosis

<40 3312 (6.5) 1.53 1.371.70

4049 9912 (19.4) 1.20 1.101.31

5059 1310 5 (25.7) 1.12 1.021.22

6069 10,724 (21.0) 1.00 1.001.00

7079 9488 (18.6) 0.90 0.810.99

80+ 4533 (8.9) 0.98 0.861.11

Race/ethnicity

Non-Hispanic white 36,671 (71.8) 1.00 1.001.00

Non-Hispanic black 2587 (5.1) 1.77 1.591.97

Hispanic 6901 (13.5) 1.23 1.141.34

Asian/Pacific Islander 4580 (9.0) 0.86 0.770.95

 No. (%) Adjusted odds ratio 95% CI

Other 335 (0.7) 1.42 1.031.97

SES

SES1, Low 5174 (10.1) 1.12 1.011.24

SES2 7881 (15.4) 1.22 1.121.34

SES3 10,314 (20.2) 1.14 1.051.24

SES4 12,493 (24.5) 1.08 1.001.17

SES5, High 15,212 (29.8) 1.00 1.001.00

Relative survival for women with triple-negative breast

cancer was poorer than for women with other types of
breast cancer, with 77% of women surviving 5 years
after diagnosis, compared with 93% survival for other
breast cancers (Fig. 1). Figure 2 demonstrates these
differences in relative survival by stage at diagnosis
and by race/ethnicity. Women with triple-negative
breast cancer had consistently poorer survival when
compared with women with other breast cancers for
each stage and race group. For women diagnosed at
AJCC stage I (Fig. 2, top), Hispanic women with triple-
negative breast cancers had the worst 5-year
cumulative relative survival, although their survival
rates were just over 90%, and the difference was not
 statistically significant. For women diagnosed at stage
II (Fig. 2, middle), non-Hispanic whites, Hispanics, and
non-Hispanic blacks with triple-negative breast cancer
had statistically significant lower survival than all race
groups among the women with other breast cancers. In
addition, among women with stage II breast cancers,
non-Hispanic black women had the poorest survival,
although the difference was not significant when
compared with other stage II triple-negative breast
cancers. Non-Hispanic black women diagnosed at late
stage (Fig. 2, bottom) with triple-negative breast cancer
had the poorest survival of any other comparable
group, with only 14% surviving 5 years after diagnosis,
compared with 49% 5-year relative survival among
non-Hispanic black women with other breast cancers
diagnosed at late stage, as well as 36% survival among
non-Hispanic white and 37% among Hispanic women
with late stage triple-negative breast cancer.

Figure 1.
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Five-year relative survival of triple-negative breast cancers
compared with other breast cancers by stage at diagnosis,
California, 19992003.
 Figure 2.
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Top: Five-year relative survival for women with breast cancer
diagnosed at AJCC stage I, triple-negative breast cancers
versus other breast cancers, California, 19992003. Middle:
Five-year relative survival for women with breast cancer
diagnosed at AJCC stage II, triple-negative breast cancers
versus other breast cancers, California, 19992003. Bottom:
Five-year relative survival for women with breast cancer
diagnosed at AJCC stage III-IV, triple-negative breast cancers
versus other breast cancers, California, 19992003.
DISCUSSION
In this large population-based study of invasive breast
cancer, we found the triple-negative phenotype to be
significantly associated with younger age, African
American race/ethnicity, more advanced stage at
diagnosis, poorly differentiated histology, lower SES,
and shortened survival.
Racial disparities in breast cancer incidence and
mortality have been well documented in the past, and
numerous studies have shown that African American
women have a lower incidence of breast cancer but
worse survival when compared with white women.2
8 Possible explanations advanced for this disparity in
breast cancer mortality include lack of access to health
insurance and medical care,25 differences in
treatment,26, 27 or socioeconomic
factors.7, 28, 29 Other investigations have shown that
equal access to medical care does not eliminate
completely the survival disadvantage for African
American women,3033 and race alone has been
suggested as an independent predictor for survival.34
36 African American women were noted to have
significantly earlier age at diagnosis, high grade
tumors, and a higher proportion of ER-negative and
PR-negative cancers,3, 6, 3742 suggesting that breast
cancer is biologically different in African American
women.
The molecular classification of breast cancer, based on
DNA microarray technology, into luminal, basal, and
HER2 subtypes with distinct differences in prognosis
and response to therapy, is a vivid illustration of the
heterogeneity of breast cancer. The basal-like subtype,
characterized by lack of expression of ER and PR, low
or absent expression of HER2, and IHC expression for
cytokeratins usually expressed in the basal cells of the
breast (CK5 and CK14), is associated with aggressive
histology, poor clinical outcomes, and BRCA1-related
breast cancer.912 First presented during the 2004
American Society of Clinical Oncology annual
meeting,43 Carey et al.44 have shown that the basal-
like breast cancer subtype is more prevalent among
premenopausal African American women and is a
contributing factor to the poor prognosis of young
African American women with breast cancer.
The present study, based solely on population-based
registry data without the benefit of microarray or IHC
confirmation of the basal-like subtype, illustrates the
value of the triple-negative phenotype as a surrogate
marker for basal-like cancer. Age less than 40 years,
being non-Hispanic black and, to a lesser extent, being
Hispanic, are clearly the most powerful risk factors for
this poor prognosis subtype of breast cancer. Because
the triple-negative phenotype is not amenable to any
form of endocrine therapy, efforts are underway to
develop appropriate targeted therapies.45
We acknowledge the limitations of this study. First,
this is strictly a population-based cancer registry
investigation. Second, histologic grading of tumors, as
well as tests for ER, PR, and HER2, were performed by
a wide variety of laboratories without central review.
Third, almost half the initial study population lacked
information about ER, PR, and HER2, with the latter
constituting the bulk of missing data. In 1999 the CCR
began collection of HER2 results but over 50% of
newly diagnosed breast cancers lacked this test result.
By 2003, HER2 testing of primary breast cancer was
more common and more than 70% of breast cancer
cases were found to have HER2 on record. The results
from our analysis comparing triple-negative cases to
other breast cancers with at least 1 tumor marker coded
as unknown were nearly identical to the comparisons
between triple-negatives and other breast cancers with
known tumor marker status. Thus, we feel confident
that these 2 groups were fairly comparable. Fourth, our
study examined the triple-negative phenotype without
confirmatory microarray or IHC assays. We recognize
that triple-negativity does not automatically equate
with the basal-like breast cancer. However, the
proportion of the triple-negative phenotype found in the
present study (12.5%) corresponds well to the reported
incidence of the basal-like breast cancer.12, 45, 46
Despite these shortcomings, our study is of value
because 1) it includes a sufficiently adequate number of
breast cancer cases; 2) it reflects real-world experience
of a large, statewide cancer registry in an ethnically
diverse population; 3) it highlights the importance of
the triple-negative phenotype, now readily available for
all new breast cancer cases, as a surrogate marker for
basal-like breast cancer; 4) it emphasizes the role of
younger age and race/ethnicity (African American and
Hispanic) as important risk factors; and 5) it clearly
reveals the survival disadvantage of the triple-negative
phenotype and may help hasten the development of
specific targeted therapy for this subtype of breast
cancer. Further research regarding the contribution of
each of the tumor markers is underway with survival
analyses adjusting for multiple risk factors.
Acknowledgements
The collection of cancer incidence data used in the
study was supported by the California Department of
Health Services as part of the statewide cancer
reporting program mandated by California Health and
Safety Code Section 103885; the National Cancer
Institute's Surveillance, Epidemiology, and End Results
Program under contract N01-PC-35136 awarded to the
Northern California Cancer Center, contract N01-PC-
35139 awarded to the University of Southern
California, and contract N02-PC-15105 awarded to the
Public Health Institute; and the Centers for Disease
Control and Prevention's National Program of Cancer
Registries, under agreement U55/CCR921930-02
awarded to the Public Health Institute