Triple-Negative Breast Cancer among Ghanaian Women Seen at Korle-Bu Teaching Hospital ASHDIN

Ashdin Publishing
African Journal of Pathology and Microbiology
Vol. 4 (2015), Article ID 235899, 5 pages
doi:10.4303/ajpm/235899
ASHDIN
publishing
Research Article
Triple-Negative Breast Cancer among Ghanaian Women Seen at
Korle-Bu Teaching Hospital
E. M. Der,1,2 R. K. Gyasi,1 Y. Tettey,1 T. M. Bayor,3 and L. Newman4
1 Department
of Pathology, Medical School, University of Ghana, P.O. Box 4236, Korle-Bu, Accra, Ghana
of Pathology, School of Medicine and Health Sciences, University for Development Studies, P.O. Box TL 1883, Tamale, Ghana
3 Department of Horticulture, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
4 Breast Care Center, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
Address correspondence to E. M. Der, [email protected]
2 Department
Received 3 December 2014; Revised 26 March 2015; Accepted 31 March 2015
Copyright © 2015 E. M. Der et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background. Women with African ancestry in the United
States and in continental Africa have been found to have exceptionally increased frequencies of triple-negative breast cancer (TNBC),
prompting speculation that this risk may have an inherited basis and
may at least partially explain breast cancer outcome disparities related
to racial/ethnic identity. Our goal was to evaluate the breast cancers
diagnosed in one of the largest health care facilities in western Africa,
and to compare the frequencies as well as risk factors for TNBC versus
non-TNBC. Methods. We reviewed all breast cancer cases that had
immunohistochemistry (Novolink Detection system), in 2010. Results.
The overall study population of 223 breast cancer cases was relatively
young (median age 52.4 y), and most had palpable tumors larger than
five centimeters in diameter. More than half were TNBC (130 cases,
58.3%). We observed similar frequencies of young age at diagnosis,
stage at diagnosis, and tumor grade among cases of TNBC compared
to cases of non-TNBC. Conclusion. Ghanaian breast cancer patients
tend to have an advanced stage distribution and relatively young age
at diagnosis. The triple-negative molecular marker pattern is the most
common seen among these women, regardless of age, tumor grade,
and stage of diagnosis. Additional research is necessary regarding the
causes of TNBC, so that we can elucidate the reasons for its increased
prevalence among women with African ancestry.
Keywords triple-negative breast cancer; Ghana; immunohistochemistry; young; high grade
1. Introduction
Breast cancer is a common cause of cancer mortality among
women in Ghana [1], motivating a call for increased breast
health awareness in this country. Developing countries, however, have limited financial resources to support populationbased tumor registries. While estimates of population-based
cancer incidence and mortality rates exist, their accuracy can
be questioned, and most studies related to specific cancer
patterns are therefore based upon reports from single institutions.
Breast cancers have traditionally been categorized
as invasive tumors with or without a noninvasive (in
situ) component. Advances in the technology of genetic
profiling for invasive breast cancer have furthermore led
to improved understanding regarding the existence of
a spectrum of tumor subtypes associated with varying
degrees of malignant virulence, and the basal subtype
is widely-acknowledged as having the most inherently
aggressive behavior. In clinical practice, we typically
rely on immunohistochemistry (IHC) to detect patterns
of expression for three molecular markers as a surrogate
strategy to characterize the cancers of newly-diagnosed
patients. Tumors that are negative for the estrogen receptor
(ER), the progesterone receptor (PR), and human epidermal
growth factor receptor-2 (HER2/neu) are commonly called
triple-negative breast cancer (TNBC). Triple-negative
status tends to be an adverse prognostic feature, because
the micrometastatic potential of these tumors cannot be
controlled with either targeted endocrine therapy or targeted
anti-HER2/neu therapy, and also because there is a strong
correlation between TNBC and the basal breast cancer
subtype. In developed countries and among women of
White/European American and European background
TNBC accounts for 10–20% of all breast cancers [1, 2, 3,
4]. TNBC is more prevalent among breast cancer patients
that are diagnosed at young ages, patients with hereditary
susceptibility derived from BRCA-1 mutations, and African
American patients [4, 5]. Frequencies of TNBC is approximately twofold higher for African American compared
to White American and European breast cancer patients,
and recent studies [6, 7, 8] have demonstrated that one-third
to more than half of sub-Saharan African breast cancer
patients have triple-negative disease. The higher proportion
of TNBC among African American and African women
has prompted speculation that shared African ancestry
might be associated with a heritable marker of TNBC
risk. However, robust data on the breast cancer burden in
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African Journal of Pathology and Microbiology
Table 1: Clinical characteristics of breast cancers from
Korle Bu Teaching Hospital 2010, total sample (223 cases).
Table 2: Histological characteristics of breast cancers that
had IHC conducted.
Number (n) Frequency (n) Percentage (%)
≤ 39
41
18.4
40–49
56
25.1
Age/y
50–59
56
25.1
60–69
38
17.0
70+
32
14.4
Total
223
100.0
2.0
22
25.6
Size of lump (cm)
2.5–5.0
38
44.2
26
30.2
≤ 5.5
Total
86
100.0
Skin involvement
22
61.1
Chest wall
2
5.6
Other associated
symptoms
Nipple discharge
4
11.1
Others
8
22.3
Total
36
100.0
≤ 16
33
49.3
17–32
12
17.9
Duration of
symptoms (w)
33–52
13
19.4
> 52
9
13.4
Total
67
100.0
Needle biopsy
95
42.6
Type of surgical
Mastectomy
68
30.5
specimen analyzed Lumpectomy
52
23.3
Incisions biopsy
8
3.6
Total
223
100.0
Variant
Number (n) Percentage (%)
IDC-NOS
169
75.8
Lobular
12
5.4
Mucinous
9
4.0
Cribriform
7
3.1
Micropapillary
6
2.7
Medullary
4
1.8
DCIS
7
3.1
Others
9
4.0
Total
223
100.0
Grade I
20
17.2
Grade II
46
39.7
Grade III
50
43.1
Total
116
100.0
Single
8
25.8
Multiple
23
74.2
Total
31
100.0
Stage I-II
11
44.0
Stage III-IV
14
66.0
Total
25
100.0
TNBC
130
58.3
HR−/HER2+
52
23.3
HR+/HER2−
18
8.1
HR+/HER2+
23
10.3
Total
223
100.0
Clinical feature
Africa are lacking because the limited healthcare workforce
and pathology infrastructure in most facilities precludes
routine IHC testing as well as epidemiologic studies.
This limitation makes it difficult to ascertain whether the
higher frequency of TNBC reported in African populations
is a real phenomenon related to some intrinsic, inherited
susceptibility or a spurious finding. Our goal was to evaluate
the clinicopathologic patterns of TNBC observed in one of
the most prominent hospitals in sub-Saharan Africa, and to
correlate these patterns with standard breast cancer features.
2. Materials and methods
The Korle Bu Teaching Hospital is affiliated with the
University of Ghana and is located in Accra, the capital
of Ghana. We retrospectively reviewed all cases of
histologically confirmed breast cancers for which IHC
analyses of ER, PR, and HER2/neu were conducted in the
Korle Bu department of pathology during the year 2010.
For each case, the patient age, clinical characteristics of
the breast cancer, histologic findings, TNM stage, and the
molecular marker profile were recorded. IHC was performed
on sections from formalin-fixed, paraffin-embedded
specimens using Novolink Detection system (brand name;
Novocastra) manufactured by Leica Microsystems GmbH.
Cases were scored as being ER or PR positive if at least 10%
nuclear staining was observed. They were scored as being
Histologic type
Histologic grade
Nodal positive
TNM stage
IHC profile
HER2/neu positive if complete membranous staining was
observed in 10% or more cells. These data were entered into
SPSS microcomputer software version 18 (Chicago), and
analyzed. The results were presented in frequency tables.
Comparisons of triple-negative and nontriple-negative
breast cancers were conducted using Spearman’s correlation
coefficient. Histologic grade of tumors was based on the
architectural and cytologic features of the tumor; the grade
was according to the modified Scarff-Bloom-Richardson
grading system and the TNM staging was that used by the
American Joint Committee on Cancer (AJCC).
3. Results
A total of 223 breast cancer cases were identified. Clinicopathologic characteristics of this study sample are shown in
Table 1. The ages ranged from 25 through 90 years with a
mean of 52.4 (SD = 13.6) y. The majority of cases (61%)
presented with palpable breast masses associated with skin
changes/involvement. Mean tumor size was 4.5 cm, with a
range of 0.5–14 cm. Information on duration of breast symptoms/palpable disease prior to biopsy was available for 67
patients, and the mean time of 35 w (range of 1–53 w).
Histopathologic characteristics and IHC were assessed
from core needle biopsy specimens in 95 cases (42.6%)
versus lumpectomy and mastectomy specimens in 19.3%
and 34.6% of cases, respectively. As shown in Table 2,
African Journal of Pathology and Microbiology
3
Table 3: Comparison of triple-negative and nontriple-negative breast cancers at the Korle-Bu Teaching Hospital in 2010.
Feature
Age < 40 ya
Age 40–49 y
Age ≥ 50 y
Tumor ≤ 2 cma
Tumor > 2 cm, ≤ 5 cm
Tumor > 5 cm
Skin involvementa
Grade III histologya
AJCC stage 1
AJCC stage 2
AJCC stage 3
AJCC stage 4
AJCC stage 1 to 2
AJCC stage 3 to 4
Invasive ductal histologya
Invasive lobular histology
Node positivea
a Total
TNBC
N = 130
N (%)
23 (17.1%)
34 (26.2%)
73 (56.1%)
8 (16.3%)
22 (44.9%)
19 (38.8%)
11 (61.1%)
33 (47.1%)
1 (6.2%)
5 (31.2%)
3 (18.8%)
7 (43.8%)
6 (37.5%)
10 (62.5%)
89 (87.1%)
2 (1.9%)
20 (44.4%)
Non-TNBC
N = 93
N (%)
18 (19.4%)
22 (23.7%)
35 (56.9%)
14 (37.8%)
16 (43.2%)
7 (19.0%)
10 (61.1%)
17 (37.0%)
0 (0.0%)
6 (60.0%)
1 (10.0%)
3 (30.0%)
6 (60.0%)
4 (40.0%)
62 (86.1%)
6 (8.3%)
11 (47.8%)
P value (comparing proportion of TNBC expressing the selected
feature with the proportion of non-TNBC cases expressing the
selected feature)
0.774
0.369
0.513
0.327
0.324
0.153
0.500
0.142
0.398
0.478
0.358
0.320
0.500
0.334
0.476
0.144
0.730
number of TNBC and non-TNBC cases do not add up to 223 because of missing data on selected patients.
the majority of cancers (169, 75.8%) were invasive
ductal carcinoma, not otherwise specified (IDC-NOS)
histology and 12 (5.4%) were invasive lobular, 7 (3.1%)
were DCIS, and the remaining 12% were various unusual
breast cancer patterns (e.g., mucinous, micropapillary, and
neuroendocrine). Nearly half of 113 cases for which tumor
grade was available (50 cases, 43.1%) were grade 3 lesions.
Complete clinicopathologic staging was available for only
25 cases and of these, two-thirds (14 cases, 66%) were stage
III or IV disease.
Regional nodal staging information was only available
to a limited extent on the 68 patients that underwent mastectomy, and of these cases there was unfortunately limited
documentation regarding the anatomic extent of the axillary dissection. However, of these cases, 31 (45.6%) were
node-positive, and the majority of these node-positive cases
(23/31, 74%) had multiple metastatic nodes, with a mean of
five positive nodes (range of 1–28).
One hundred and thirty (58.3%) of the 223 cases were
TNBC and another one-quarter (52, 23.3%) were negative
for ER and PR but positive for HER2/neu. Only 41 (18%)
were positive for ER and/or PR, and among these hormone
receptor-positive tumors more than half (23/41, 56%) were
HER2/neu-positive.
Age range for the 130 TNBC cases was 25–90 y,
with a mean of 51.7 (SD 13.3) y; while the range for the
93 non-TNBC cases was 25–84 y, with mean age 52.9
(SD 14.2) y. Mean size for the TNBC tumors was 5.1 cm
(range of 1–14 cm), and patients reported the presence of a
palpable mass that was present for 1–156 w (mean 37 w).
A comparison of the TNBC and non-TNBC tumors is
shown in Table 3. No significant differences were observed
between these subsets in distribution by age, histology,
stage, or tumor grade.
4. Discussion
Breast cancer is well-known as a lower-burden disease in
developing countries of Asia and Africa compared to western, industrialized areas of the world such as North America
and Europe. Financial resources to support accurate and
updated statistics are limited, but recent estimates report
incidence rates of 15–53 per 100,000 women in western,
sub-Saharan Africa [19]. By comparison, population-based
incidence rates in the United States are 125 and 116 per
100,000 White American and African American women,
respectively [20]. Historically, this difference in breast
cancer burden has largely been attributed to variation in
reproductive history risk factors, such as age at first live
birth and number of pregnancies. Women in developing
countries typically begin childbearing at relatively young
ages and they have multiple pregnancies, which would
account for a lower population-based breast cancer burden.
At least two lines of evidence have generated speculation
that hereditary factors may also be contributing to the
patterns of breast cancer observed in women from the
developing countries of western, sub-Saharan Africa:
(i) similarities in the breast cancer burden of western,
sub-Saharan Africans, and African Americans, who
would be expected to have a significant degree of
shared ancestry dating back to the colonial slave trade.
Both of these populations have a lower lifetime risk
of female breast cancer, yet they face a higher risk of
early-onset disease, and an increased risk of male breast
cancer. These same patterns are characteristically seen
4
African Journal of Pathology and Microbiology
Table 4: Selected studies reporting frequency of triple-negative breast cancer in African nations compared to other
developing countries.
Study
Trinkaus et al. [9]
Gakinya et al. [10]
Bird et al. [7]
Roy and Othieno [8]
Country
Kenya
Kenya
Kenya
Uganda
Region of Africa
East Africa
East Africa
East Africa
Southern, sub-Saharan Africa
Huo et al. [11]
Nigeria and Senegal
Western, sub-Saharan Africa
Stark et al. [6]
Awadelkarim et al. [12]
Abdelkrim et al. [13]
Ambroise et al. [14]
Teoh et al. [15]
Tan et al. [16]
Ghosh et al. [17]
Ng et al. [18]
Ghana
Sudan
Tunisia
India
Malaysia
Malaysia
India
Indonesia
Western, sub-Saharan Africa
Northern Africa
Northern Africa
South Asia
Southeast Asia
Southeast Asia
South Asia
Southeast Asia
in families with documented hereditary susceptibility
for BRCA1 mutation-associated breast cancer;
(ii) advances in the understanding of breast cancer subtypes
have led to an appreciation for particular disease patterns
that have different risk factors as well as inherent
virulence. TNBC (tumors that lack expression of ER,
PR, and HER2/neu) are biologically more aggressive
lesions because they are resistant to targeted endocrine
and anti-HER2/neu therapies, and also because they are
more likely to belong to the biologically more aggressive
basal breast cancer subtype. TNBC is now considered
to be a hallmark of inherited susceptibility for breast
cancer, prompting a genetic counseling referral when
detected in women up to the age of 50 y [21]. TNBC is
more common in African American compared to White
American women, and as shown in Table 4, frequency of
triple-negative breast cancer is also higher in women of
western, sub-Saharan Africa compared to those of other
developing countries, suggesting that African ancestry
may be the common denominator link to TNBC risk.
While parallels in the breast cancer burden of African
American and African women are provocative and suggestive of heritable risk, the paucity of tumor registry and
molecular marker information in Africa makes it difficult to
draw definitive conclusions. Additional data characterizing
the breast cancer burden of African women is therefore
necessary.
The scarcity of financial resources to support maintenance of basic pathology services and IHC facilities for
routine molecular marker assessment in Ghana prompts
the question of whether the absence of ER, PR, and HER2
staining might simply reflect suboptimal tissue processing
with universal antigen decay. However, other studies have
demonstrated increased expression of other molecular
markers in African populations, such as cytokeratins (which
Frequency of TNBC
32%
23%
44%
36%
27% (proportion of cases that were TNBC
and cytokeratin-positive)
82%
15.9%
18%
25%
15%
17.6%
29.8%
21%
are associated with the inherently aggressive basal-TNBC
subtype) [11, 22], and ALDH1 (a mammary stem cell
marker) [23].
Ghana is located in western, sub-Saharan Africa. Accra
is the capital of Ghana, and its Korle Bu Teaching Hospital,
affiliated with the University of Ghana, is one of the few
facilities where breast cancer specimens are routinely
referred for IHC to assess ER, PR, and HER2/neu expressions. In this study of 223 breast cancer cases that had IHC
for hormone receptor and human epidermal growth factor
(ER, PR, and HER2-neu), the majority of cases (58.3%)
were triple-negative tumors. While studies of TNBC in
North America and Europe have consistently demonstrated
an association between TNBC and young age at breast
cancer diagnosis [3, 4, 24], our study revealed a similar
prevalence of TNBC among Ghanaian breast cancer patients
in all age categories. Similarly, at least one population-based
study from California has demonstrated an increased risk of
TNBC among African American compared to White American women in the fourth, fifth, sixth, and seventh decades of
age [25]. These observations suggest that African ancestry
may be associated with some heritable pattern of mammary
tissue that is more susceptible to the development of TNBC
in both the pre- and post-menopausal age categories.
5. Conclusion
Triple-negative breast cancer is the common pattern of
invasive breast cancer seen among Ghanaian women, based
upon our retrospective review of cases evaluated at one
of the largest hospitals in western Africa during a recent
one-year period. Presentation for all breast cancers from
this region tends to be late with most cases characterized
by large/palpable, node-positive, and high grade tumors.
Increased breast health awareness and improved access
to health care in Africa may strengthen early detection
efforts. However, the increased prevalence of TNBC among
African Journal of Pathology and Microbiology
5
Ghanaian breast cancer patients of all ages suggests that
research regarding the genetics of breast cancer related to
African ancestry warrants further study.
Acknowledgments The authors wish to express their sincere gratitude
to the technical staff, especially, Miss Nahima (data collection) and
Mr. Andrews (immunostaining) of the histology department. They also
thank colleagues, residents and specialists in the department for their
support. Finally, the first author personally wishes to acknowledge the
Ghana-Michigan PARTNER Program.
[16]
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