|Year : 2012 | Volume
| Issue : 3 | Page : 169-175
Biology of breast cancer in Nigerian women: A pilot study
CA Adisa1, N Eleweke1, Au A Alfred2, MJ Campbell3, R Sharma3, O Nseyo3, V Tandon3, R Mukhtar3, A Greninger4, J Di Risi4, LJ Esserman3
1 Department of Surgery, Abia State University Teaching Hospital, Aba, Nigeria
2 Department of Pathology, University of California, San Francisco, USA
3 Department of Surgery, University of California, San Francisco, USA
4 Department of Biochemistry and Biophysics, University of California, San Francisco, USA
|Date of Web Publication||5-Jun-2012|
C A Adisa
Department of Surgery, Abia State University Teaching Hospital, Aba
| Abstract|| |
Background: Compared to the developed world, there are relatively few studies that describe the tumor biology of breast cancer in African women. While little is known about the tumor biology, clinical and epidemiologic studies suggest that breast cancer in African women are characterized by presentation at late stage and poor clinical outcomes. Analysis of the biological features of breast cancers in Nigerian women was designed to bring additional insight to better understand the spectrum of disease, the phenotypes that present, and the types of interventions that might improve outcomes.
Materials and Methods: We performed histological analyses for hormone receptors (estrogen and progesterone receptors), HER2, and tumor infiltrating macrophages (TAM) on 17 breast cancers, obtained from Abia State University Teaching Hospital (Aba, Nigeria), between November 2008 and October 2009. On a subset of these cases, we investigated the potential role of a virus in the etiology of these aggressive cancers.
Results: The majority of cases in this cohort were characterized as high grade (100% were grade III), triple-negative (65%), and occur in young women (mean age 47 years). We observed high infiltration of TAMs in these tumors, but no evidence of a viral etiology.
Conclusion : Our findings indicate that breast cancers in Nigerian women have a highly aggressive phenotype (high grade, hormone receptor negative), which is similar to other studies from Africa and other developing nations, as well as from African American women, but is significantly different from Caucasian women in the developed world. The presence of high numbers of TAMs in these tumors raises the possibility of targeting the immune microenvironment for therapeutic interventions.
| Abstract in French|| |
Contexte: Par rapport à des pays développés, il y a relativement peu d'études qui décrire la biologie de la tumeur le cancer du sein chez les femmes africaines. Bien que peu est connu sur la biologie des tumeurs, des études cliniques et épidémiologiques suggèrent que le cancer du sein chez les femmes africaines sont caractérisés par la présentation au stade tardif de pauvres cliniques résultats. Analyse des caractéristiques biologiques des cancers du sein chez les femmes nigérianes a été conçu pour apporter des mieux comprendre pour mieux comprendre le spectre de la maladie, les phénotypes qui présentent et les types d'interventions qui pourrait améliorer les résultats.
Des matériaux et des procédés: Nous avons effectué des analyses histologiques des récepteurs hormonaux (oestrogènes et progestérone récepteurs), HER2 et s'infiltrer dans les macrophages (TAM) sur 17 cancers du sein, des tumeurs obtient Abia State University Teaching Hospital (Aba, Nigéria), entre novembre 2008 et octobre 2009. Sur un sous-ensemble de ces cas, nous a étudié le rôle possible d'un virus dans l'étiologie de ces cancers agressifs.
Résultats: La majorité des cas de cette cohorte ont été caractérisée comme grade élevé (100 % étaient de grade III), triple négatif (65 %) et se produisent chez les femmes jeunes (âge moyen 47 ans). Nous avons observé forte infiltration des TAMs dans ces tumeurs, mais aucune preuve d'une étiologie virale.
Conclusion: Nos résultats indiquent que les cancers du sein chez les femmes nigérianes ont un phénotype très agressif (haute grade, récepteur hormonal négatif), qui est similaire à d'autres études d'Afrique et d'autres pays en développement, ainsi à partir des femmes afro-américaines, mais est sensiblement différent de femmes de race blanche dans les pays développés. Le présence d'un nombre élevé de TAMs dans ces tumeurs soulève la possibilité de cibler le microenvironnement immunitaire pour des interventions thérapeutiques.
Mots clés: Cancer du sein, les macrophages de la tumeur associée, microenvironnement tumoral
Keywords: Breast cancer, tumor associated macrophages, tumor microenvironment
|How to cite this article:|
Adisa C A, Eleweke N, Alfred AA, Campbell M J, Sharma R, Nseyo O, Tandon V, Mukhtar R, Greninger A, Risi J D, Esserman L J. Biology of breast cancer in Nigerian women: A pilot study. Ann Afr Med 2012;11:169-75
|How to cite this URL:|
Adisa C A, Eleweke N, Alfred AA, Campbell M J, Sharma R, Nseyo O, Tandon V, Mukhtar R, Greninger A, Risi J D, Esserman L J. Biology of breast cancer in Nigerian women: A pilot study. Ann Afr Med [serial online] 2012 [cited 2013 Jun 19];11:169-75. Available from: http://www.annalsafrmed.org/text.asp?2012/11/3/169/96880
| Introduction|| |
Breast cancer incidence and clinical outcomes differs across various populations, age and racial groups with higher incidence rates in developed countries, white Caucasians and older women.  However, breast cancer is not a homogeneous disease, and there are various subtypes of this malignancy. One of the important ways of dividing breast cancer into subtypes is by using hormone receptor status.  The need to develop these subtypes of breast cancer arose due to their differential response to different modes of therapy.
Several studies including the SEER program have documented the increased frequency of poorly differentiated, estrogen- and progesterone receptor-negative tumors in women of African descent, especially African American women. ,, Available data on the epidemiology of breast cancer in Africa, reveal similarities to breast cancer in African American women. , Breast cancer has recently overtaken cervical cancer as the most common female malignancy in areas of Western and Eastern Nigeria. It is characterized by high mortality, younger age distribution, more advanced stage distribution and increased frequency of high-grade tumors, as found in African American women. ,
Most of the studies done on breast cancer in Nigeria are descriptive epidemiological studies and they confirm the rather late presentation with advanced disease and poor clinical outcome. , The aim of this study is to better understand the biologic characteristics (hormone and HER2 receptor status, immune microenvironment, potential viral etiology) of these tumors, and to begin to unravel the factors that drive their virulent clinical presentation.
| Materials and Methods|| |
Patients were women who presented to Abia State University Teaching Hospital (Aba, Nigeria), with a breast mass between November 2008 and October 2009 (recruited from the surgical clinic of Dr. Charles Adeyinka Adisa). 22 consecutive women consented to participate in the study, and underwent standard treatment with the addition of two core biopsies, obtained during the time of surgical excision. The institutional review boards at Abia State University and the University of California, San Francisco approved this project.
Upon surgical excision, a portion of tumor tissue was collected for immunohistochemical analyses. Tumor tissue was fixed in 10% neutral buffered formalin for 24 hours, and then shipped to UCSF in 70% alcohol. Upon arrival, tumor tissue was cut into blocks, placed in cassettes, and again fixed in 10% formalin, prior to embedding in paraffin.
Fresh tissue was also obtained using a 16 gauge core biopsy needle, sampling both tumor and adjacent normal tissue at the time of surgical excision. These core biopsy specimens were stored in RNAlater? and shipped to UCSF.
Immunohistochemical analyses on 17 cases were carried out in the UCSF immunohistochemistry core laboratory, using standardized techniques and controls. 5 μm sections were deparaffinized in xylene and rehydrated in decreasing ethanol dilutions. For ER, PR, and Her-2 staining, the avidin biotin complex (ABC) method was used. Prior to antigen retrieval, endogenous peroxidase activity was blocked with 3% H 2 O 2 . After incubation with 10% normal horse serum for 30 minutes, slides were treated with the monoclonal mouse primary antibody overnight at 4°C. Slides were then treated with biotinylated horse anti-mouse antibody (Vector Labs BA2000, 1 : 200 dilution) for 30 minutes, and then with avidin / biotinylated complex-horseradish peroxidase (Vector Labs PK6100 Vectastain ABC Kit, 1 : 100 dilution). Peroxidase activity was developed with diaminobenzidine (DAB, Sigma D5905). Slides were then stained with hematoxylin for 10 seconds, dehydrated with graded alcohols, cleared with xylene, and coverslipped. Mouse monoclonal antibodies were used for ER (Dako M7047, 1 : 400 dilution), PR (Dako M3569, 1 : 200 Dilution), and erbB-2 (Invitrogen 28-0003z, 1 : 200 dilution). Samples were scored as ER or PR positive if at least 10% of nuclei stained positively. Her2 expression was scored as 0, 1+, 2+, or 3+, and 3+ cases were considered positive.
CD68 / PCNA double staining was performed using a standard streptavidin-biotin peroxidase method. Sections were deparaffinized in xylene and rehydrated using graded ethanol. Antigen retrieval was performed using microwave-heated 10 mM citrate buffer for 10 minutes. Sections were double stained for CD68, a pan-macrophage marker, and PCNA, a proliferation marker. Double staining for CD68 / PCNA was performed using dual endogenous enzyme block (Dako) for 10 minutes and incubation with anti-CD68 mouse monoclonal antibody (Dako M0876, 1 : 50 dilution) for 30 minutes, followed by a second incubation with anti-PCNA mouse monoclonal antibody (Dako M0879, 1 : 500 dilution), overnight at 4°C. For anti-CD68, DAB plus (Dako K1395) was used as a substrate, and for anti-PCNA, BCIP / NPT substrate (Dako K0598) was used. The slides were counterstained with periodic acid Schiff reagent (American Master Tech Scientific KTPAS), for 10 minutes at room temperature.
Antigen retrieval for Mac387 staining was performed with a pressure-cooker in 1 mM EDTA. Sections were stained with an anti-Mac387 mouse monoclonal antibody (Dako # M0747; Clone # MAC387; 1 : 6400 dilution) for 30 minutes, then labeled with the Envision Dual Link System-HRP (Dako # K4063). Slides were then incubated in DAB (Liquid DAB + Substrate Chromogen System, Dako # K3468), and counterstained with hematoxylin.
Two independent pathologists blinded to clinical characteristics or outcomes read all slides. Cells staining doubly positive for CD68 and PCNA were counted in each of the 3 representative high power fields (hpf), and the mean number was used for the final CD68 / PCNA TAM count. Mac387 was evaluated as the percentage of tumor area that stained positively.
Tumor and adjacent normal tissue was received in RNA later. Total RNA was extracted in Trizol using RNA purification columns, treated with DNAse, then amplified. Amplified RNA was then used to synthesize cDNA, which was amplified, labeled, and hybridized to a Virochip. The Virochip is a microarray platform, consisting of oligonucleotide probes that represent all fully or partially sequenced viruses found in GenBank as of 2004. , Microarrays were scanned and analyzed with visual inspection, the E-Predict algorithm, and cluster analysis. 2 patients had deep sequencing performed on amplified cDNA using the Solexa platform.
| Results|| |
[Table 1] shows clinico-pathological features of the 22 cases enrolled in this study. The mean age of the patients was 47 years and most were pre-menopausal (77.3%). The majority (90.9%) of the patients presented with advanced tumors (Stages III / IV). All but one were multiparous, and all of the multiparous women breastfed their babies for at least 1 year.
Of the 22 tissue samples obtained in this study, 17 were suitable for histological and immunohistochemical analyses [Table 2]. All the 17 tumors were histological grade III, with the most common histological type being invasive ductal cancer (53%). There were no cases of DCIS or LCIS. Tissue sections were stained for hormone receptors (estrogen and progesterone) and for HER2. A high percentage of the cases were hormone receptor negative (77%), with 65% being triple negative (hormone receptor and HER2 negative).
|Table 2: Distribution of age, histological grade, and tumor type by receptor status|
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Tissue sections were also stained for the presence of tumor associated macrophages (TAMs). We used two stains in these analyses. The first, CD68 plus PCNA, marks a subset of TAMs that have been shown to be associated with poor outcomes in breast cancer. , As shown in [Table 3], 82% of the cases had high levels (> 10 per high power field) of CD68 / PCNA positive TAMs. These CD68 / PCNA positive TAMs were more prevalent in HR- or triple-negative cases, compared to HR+ cases. A second marker, Mac387, was also used and we found 65% of the cases had high numbers of Mac387 cells. As with the CD68 / PCNA TAMs, Mac387 cells were most prevalent in HR- or triple-negative tumors [Figure 1].
|Figure 1: Tumor 1: is a triple negative tumor (ER, PR and HER2 negative). It has a high density of tumor associated macrophages (TAM) using the CD68 / PCNA stain. The TAM are identified with the black arrows, Tumor 2: is ER / PR / HER2 positive, but has low density of TAM using the CD68 / PCNA stain. The TAM are identified with the black arrows|
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|Table 3: Distribution of Mac387+ and CD68 / PCNA+ tumor associated macrophages by receptor status in breast cancers from Nigerian women|
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No viruses were detected on Virochip analyses of 22 tumors and matched normal tissue samples. Deep sequencing on amplified cDNA from 2 tumor samples yielded 7,358,886 and 8,362,642 high-quality reads. Approximately, 92% of the sequences aligned to the human genome while 7% - 8% of the sequences remained unalignable to NT at BLASTN W11E-5. No known viruses were found in the samples via deep sequencing.
| Discussion|| |
The patient characteristics in this pilot study showed a preponderance of advanced / late stage disease (90.9%) women in their active reproductive years (30 - 50 years) and multiparty (95.5%). All of the women with children, breastfed for more than a year. Virtually, all cases were sporadic as there was no obvious family history of breast cancer in any of the women. These results are consistent with findings by other workers in Nigeria that most patients with breast cancer, present with advanced disease and poor clinical outcomes. ,
The relative young age of the women in our cohort has also been observed in other studies. ,, Some are of the opinion that breast cancer epidemiology in African women and African American women is predominantly a disease of young women, compared with white women and that the biology might be different in the two races. However, it is also possible that the relative absence of older women in the cohort may have skewed the result in favor of younger women. This is understandable in Nigeria as the life expectancy is < 50 years.
Results of the immunohistochemical staining for hormone receptors showed that 64.7% of the tumor specimens were triple negative (ER negative, PR negative and HER2 negative). This is much higher than the prevalence of triple negative breast cancer among Caucasian women (< 20%), and is even higher than what is observed in African American women. ,,,, Triple negative breast cancers, though a heterogeneous group, usually have poor prognosis with poor response to hormone therapy and chemotherapy.
In most centers in Nigeria and sub-Saharan Africa, routine immunohistochemistry is not done on breast specimens due to cost and availability of good pathological services for the analysis. Invariably, all patients are assumed to be hormone receptor positive and routinely receive tamoxifen. This practice has been the norm as data were extrapolated from western literature where the majority of breast cancers are hormone receptor positive. In fact, the 2005 breast global health initiative (BHGI)  recommended the use of tamoxifen in resource constrained settings when ER / PR status is unknown. This recommendation needs to be reevaluated in the light of recent data from Africa and our own findings.
There are few studies in the literature, describing hormone receptor status in women with breast cancer from developing nations. 4 studies reported on estrogen receptor (ER) status in women from 5 African countries (Nigeria, Senegal, Tanzania, Kenya, and Ghana). ,,, Similar to our results, these investigators found a high proportion of ER-negative breast cancers in these populations, ranging from 57% to 76% [Table 4]. Additional studies from India and Sri Lanka also report a high prevalence of ER-negative breast cancers [Table 4]. ,, A common feature of these countries is that they are all poor countries with generally poor sanitation, lack of clean drinking water, relative inaccessibility to health care and medicines (especially antibiotics), and crowded living conditions. All of these factors contribute to frequent exposures to infectious agents, beginning at an early age. This led us to hypothesize that a viral agent may be driving these ER-negative, high grade, aggressive breast cancers. We performed ViroChip , analyses as well as Solexa deep sequencing on breast cancer RNA samples from Nigerian women, but found no evidence of an associated virus.
A high infectious burden can also lead to chronic inflammation, which in turn has been associated with an increased risk of developing a variety of cancers, including breast cancer. ,,, One of the key components of the tumor microenvironment is the inflammatory cell infiltrate, in particular, tumor associated macrophages (TAM). TAM play a prominent role in tumor growth and progression by promoting angiogenesis, metastasis and inhibiting the host immune response. ,,, We have previously shown that a subset of macrophages (CD68+ / PCNA+), are associated with ER-negative, high grade breast cancers and poor outcomes. , In the present study, we observed high numbers of these CD68+/ PCNA+ TAMs (> 10 /high power field), in 82% of the tumors. We also examined another macrophage-related marker, Mac387, a heterodimeric complex of S100A8 and S100A9 proteins. This complex is involved in innate immunity, leukocyte adhesion, endothelial transmigration, and plays an important role in inflammation.  Thought to identify recent blood-derived monocytes / macrophages recruited into the tumor, Mac387 has been found to be elevated in cholangiocarcinoma with poor outcomes, and to identify macrophages that express matrix metalloproteinase-9.  We observed high numbers of Mac387 positive cells (> 10% of tumor area) in 65% of the Nigerian breast cancer cases.
| Conclusion|| |
We observed that breast cancer in Nigerian women has a very aggressive phenotype, occurs in relatively young women, highly infiltrated with TAM and majority are hormone receptor negative favoring chemotherapy rather than hormonal treatment
In addition, given the young age of onset and aggressiveness of this disease, it will be critical to identify women at risk and to elevate awareness, target screening, and develop prevention strategies.
The heavy infiltration of TAM raises the possibility of using them as markers for the disease if low fidelity kits that can assay signature candidates or molecules of TAM can be found in the peripheral blood.
Further collaborative studies on a wider scale that cuts across many centers and include women from the over 250 ethnic groups in Nigeria will be a logical step to this study.
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[Table 1], [Table 2], [Table 3], [Table 4]