Introduction

Globally, breast cancer is the most frequently diagnosed life threatening cancer and leading cause of cancer death among women (1). In Uganda, breast cancer is the third most commonly diagnosed cancer after Kaposi’s sarcoma and cancer of the cervix with a peak age of 30-39 years (2). It is increasing rapidly at a rate of 4.5% per year tripling from 11:100,000 to 31:100,000 in four decades (3). Breast cancer prevalence is known to vary with age, race, and ethnicity being more common in the Western world than in the African populations and has a strong relation to age with only 5% of all breast cancer occurring in women under 40 years in the developed nations (3). In Uganda and other African countries patients are more likely to be premenopausal with a peak age of onset a decade or so earlier than in the Western world (1, 5, 6, 7). Black women have a lower incidence rate of breast cancer compared to white women, but they have poorer survival outcomes (8). Considering that socioeconomic factors lead to later stage at diagnosis and that limited access to health care contributes substantially to this disparity, differences in outcome are still observed between black and white women after accounting for stage, socioeconomic status, and age (9-10). Although receptor status is a pivotal prognostic factor in light of treatment and has been found to vary among patients of different age groups, it is not routinely done in most resource constrained countries. Even though some studies in Africa suggest disparities of ER positive tumours between Africans and Caucasians, not enough has been documented about the subject to form the basis of change in the way breast cancer is treated (11,12,13). For example most patients with breast cancer are given tamoxifen routinely under the assumption that the majority are ER positive.

 

The aim of this study therefore was to determine the ER status and describe the associated clinico-histopathological characteristics among women with breast cancer at a tertiary hospital in Uganda.

 

Methods

This was a cross sectional descriptive study carried out in the Breast unit of Mulago Hospital from January 2012 - May 2012. Mulago Hospital is a national referral hospital and the teaching hospital for the Makerere University College of Health Sciences, Uganda. About 200 incident cases of breast cancer are received per year from all over the country. All consenting non pregnant women with histologically confirmed breast cancer were included. An experienced consultant pathologist reviewed all the slides and the tumours were classified according to Nottingham modification of the Scorff Bloom Richardson criteria.

 

Triple Negative Breast Cancer (TNBC) was defined as all ER, PR and HER2 receptors staining negative. HER2 positives were ER and PR negative and the HER2 positive staining. Luminal A was either ER or PR positive with a negative HER2. Luminal B was either ER positive /negative and or PR positive with a positive HER2. Antibodies used were: ER (clone SP-I), ASR PR (clone Y85), ASR and HER2/neu (c-erbB-2), clone CB-11 (Cell marquee corporation, Rocklin, CA). ER/PR scoring system staining of <5% of tumour cell nuclei was considered negative. Both border line and overtly positive stains were considered positive.

 

Her2/neu; negative was considered when no staining was observed or membrane staining was <10% of the tumour cells.

 

We used the quality assurance guidelines of the College of American Pathologists (CAP). The laboratory control tissue had a proven positive slide for each of the antibodies. A section of the positive and negative controls were used at every run of the day. Paraffin block specimens were cut into four sections and mounted on positively charged slides. The slides were paraffinized and rehydrated in xylene followed by graded alcohols, then washed in Tris buffered saline. The immunochemistry assays were performed using an immunostainer with antibodies and antigen unmasking.

 

Appropriate negative controls for the immuno-staining were prepared by omitting the primary antibody step. The results were scored semi quantitatively using Reiner’s four point scale based on intensity and percentage of IHC reaction, HER2 staining were evaluated according to manufacturer’s instructions.

 

Variables collected for the study included; age, duration of symptoms, age at menarche, age at menopause, family history of breast cancer, parity, age at first child birth, lactation history, history contraceptive use, history of benign breast disease, clinical stage of the disease (only T and N), histological type and grade, oestrogen receptor, progesterone receptor and Her2 receptor status. The relationship between the receptor status and the various clinico-pathological factors listed above was determined by sub-analysis.

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The data were collected using a structured questionnaire and entered into EpiData computer software version 3.1, and exported to SPSS version 17 for analysis. Frequency tables and cross tabulations were used to summarize the categorical variables. Means and Standard deviations were used to summarize the continuous variables.Odds ratios and P-values were used to test for associations.

 

Ethical approval was granted by the institutional ethics committee.

 

Results

A total of 114 women were consecutively enrolled. Basic characteristics of study participants are shown in Table 1

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Click to view table 1

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*Other cancers included cancer cervix (5) cancer oesophagus (4) hepatocellular cancer (2) cancer colon (2)

 

 

†missing values 75

 

Sixty one per cent (61%) of participants were premenopausal, 80% had duration of symptoms exceeding 6 months and 41% had used contraceptives.

 

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Click to view table 2

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Luminal A 43/114 (38%), Luminal B 21/114 (18%), TNBC 23/114 (20%), HER2 27/114 (24%) T1=< 2cm, T2 = 2-5cm, T3 > 5 cm T4- any size of tumour with skin changesN1= Mobile axillary nodes N2=Fixed matted axillary nodes N3=Supraclavicular or infraclavicular nodes, N4=Distant nodes Majority of patients had skin ulceration (54 %), lump (99%) and no nipple discharge (88%). Most of the patients were of clinical stage -T4 N1. The commonest histological subtype was invasive ductal carcinoma in 86% of the patients. Other types of breast cancer included Ductal carcinoma in situ, lobular carcinoma in situ medullary carcinoma, Tubular carcinoma, mucinous carcinoma and cribriform carcinoma. ER negative tumors contributed 44% (50/114), ER+ were 56%, Triple negative tumors were 20% (23/114).

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Click to view table 3

Click to view table 4

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Discussion

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In this study we set out to determine the ER status and describe the clinicopathological characteristics of breast cancer among women presenting at a tertiary hospital in sub-Saharan Africa. ER status established by IHC staining techniques is not routinely done in clinical practice in Uganda due to resource constraints. We found that breast cancer was occurring mostly among young premenopausal women, with T4 tumours and more than half were ER negative similar to what previous accounts from Uganda, Mali and Nigeria (7, 11 -14). We therefore concluded that there was over representation of ER negative tumours. The reasons for this scenario are not clear and ought to be investigated.

 

Risk Factors

Premenopausal women were the majority (61%) as other various studies in African women have reported (4-7). This in part can be explained by the relatively young population structure in Uganda. Majority (59%) had no prior history of oral contraceptive use which is a risk factor for development of cancer of the breast (15). Few women were nulliparous, women who give birth to ≥ 5 children have half the risk of women who have not given birth (16). Only 22% had a positive history of breast cancer. A woman’s risk of breast cancer is higher if her first degree relative had breast cancer, and the risk becomes significant if at least two close relatives had breast or ovarian cancer and also if the family member got breast cancer before age 40 (17). A significant proportion (42%) presented more than 12 months after onset of symptom-a reflection of delay in presenting for breast cancer care. The reasons were not elicited in this study. Clearly, most patients presented with locally advanced disease characterized by skin ulceration in (54%), breast masses > 2cm in size (48%) and T4 tumours in (49%) and N1 nodal status among (42%) of participants.

 

Studies in the region (1,7) show that majority of patients with breast cancer present with locally advanced disease with skin involvement (including ulceration) or chest wall fixation. We found patients with invasive ductal carcinoma in 86% of the cases and this was followed by lobular carcinoma (6%) other types of breast cancer contributed 8%. Most of these tumours were poorly differentiated (54%) and this is an indication of the tumour’s aggressive nature among these women

 

Hormonal Status

The most frequent tumour subtype based on IHC was (luminal A) (29%) followed by HER2+ in 24%. TNBC had a prevalence of 20%. This figure is comparable to that in some studies done among African American women though most post higher values (18, 23). TNBC was mostly found in young women {≤ 50years (78%), premenopausal (74%)}. The odds ratio of having TNBC among women less than 50 years was

 

1. This was not statistically significant; neither was contraceptive use (OR=1.7, P=0.246). TNBC presented earlier and at an advanced stage (T ≥5cm (87%), nodal involvement (52%) and less than a year of symptomatology in 65%). Over a third (39%) of these patients had a positive family history.Triple-negative breast cancer, characterized by tumours that do not express oestrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represent an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple-negative breast cancer is similar to that of other breast cancer subtypes, but these tumours are associated with a shorter median time to relapse and death.

 

The presence of receptors in breast cancer is associated with a good response to hormonal therapy and is also important in predicting likelihood of response to hormonal therapy in metastatic breast cancer (19-22). In addition HER2 + tumours have a poor prognosis, however drugs like monoclonal antibodies have been able to improve its prognosis significantly. A number of studies-have suggested that after menopause the rates of ER positive tumours increase with increasing age whereas rate of ER negative tumours do not (17).

 

Study Limitations

Whereas, this was a single site hospital based study and therefore with limited generalizability, the results are consistent with the emerging picture of breast cancer patterns among African women with breast cancer. This evidence adds the data that characterizes breast cancer disease in the African woman. The duration of onset of symptoms is subject to recall bias and may not reflect when the tumour truly started however, it gives some sense of how long it takes to present to where appropriate care is

 

Conclusion

Breast  cancer  is  common  among  young  African premenopausal women, it presents mostly as T4 tumours and close to half are ER negative. This is an over representation of ER negative tumours.

 

Acknowledgement

Breast Unit staff at Mulago hospital and department of Surgery, Makerere University

 

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