Breast cancer is the most frequent cancer in women, accounting for 6.9% of all cancer deaths globally.¹ In 2022, breast cancer represented 11.6% of all cancer cases with an incidence of 2.3 million and the highest incidence rates observed in France, Australia and New Zealand.¹ There is a high prevalence of breast cancer among elderly women particularly in Europe and America. However, in Africa, it occurs predominantly among younger women. ²,³ In Limpopo province, South Africa over 38% of breast cancer cases occurred in younger women under 50 years of age. ³ In a study in Nigeria, the mean age of women with breast cancer was reported to be 49. ⁴ Vanderpuye et al. mentioned that the age range of women with breast cancer in Kenya and Tanzania was from 35 to 45 years.⁵ In Africa, patients with breast cancer tend to present at an advanced stage. A study in Limpopo, South Africa, showed that 76% of female breast cancer patients presented at a late stage. ⁶ Advanced-stage diagnoses are common in low- and middle-income countries⁷ and in many sub-Saharan African countries.⁸,⁹

Breast cancer is a heterogeneous disorder, involving different patterns of cellular compositions, molecular variations and clinical behaviour.¹⁰ Phenotypically and histologically identical breast tumors can have a wide range of clinical outcomes and responses to therapy due to the presence or absence of hormones receptors and human epithelial growth factor 2 (HER2/neu) and classification methods have been developed based on immunohistochemistry and molecular findings. ¹¹,¹² Molecular subtypes of breast cancer are classified based on immunohistochemistry into Luminal A (ER+/PR+/HER2-/lowKi-67); Luminal B (ER+/PR+/HER2-/+/high Ki-67); HER2-overexpression (ER-/PR-/HER2+) and triple negative breast cancers/TNBCs (ER-/PR-/HER2-).¹² Molecular classifications are considered as a useful tool in predicting the response to treatment. These classifications have been used to predict prognosis and guide therapy in patients with breast cancer. ¹⁰,¹¹,¹² Luminal A breast cancer is hormone-receptor positive (oestrogen-receptor and/or progesterone-receptor positive), HER2 negative, and possess low levels of the protein Ki-67. Luminal A cancers are low-grade, tend to grow slowly and have the best prognosis. Luminal B breast cancer is hormone-receptor positive (oestrogen-receptor and/or progesterone-receptor positive), and either HER2 positive or HER2 negative with high levels of Ki-67. The growth of Luminal B cancers is generally slightly faster than that of luminal A cancers and their prognosis is slightly worse, but both Luminal A and Luminal respond to hormonal therapy. HER2-enriched breast cancer is hormone-receptor negative (oestrogen-receptor and progesterone-receptor negative) and HER2 positive. The growth of HER2-enriched cancers tends to be faster than that of luminal cancers and can have a worse prognosis; nonetheless, they are often successfully treated with targeted therapies aimed at the HER2 protein such as trastuzumab, pertuzumab, lapatinib, neratinib, and T-DM1 or ado-trastuzumab emtansine. Triple-negative/basal-like breast cancer is hormone-receptor negative (oestrogen-receptor and progesterone-receptor negative) and HER2 negative with poor prognosis. Ki-67 is an indication of tumor proliferation and an elevated/high Ki-67 is associated with poor prognosis. ¹³,¹⁴,¹⁵,¹⁶

Systemic therapy and management strategies for patients with breast cancer have been developed based on molecular subtypes. Endocrine receptor positive cancers had been reported to have good clinical response to the endocrine therapy, while non-endocrine receptor cancers have been shown to respond to cytotoxic therapy. ¹²,¹⁷ Therefore, it is vital to identify patients benefiting from hormonal therapy and treatment targeting the HER-2/neu receptors.

The main objectives of the study were to identify the characteristics of breast cancer in women >50 and <50 years and to categorise any differences (histological type, stage, grading and molecular subtype) that exist between these two groups of breast cancer patients in the Limpopo province. Based on the findings of this study, a recommendation could be made to the health authority to use prevention and management strategies for patients with breast cancer in Limpopo province.

A total of 269 female breast cancer patients were reviewed and 47 were excluded owing to lack of complete histology results with immunohistochemistry and some information in the file missing. A total of 222 cases met the inclusion criteria of the present study. Of these, 131 (59%) were aged >50-years and 91 (41%) were aged <50 years. Regarding the stage of presentation, 80 (36%) presented at an early stage and 142 (64%) at a late stage. A detailed descriptive summary of the results is presented in Table 1, Figure 1 and Figure 2.

With regard to molecular type in this study, the luminal B molecular subtype type was more frequent in both groups (Figure 1), accounting for 51% in the >50-year group and 44% in the <50-year group. Luminal A accounted for 18%, triple negative for 15% and HER2 overexpression for 16% of cases in the >50-year group and luminal A accounted for 31%, triple negative for 20% and HER2 overexpression for 5% in the <50-year group.

When viewing the molecular subtype in relation to the age group, HER2 overexpression prevalence was found higher in the >50-year group at 16%, while in the <50-year group, it was 5%. The prevalence of triple negative was 15% in the >50-year group and 20% in the <50-year group. Luminal A was more prevalent in the younger age group at 31%. A significant association was found between the HER2 overexpression molecular subtype and other molecular subtypes. HER2 overexpression was higher in the >50-year patient group (P-value 0.016).

In relation to the grading of the tumor, over 60% of the patients in both groups had a grade 2 tumor followed by a grade 3 tumor as the second most prevalent (Figure 2).

In this study, 222 breast cancer patients were assessed, with the group of women >50 years of age comprising 59% of the sample and the group <50 years comprising 41%. Concerning the histological type of breast cancer, over 90% of the patients in both age groups had invasive ductal carcinoma (IDC). IDC is the most common histological type around the globe and in many sub-Saharan African countries. A study on breast cancer by Bhatia et al. (2015) found IDC to represent 86% of all cases in Malawi ¹⁸ and approximately 89% in Nigeria.⁴

In this study, the luminal B molecular subtype was more frequent in both groups (Figure 1). Across the globe, usually luminal A is the most common molecular subtype (50%-60%), with luminal B and HER2 overexpression cancer accounting for 15% - 20% of breast cancer subtypes. The triple negative subtype represents between 8% and 37% of all subtypes. ¹⁹ However, research has observed the luminal A subtype at 58.5%, followed by triple negative at 16%, luminal B at 14%, and HER2 overexpression to be the least prevalent at 11.5%. ¹⁰ Some studies have reported that luminal B, HER2 overexpression, and triple negative are more prevalent in younger women compared to older breast cancer patients. ²⁰,²¹ Different populations have variations of incidences of molecular subtypes. Goldhirsch et al. have argued for endocrine therapy alone for patients with clinicopathologically classified ‘Luminal A’ disease (except in defined high-risk cases), chemo endocrine therapy for Luminal B, the addition of anti-HER2 therapy in the presence of ‘HER2 positivity’, and a reliance on chemotherapy for most patients with ‘Triple negative’ disease with invasive ductal carcinoma. ¹²

In terms of prognosis, Luminal A and Luminal B have good prognosis and majority of these subtypes in both age groups respond better to hormonal therapy. HER2 overexpression was found to be higher in the >50-year patient group with worse prognosis than the Luminal type but a better response to targeted therapy (trastuzumab, pertuzumab, lapatinib). Triple negative was found to be higher in the <50-year group with poor short-term (5 years) prognosis not responding to hormonal and targeted therapy. ¹⁴,¹⁵,¹⁶ The triple negative type has a good prognosis for patients who survive the first 5 years after diagnosis. ¹⁵

In relation to the grading of the tumor, no obvious difference was found between the two groups. However, when comparing grading with the molecular subtype of triple negative between the age groups, grade 3 was more prevalent in the <50-year group. Grade 3 was found in 65% of patients in the >50-year group and 83% of patients in the <50-year group (Figure 3). Overall, 38 patients had triple negative breast cancer, and no patient had grade 1 in the triple negative molecular subtype. This shows that the triple negative types are more aggressive appearing in tumor biology. Sheppard et al. found that triple negative disease patients usually present at an advanced stage, which is more common in women with BRCA1 gene mutations and among young black women. ¹⁶ Grade 3 had proportionally higher prevalence in triple negative molecular subtype in patients in the <50-year group compared to those in the >50-year group.

Regarding the stage of presentation, 36% of the sample presented at an early stage and 64% at a late stage and no significant associations were found between the stage and patients’ age in this study. The majority of patients in both age groups presented at an advanced stage (Figure 4). It is a big concern that women of Limpopo province are presenting late with an advanced stage of breast cancer. Awareness campaigns are essential for all women, young and elderly in the Limpopo province. Research has shown that in many sub-Saharan Africa and other low and middle-income countries patients usually present at an advanced stage. ⁷,⁹

In many countries, there are many challenges, diagnostic delays, and limited awareness of female breast cancer. ² A study in Johannesburg, South Africa found that limited education and lack of breast cancer knowledge were associated with an advanced stage diagnosis. ²² Another South African study found that low levels of education were a major factor causing a delayed diagnosis. ²³ Furthermore, there is a lack of understanding of the severity of breast cancer responsible for presentation at the late stage in the rural population of KwaZulu-Natal, South Africa. ²⁴ A previous study from Limpopo province, South Africa identified the most common reason for a delay in diagnosis to be a lack of knowledge about breast cancer and its symptoms. ⁶

Early diagnosis of breast cancer is important for effective management as it reduces the suffering of the patient and increases the chances of survival. Costa et al. recommended increasing awareness and educational programs to identify signs and symptoms and to develop clear diagnostic guidelines and screening strategies.² The 2017 South African Breast Cancer Control Policy advocated for direct access to a specialist breast cancer clinic to reduce delays in presentation and improve time to diagnosis and care. ²⁵

Majority of patients presented at an advanced stage in both groups. Health education and breast cancer awareness campaigns are essential for all women, young and elderly in Limpopo province. Over 40% of the patients in this study were under 50 years of age. This showed that breast cancer screening should start earlier in Limpopo province. HER2 overexpression molecular subtype was higher in the >50-year patient group compared to <50 years of age group. In breast cancer patients under <50, triple negative molecular subtype is more prevalent. Further studies are required to elucidate the genetics, environmental influences, and clinical behaviors of breast cancer to guide our understanding and aid in the formulation of management protocols relevant to this population.