Breast cancer in sub-Saharan Africa: The current state and uncertain future

Detection

Certain cultural beliefs and breast cancer treatment-related stigma hinder health-seeking and early diagnosis in SSA. ¹⁷ In some regions, the disease has been ascribed to supernatural forces, thereby diminishing a sense of personal control over the outcomes. The idea of “beauty” in other countries involves a “whole” woman; hence, needing a mastectomy may evoke a sense of worthlessness, which impedes early health-seeking. ¹⁸ Ignorance of the disease, unavailability of tests, and inaccessibility of treatment and detection facilities bedevil screening and early detection in SSA. ¹⁹ Guidelines for breast cancer screening differ mostly depending on age at which screening begins (45 vs. 50 years) and intervals (1 vs. 2 years) between screens. Prognosing women with breast cancer in SSA is also impaired by shortage of trained personnel, noncompliance, and poor drug supplies. ¹⁹ The majority of late detections has been recorded in South Africa, Cameroon, the Central African Republic, Malawi, and Tanzania. ²⁰ This does not suggest early detection in other countries, but a lack of comprehensive data to make substantive conclusions. The younger age at diagnosis in SSA has been widely attributed to the younger population age (Table 1) structure in the region, but this is not conclusive. ¹⁰

Treatment

Breast cancer treatments generally depend on the disease type, and stage, and current options include surgery, chemotherapy, or hormonal, biological, and radiation therapies. ²¹ In SSA, options for advanced stages are limited and coupled with a scarcity of chemotherapy and radiotherapy facilities, most women undergo mastectomy. ¹⁸ About two-thirds of SSA countries lack radiotherapy facilities, ²² while those available meet only approximately 18% of the projected need. ²³ Furthermore, tumor marker histological classification and identification facilities are limited in SSA, as are hormonal therapies and other targeted treatments. ²³ Patients with human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer exhibit poor survival rates, especially in the absence of targeted therapies, which is the case in most SSA countries. Breast cancer management is often deterred by treatment- and travel-related costs, particularly for those not living close to the medical centres. ¹⁸ Most women resort to other alternatives such as the use of herbs, visiting prayer camps and native doctors, which impede treatment and consequently translate to poor prognoses. ²⁴ Another pivotal breast cancer treatment challenge in SSA is the scarcity of trained health professionals in cancer care and diagnosis. Additionally, medical oncologists, well-equipped and reliable pathology laboratories, and pathologists are rare, especially in the poorest countries. ²⁵ As seen in Figure 4, the majority of SSA countries are poor. ²⁶

Survival

The five-year breast cancer survival rate in SSA is less than 40% compared to 86% in the USA. ²⁰ The low survival rate borders on factors including low awareness, late detection and treatment, poor prognosis, unavailability of treatment facilities and advanced therapies, high cost, and lack of prevalence documentation. Breast examination and early detection practices are low and contribute to late-stage diagnoses. ¹ There is a notable delay between symptom onset and seeking healthcare in SSA. Most countries in SSA have not implemented and sustained screening programs owing to logistical, sociocultural, and financial constraints. ¹ Breast cancer molecular subtypes also affect the survival rates. Breast cancer is population-specific, and the different prevalence rates of subtypes suggest heterogeneity in oncogenesis and partly explain the differing survival outcomes observed among ethnicities. ²⁷ Survival outcomes in HICs have been improved by targeted therapies, which are hardly accessible to women in poor countries. ²⁷ Further, survival has been enhanced by advances in population-specific genetic research, which has led to the development of molecular diagnostics for risk assessment. This has redefined the quality of treatments available in HICs. This is lacking in the African population, and a key determinant of the survival rates observed.

Clinical features and molecular subtypes in SSA

In SSA, about 80% of breast cancers are diagnosed at late stages (stages III or IV) compared with 15% in HICs. ²² The high late-stage disease presentation rate in SSA has been attributed to low awareness and detection in patients and the absence of diagnosis facilities and limited early detection programs. ²⁸ Reports show that stages III and IV constituted 77% of breast cancer patients at the Mulago Hospital in Uganda; ²⁹ 77% at the Butaro Cancer Centre of Excellence in Rwanda; ³⁰ 78% at the Angolan Institute of Cancer Control; ³¹ and 87.7% at the Komfo Anokye Teaching Hospital in Ghana. ³² This is compounded by the breast cancer histological subtypes. A prevalence study on the molecular subtypes reported 34% triple-negative breast cancer (TNBC), 38% Luminal A, 22% HER2⁺, and 5% Luminal B in Uganda. ²⁷ High-grade (grade 3) tumors made up 68% and late stage, 75% of the presentations; invasive ductal carcinoma was the predominant histological type recorded in the same population. TNBC is aggressive, recurs and metastasizes more often than the other subtypes, ³³ and disproportionately affects women of African descent, with worse clinical outcomes compared to women of European ancestry.^34,35 Studies have associated a high frequency of TNBC, particularly in women of West African ancestry. ³⁶ An estimated TNBC incidence ranging between 20.8 and 46.4% was reported in African-American women in the United States. ³⁷ This seems consistent with the 2–3-fold TNBC over-representation (34%) reported in SSA; both rates are relatively high in comparison with Caucasians, where prevalence is 12–17% or less, with TNBC and HER2⁺ tumors together constituting about 60% of the molecular subtypes and the majority of women aged 50 years and younger.^33,38 The estrogen receptor-negative (ER^–) subtypes, including TNBC and some HER2⁺, have been associated with higher proliferative capacity and grade. ²⁷ HER2⁺ and TNBC subtypes have the most unfavorable treatment outcomes. Mediators of the relatively high HER2⁺ and TNBC proportions are not fully understood. Genetic differences, including unidentified founder mutations in breast cancer, have been suggested to partly account for the disparities.^39,40 Exploring the mutation patterns and other genetic risk factors of breast cancer is an imperative. ⁴¹

Women with breast cancer in SSA are reportedly younger with peak incidence a decade earlier (50.2 years) in comparison with African Americans and White Americans with peak incidences of 60.8 and 62.4 years, respectively.^10,42 Current reports in SSA show an increasing number of diagnosed cases between the ages of 35 and 49 years, with most presenting with advanced late-stage disease. ²⁸ This was corroborated by a systematic review of population- and hospital-based breast cancer registries, ¹³ which revealed a mean age range between 30.6 and 60.8 years, with over 33 and 81% of the African population aged 30–49 and 30–59 years, respectively. Although inconclusive, these data suggest a high breast cancer incidence in the younger age groups in Africa. There are limited treatment options with advanced disease, which translates into poor prognosis.

Risk factors

Studies show that most breast cancer risk factors in SSA are similar to those in HIC (age, race, genetic mutation, reproductive history, familial susceptibility, personal breast cancer history or any other non-breast cancer, lifestyle choices, etc.).^21,22 Data on risk factors unique to SSA, including environmental exposures and infections, are limited and not conclusive. ²³

Pathogens like viruses, which have been implicated in about a fifth of all cancers, may be major risk factors in breast cancer in SSA.^43–45 The human papillomavirus (HPV) and human immunodeficiency virus (HIV) have been associated with breast cancer in SSA. ⁴³ Reports indicate that chronic infectious diseases, specifically lifelong exposure to malaria, lead to loss of cell-mediated immunity and promote viral carcinogenesis, which has been observed in HPV-associated cervical cancer. ⁴⁶ SSA is a malaria-endemic region, ⁴⁷ and the association between insecticide exposure and hormone receptor-positive breast cancers is still debated. ¹

Contraceptive use is another implicated breast cancer risk factor. The Collaborative group in hormonal factors in breast cancer analyzed data from 54 epidemiological studies using 53,297 breast cancer and 100,239 non-cancer patients and reported a 24% increase in relative risk in women currently using contraceptives and 7% in women who have ever used, compared to women who have never used them. ⁴⁸ A population-based cross-sectional study in SSA reported an average contraceptive use of 17%, which is relatively low; however, the prevalence varied substantially across the individual countries. ⁴⁹ This conclusion was drawn from data on contraceptive use from Demographic and Health Surveys (DHS) from 17 out of the 48 SSA countries. All SSA regions were not adequately covered; thus, the actual contraceptive use may probably be underreported. The relationship between contraceptive use and breast cancer cases reported has been observational; thus, inferences indicating their use as a risk factor are not enough to account for the incidence of breast cancer. More so, other factors, including duration of use and age of start of use, had no significant effect on the general risk, once recency of use has been established. Interestingly, no pronounced variation in recency of use has been reported between women of different backgrounds (ethnicity and race), reproductive histories, and breast cancer risks. ⁴⁸

Breast-associated conditions including lobular carcinoma in situ and atypical ductal hyperplasia have been correlated with an increased risk of breast cancer. ⁵⁰ Diabetes mellitus has been proposed to increase the risk of breast cancer. ⁵⁰ Reproductive factors including early menarche and menopausal status have been acclaimed breast cancer risk factors; however, no association was found between these risk factors and breast cancer in Senegalese women. ⁵¹ Some breast cancers have been attributed to postmenopausal body mass index (Figure 5) globally. Possibly, many more risk factors are unexplored; hence there is an urgent need to exhaustively investigate breast cancer-associated risk factors in SSA. More so, data on risk factors in SSA are evidently old, mostly from 2012, and according to data available on GLOBOCAN, very few countries have made progress in investigating them.

Family history or susceptibility is an important breast cancer-predisposing factor. ⁵² Early age at diagnosis and a positive breast cancer history may be suggestive of familial predispositions, which have not been thoroughly investigated in the SSA population. ⁵¹ Women with a familial breast cancer history with one or two first-degree premenopausal breast cancer relatives are at a 3.3-fold and 3.6-fold greater risk of developing breast cancer, respectively, compared to women without a family history. ⁵³ Approximately 13–19% of diagnosed breast cancer patients had an affected first-degree relative. ⁵⁴ This includes individuals carrying breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations. Other significant driver mutations include those in tumor protein P53 (TP53), phosphatase and tensin homolog (PTEN), and serine/threonine kinase 11 (STK11), which have also been implicated in Li–Fraumeni syndrome, Cowden syndrome, and Peutz–Jeghers syndrome, respectively. ⁵⁵

Genetics

Breast cancer is heterogeneous and complex, with ethnic and racial variations in both histology and tumor behavior. ⁵⁶ While 10–15% of cases have a familial predisposition, approximately 90% are sporadic and associated with somatic mutations acquired during an individual’s lifetime.^55,57 Genetic data in SSA are scant, ⁵⁸ and efforts to establish the genetic diversity in SSA peaked with the African Genome Variation Project involving 1481 individuals from the region. ⁵⁹ However, data on the genetic profile of breast cancer is still lacking as not enough people are captured by such studies to represent the regional and subregional diversities.

Extant African populations have significantly higher genetic diversity in comparison to other populations, and this reflects in over 2000 distinct languages and ethnic groups. ⁶⁰ Adaptations to climate-change, strong pathogen burden, and diet have contributed critically to shaping genomic diversity in the African population. ⁶¹ Additionally, the intrinsic “within continent” variations owing to population structure, isolation, and back migration of the Eurasian populations into Africa have contributed significantly to the genetic diversity.^62,63 Comprehensive genetic characterization of these migrations on the extant populations threw some light on the strong diversities between some geographically neighboring populations. ⁶¹

Owing to the genetic diversity, African populations are expected to have the highest levels of sequence diversity.^60,64 Approximately 25% of hereditary cases are mediated by mutations in any of the few identified highly penetrant, but rare genes (PTEN, BRCA1, TP53, BRCA2, CDH1, and STK11) and these confer an 80% lifetime risk of breast cancer. ⁶⁵ Causality has been established between early-onset breast cancer and germline mutations in BRCA1 and BRCA2^66,67 in African-American women,^66–68 but the contribution of these genes to the disease in extant African women remains uncertain.^69–71

Diverse BRCA1 and BRCA2 mutation and sequence variation spectra unique to Africans have been reported. ⁷² A global BRCA2 sequence diversity study detected 42% of the sequence variants exclusively in Africa, although chromosomes of African origin constituted only 13% of the 332 chromosomes screened. ⁷² Additionally, 2–3% of breast cancer cases are attributed to mutations in rare, moderately penetrant genes including BRIP1, CHEK2, PALB2, and ATM. ⁶⁵ Corroborating this is the observation of PALB deleterious mutations accounting for up to 2% of early-onset breast cancer cases in white South Africans. ⁷³ The known familial breast cancer genes account for only about 20% of reported cases, ⁷⁴ implying that most familial susceptibility genes are unknown. Genetic studies have indicated considerable linkage disequilibrium structure differences and extensive population substructure between African and Caucasian populations. ⁷⁵ The African-American population is the closest population of reference for the extant African population; however, they are an admixed population estimated to be approximately 80% West African and 20% European. ⁷⁶ Inferences from this population are not entirely representative of the situation in the extant African population. Africans possess several genetic adaptations, which have evolved in response to exposure to infectious diseases, diverse climates, and diets. These may have influenced breast cancer manifestation in the African population. ⁷⁷