Triple-negative breast cancer prevalence in Africa: a systematic review and meta-analysis.

OBJECTIVE: The aggressive triple-negative breast cancer (TNBC) subtype disproportionately affects women of African ancestry across the diaspora, but its frequency across Africa has not been widely studied. This study seeks to estimate the frequency of TNBC among African populations. DESIGN: Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. DATA SOURCES: PubMed, EMBASE, African Journals Online and Web of Science were searched on 25 April 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included studies that use breast cancer tissue samples from indigenous African women with sample size of eligible participants ≥40 and full receptor status for all three receptors (oestrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2)) reported. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias using the modified assessment tool by Hoy et al. (2012) for prevalence studies. A random-effects meta-analysis was performed, and data were pooled using the inverse-variance method and logit transformation. Pooled frequencies were reported with 95% CIs calculated with the Clopper-Pearson method and heterogeneity quantified with I2 statistic. GRADE assessed the certainty of the evidence. RESULTS: 1808 potentially eligible studies were identified of which 67 were included in the systematic review and 60 were included in the meta- analysis. Pooled TNBC frequency across African countries represented was estimated to be 27.0%; 95% CI: 24.0% to 30.2%, I2=94%. Pooled TNBC frequency was highest across West Africa, 45.7% (n=15, 95% CI: 38.8% to 52.8%, I2=91%) and lowest in Central Africa, 14.9% (n=1, 95% CI: 8.9 % to 24.1%). Estimates for TNBC were higher for studies that used Allred guidelines for ER/PR status compared with American Society of Clinical Oncology(ASCO)/College of American Pathologists(CAP) guidelines, and for studies that used older versions of ASCO/CAP guidelines for assessing HER2 status. Certainty of evidence was assessed to be very low using GRADE approach. CONCLUSION: TNBC frequency was variable with the highest frequency reported in West Africa. Greater emphasis should be placed on establishing protocols for assessing receptor status due to the variability among studies.

Analysis of the genomic landscapes of Barbadian and Nigerian women with triple negative breast cancer.

PURPOSE: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women of African ancestry (WAA) and is often associated with poor survival. Although there is a high prevalence of TNBC across West Africa and in women of the African diaspora, there has been no comprehensive genomics study to investigate the mutational profile of ancestrally related women across the Caribbean and West Africa. METHODS: This multisite cross-sectional study used 31 formalin-fixed paraffin-embedded (FFPE) samples from Barbadian and Nigerian TNBC participants. High-resolution whole exome sequencing (WES) was performed on the Barbadian and Nigerian TNBC samples to identify their mutational profiles and comparisons were made to African American, European American and Asian American sequencing data obtained from The Cancer Genome Atlas (TCGA). Whole exome sequencing was conducted on tumors with an average of 382 × coverage and 4335 × coverage for pooled germline non-tumor samples. RESULTS: Variants detected at high frequency in our WAA cohorts were found in the following genes NBPF12, PLIN4, TP53 and BRCA1. In the TCGA TNBC cases, these genes had a lower mutation rate, except for TP53 (32% in our cohort; 63% in TCGA-African American; 67% in TCGA-European American; 63% in TCGA-Asian). For all altered genes, there were no differences in frequency of mutations between WAA TNBC groups including the TCGA-African American cohort. For copy number variants, high frequency alterations were observed in PIK3CA, TP53, FGFR2 and HIF1AN genes. CONCLUSION: This study provides novel insights into the underlying genomic alterations in WAA TNBC samples and shines light on the importance of inclusion of under-represented populations in cancer genomics and biomarker studies.

Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression.

Mortality from triple negative breast cancer (TNBC) is significantly higher in African American (AA) women compared to White American (WA) women emphasizing ethnicity as a major risk factor; however, the molecular determinants that drive aggressive progression of AA-TNBC remain elusive. Here, we demonstrate for the first time that AA-TNBC cells are inherently aggressive, exhibiting elevated growth, migration, and cancer stem-like phenotype compared to WA-TNBC cells. Meta-analysis of RNA-sequencing data of multiple AA- and WA-TNBC cell lines shows enrichment of GLI1 and Notch1 pathways in AA-TNBC cells. Enrichment of GLI1 and Notch1 pathway genes was observed in AA-TNBC. In line with this observation, analysis of TCGA dataset reveals a positive correlation between GLI1 and Notch1 in AA-TNBC and a negative correlation in WA-TNBC. Increased nuclear localization and interaction between GLI1 and Notch1 is observed in AA-TNBC cells. Of importance, inhibition of GLI1 and Notch1 synergistically improves the efficacy of chemotherapy in AA-TNBC cells. Combined treatment of AA-TNBC-derived tumors with GANT61, DAPT, and doxorubicin/carboplatin results in significant tumor regression, and tumor-dissociated cells show mitigated migration, invasion, mammosphere formation, and CD44+/CD24- population. Indeed, secondary tumors derived from triple-therapy-treated AA-TNBC tumors show diminished stem-like phenotype. Finally, we show that TNBC tumors from AA women express significantly higher level of GLI1 and Notch1 expression in comparison to TNBC tumors from WA women. This work sheds light on the racial disparity in TNBC, implicates the GLI1 and Notch1 axis as its functional mediators, and proposes a triple-combination therapy that can prove beneficial for AA-TNBC.

High triple-negative breast cancer prevalence and aggressive prognostic factors in Barbadian women with breast cancer.

BACKGROUND: Women of African ancestry (WAA) are disproportionately affected by triple-negative breast cancer (TNBC), which remains one of the most clinically challenging breast cancer (BCa) subtypes. This study investigated the prevalence of TNBC and epidemiological trends for BCa in Barbados, a Caribbean island with a high percentage of African ancestry. METHODS: Pathology reports for all BCa cases between 2007 and 2016 were collected from the sole hospital in Barbados and reviewed. The clinicopathological data collected included age, tumor grade, lymph node status, and hormone receptor status as determined by immunohistochemistry. BCa data for non-Hispanic white (NHW) and non-Hispanic black (NHB) American populations were accessed from the Surveillance, Epidemiology, and End Results database. RESULTS: There were 1997 BCa cases in Barbados between 2007 and 2016 for an estimated incidence rate of 135.1 per 100,000 women in Barbados (standardized to the US population, where the standardized incidence rates for NHBs and NHWs were 141.4 and 152.6 per 100,000, respectively). Age-specific incidence rates in Barbados for this period were consistently higher in younger age groups (15-59 years) in comparison with NHWs and NHBs. Between 2010 and 2016 in Barbados, a TNBC prevalence of 25% was observed, whereas TNBC prevalences of 21% and 10% were observed in NHBs and NHWs, respectively. CONCLUSIONS: The BCa incidence was higher in younger Barbadian women than NHWs and NHBs, and the TNBC prevalence was ~2.5 times higher than the prevalence in NHWs. This hints at a possible genetic predisposition and other socioeconomic factors that could explain the high TNBC prevalence and aggressive clinical course in WAA globally.

Dancing from bottoms up - Roles of the POZ-ZF transcription factor Kaiso in Cancer.

The POZ-ZF transcription factor Kaiso was discovered two decades ago as a binding partner for p120ctn. Since its discovery, roles for Kaiso in diverse biological processes (epithelial-to-mesenchymal transition, apoptosis, inflammation) and several signalling pathways (Wnt/ß-catenin, TGFß, EGFR, Notch) have emerged. While Kaiso's biological role in normal tissues has yet to be fully elucidated, Kaiso has been increasingly implicated in multiple human cancers including colon, prostate, ovarian, lung, breast and chronic myeloid leukemia. In the majority of human cancers investigated to date, high Kaiso expression correlates with aggressive tumor characteristics including proliferation and metastasis, and/or poor prognosis. More recently, interest in Kaiso stems from its apparent correlation with racial disparities in breast and prostate cancer incidence and survival outcomes in people of African Ancestry. This review discusses Kaiso's role in various cancers, and Kaiso's potential for driving racial disparities in incidence and/or outcomes in people of African ancestry.

Social determinants of prostate cancer in the Caribbean: a systematic review and meta-analysis.

BACKGROUND: Prostate cancer remains the leading cause of cancer deaths among Caribbean men. However, little data exists on the influence of social factors on prostate cancer in the Caribbean setting. This article supports the 2011 Rio Political Declaration on addressing health inequalities by presenting a systematic review of evidence on the role of social determinants on prostate cancer in Caribbean men. It aims to determine the distribution, by known social determinants of health, of the frequency and adverse outcomes of prostate cancer among Caribbean populations. METHODS: Observational studies reporting an association between a social determinant and prostate cancer frequency and outcomes were sought in MEDLINE, EMBASE, SciELO, CINAHL, CUMED, LILACS, and IBECS databases. Fourteen social determinants and 7 prostate cancer endpoints were chosen, providing 98 possible relationship groups exploring the role of social determinants on prostate cancer. Observational studies with > 50 participants conducted in Caribbean territories between 2004 and 2016 were eligible. The review was conducted according to STROBE and PRISMA guidelines. Random-effects meta-analyses were performed. RESULTS: From 843 potentially relevant citations, 13 articles from 9 studies were included. From these included studies, 24 relationships were reported looking at 11 distinct relationship groups, leaving 90 relationship groups (92% of all relationship groups) unexplored. Study heterogeneity and risk of bias restricted results to a narrative synthesis in most instances. Meta-analyses showed more diagnosed prostate cancer among men with less formal education (n = 2 studies, OR 1.60, 95%CI 1.18-2.19) and among men who were married (n = 3 studies, OR 1.54, 95%CI 1.22-1.95). CONCLUSIONS: This review highlights limited evidence for a higher occurrence of diagnosed prostate cancer among Caribbean men with lower levels of education and among men who are married. The role of social determinants on prostate cancer among Caribbean men remains poorly understood. Improvements in study quantity and quality, and reduced variability in outcomes and reporting are needed. This report represents the current evidence, and provides a roadmap to future research priorities for a better understanding of Caribbean prostate cancer inequalities.

Kaiso is highly expressed in TNBC tissues of women of African ancestry compared to Caucasian women.

PURPOSE: Triple-negative breast cancer (TNBC) is most prevalent in young women of African ancestry (WAA) compared to women of other ethnicities. Recent studies found a correlation between high expression of the transcription factor Kaiso, TNBC aggressiveness, and ethnicity. However, little is known about Kaiso expression and localization patterns in TNBC tissues of WAA. Herein, we analyze Kaiso expression patterns in TNBC tissues of African (Nigerian), Caribbean (Barbados), African American (AA), and Caucasian American (CA) women. METHODS: Formalin-fixed and paraffin embedded (FFPE) TNBC tissue blocks from Nigeria and Barbados were utilized to construct a Nigerian/Barbadian tissue microarray (NB-TMA). This NB-TMA and a commercially available TMA comprising AA and CA TNBC tissues (AA-CA-YTMA) were subjected to immunohistochemistry to assess Kaiso expression and subcellular localization patterns, and correlate Kaiso expression with TNBC clinical features. RESULTS: Nigerian and Barbadian women in our study were diagnosed with TNBC at a younger age than AA and CA women. Nuclear and cytoplasmic Kaiso expression was observed in all tissues analyzed. Analysis of Kaiso expression in the NB-TMA and AA-CA-YTMA revealed that nuclear Kaiso H scores were significantly higher in Nigerian, Barbadian, and AA women compared with CA women. However, there was no statistically significant difference in nuclear Kaiso expression between Nigerian versus Barbadian women, or Barbadian versus AA women. CONCLUSIONS: High levels of nuclear Kaiso expression were detected in patients with a higher degree of African heritage compared to their Caucasian counterparts, suggesting a role for Kaiso in TNBC racial disparity.

Social determinants of depression and suicidal behaviour in the Caribbean: a systematic review.

BACKGROUND: Depressive disorder is the largest contributor to years lived with disability in the Caribbean, adding 948 per 100,000 in 2013. Depression is also a major risk factor for suicidal behaviour. Social inequalities influence the occurrence of depression, yet little is known about the social inequalities of this condition in the Caribbean. In support of the 2011 Rio Political Declaration on addressing health inequities, this article presents a systematic review of the role of social determinants on depression and its suicidal behaviours in the Caribbean. METHODS: Eight databases were searched for observational studies reporting associations between social determinants and depression frequency, severity, or outcomes. Based on the PROGRESS-plus checklist, we considered 9 social determinant groups (of 15 endpoints) for 6 depression endpoints, totalling 90 possible ways ('relationship groups') to explore the role of social determinants on depression. Studies with ≥50 participants conducted in Caribbean territories between 2004 and 2014 were eligible. The review was conducted according to STROBE and PRISMA guidelines. Results were planned as a narrative synthesis, with meta-analysis if possible. RESULTS: From 3951 citations, 55 articles from 45 studies were included. Most were classified as serious risk of bias. Fifty-seven relationship groups were reported by the 55 included articles, leaving 33 relationship groups (37%) without an evidence base. Most associations were reported for gender, age, residence, marital status, and education. Depression, its severity, and its outcomes were more common among females (except suicide which was more common among males), early and middle adolescents (among youth), and those with lower levels of education. Marriage emerged as both a risk and protective factor for depression score and prevalence, while several inequality relationships in Haiti were in contrast to typical trends. CONCLUSION: The risk of bias and few numbers of studies within relationship groups restricted the synthesis of Caribbean evidence on social inequalities of depression. Along with more research focusing on regional social inequalities, attempts at standardizing reporting guidelines for observational studies of inequality and studies examining depression is necessitated. This review offers as a benchmark to prioritize future research into the social determinants of depression frequency and outcomes in the Caribbean.

Social determinants of breast cancer in the Caribbean: a systematic review.

BACKGROUND: Breast cancer is the leading cause of cancer deaths among women in the Caribbean and accounts for >1 million disability adjusted life years. Little is known about the social inequalities of this disease in the Caribbean. In support of the Rio Political Declaration on addressing health inequities, this article presents a systematic review of evidence on the distribution, by social determinants, of breast cancer risk factors, frequency, and adverse outcomes in Caribbean women. METHODS: MEDLINE, EMBASE, SciELO, CINAHL, CUMED, LILACS, and IBECS were searched for observational studies reporting associations between social determinants and breast cancer risk factors, frequency, or outcomes. Based on the PROGRESS-plus checklist, we considered 8 social determinant groups for 14 breast cancer endpoints, which totalled to 189 possible ways ('relationship groups') to explore the role of social determinants on breast cancer. Studies with >50 participants conducted in Caribbean territories between 2004 and 2014 were eligible for inclusion. The review was conducted according to STROBE and PRISMA guidelines and results were planned as a narrative synthesis, with meta-analysis if possible. RESULTS: Thirty-four articles were included from 5,190 screened citations. From these included studies, 75 inequality relationships were reported examining 30 distinct relationship groups, leaving 84% of relationship groups unexplored. Most inequality relationships were reported for risk factors, particularly alcohol and overweight/obesity which generally showed a positive relationship with indicators of lower socioeconomic position. Evidence for breast cancer frequency and outcomes was scarce. Unmarried women tended to have a higher likelihood of being diagnosed with breast cancer when compared to married women. While no association was observed between breast cancer frequency and ethnicity, mortality from breast cancer was shown to be slightly higher among Asian-Indian compared to African-descent populations in Trinidad (OR 1.2, 95% CI 1.1-1.4) and Guyana (OR 1.3, 95% CI 1.0-1.6). CONCLUSION: Study quantity, quality, and variability in outcomes and reporting limited the synthesis of evidence on the role of social determinants on breast cancer in the Caribbean. This report represents important current evidence on the region, and can guide future research priorities for better describing and understanding of Caribbean breast cancer inequalities.

Kaiso depletion attenuates the growth and survival of triple negative breast cancer cells.

Triple negative breast cancers (TNBC) are highly aggressive and lack specific targeted therapies. Recent studies have reported high expression of the transcription factor Kaiso in triple negative tumors, and this correlates with their increased aggressiveness. However, little is known about the clinical relevance of Kaiso in the growth and survival of TNBCs. Herein, we report that Kaiso depletion attenuates TNBC cell proliferation, and delays tumor onset in mice xenografted with the aggressive MDA-231 breast tumor cells. We further demonstrate that Kaiso depletion attenuates the survival of TNBC cells and increases their propensity for apoptotic-mediated cell death. Notably, Kaiso depletion downregulates BRCA1 expression in TNBC cells expressing mutant-p53 and we found that high Kaiso and BRCA1 expression correlates with a poor overall survival in breast cancer patients. Collectively, our findings reveal a role for Kaiso in the proliferation and survival of TNBC cells, and suggest a relevant role for Kaiso in the prognosis and treatment of TNBCs.