The role of tissue inflammation in Kenyan women with breast cancer

Doctoral Thesis


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Background The immune landscape of breast cancer (BC) molecular subtypes from Sub Saharan Africa is understudied and findings are mainly extrapolated from studies in Caucasians. The objective of this study was to describe the cellular and signalling milieu of BC tumour microenvironment and its associations with BCrisk factors, tumour characteristics and molecular subtypes in Kenyan women with breast cancer. Methods: Molecular subtyping of 838 cases of BC was performed based on Immunohistochemistry (Figure 1). Risk factor data and tumour characteristics were retrieved from an existing database. Visual quantification of overall Tumour Infiltrating Lymphocytes (TILs) was performed on Haematoxylin and Eosin-stained whole slide sections of 226 BC cases based on the guidelines of the International TIL working group. Tissue Microarrays (TMAs) of tumour were constructed, stained with immunohistochemistry for CD3, CD4, CD8, CD68, CD20 and Fox P3, scanned and analysed on the Leica Aperio platform. Cytokine profiles of ER positive and Triple Negative BC were performed using microarray gene arrays and results validated with the ELISA platform. Multivariable polytomous logistic regression models were used to determine associations between BC risk factors and tumour molecular subtypes. Linear and logistic regression models were used to assess the associations between risk factors and tumour features with TILs and TIL subtypes. Results: Distribution of molecular subtypes for luminal A, luminal B, HER2-enriched, and triple negative (TN) breast cancers was 34.8%, 35.8%, 10.7%, and 18.6%, respectively. Higher TILs were associated with high KI67, high grade and HER2 status, luminal B subtype, and smaller tumour size. The TILs were predominantly composed of CD3, CD8 and CD68 with a much smaller contribution of CD4 and CD20 and FOxP3. Differential expression of inflammatory related cytokines (GM-CSF, IL8, TGF β1 and MDC), at both the gene and the protein expression level were observed between Triple negative and ER positive BC. Conclusions: Our findings with regards to enrichment of TILs in more aggressive breast cancers are like what has been previously published, however the differential expression of inflammatory cytokines in breast cancer subtypes some of which has also been described in Caucasian and Asian populations warrants further studies as potential targets for therapeutic approaches and biomarkers of diagnosis and prognosis.