Clinical utility of biomarkers for basal-like breast cancer

The genomic subtyping of breast cancers into luminal A, luminal B, human epidermal growth factor receptor-2 (Her2)-Enriched and basal-like has remarkably advanced breast cancer diagnosis, treatment, and outcome. However, comparatively few advancements have been made in identifying biomarkers that can tailor treatments for the aggressive basal-like subtype. This group is clinically approximated as triple negative breast cancer (TNBC), characterized by immunohistochemical negativity for estrogen receptor, progesterone receptor, and Her2. However, this definition identifies a biologically heterogenous group, highlighting the complexity of guiding therapeutic choices for TNBC including those with basal-like molecular biology. My research goals have included identifying improved diagnostic biomarkers that can guide better therapeutic options for these aggressive cancers in a clinically-applicable manner using immunohistochemistry, RNA expression, and proteomic profiling. First, applying an optimized immunohistochemical panel, defined by nestin positivity or INPP4B negativity, on 239 specimens from the phase III SBG0102 clinical trial, I was able to identify those with a basal-like gene expression subtype and to predict which metastatic breast cancer patients benefit from gemcitabine chemotherapy. Then, using a 770-gene RNA panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism on 111 TNBC specimens from the phase III FinXX adjuvant capecitabine trial, I found that genes and metagenes related to immune response (cytotoxic cells, PDL2), endothelial, mast cells and 38 individual genes are the most significantly associated with capecitabine benefit. Finally, to characterize the heterogeneity of basal-like and triple negative breast cancers beyond current genomic classifications, I used a method called SP3-Clinical Tissue Proteomics, compatible with routine clinical specimens, for comprehensive protein profiling which revealed distinct subgroups within basal-like and triple negative breast cancers. Specifically, within 88 TNBC samples, four proteomic clusters were evident, which had features of “basal-immune hot”, “basal-immune cold”, “mesenchymal”, and “luminal”, each with distinct clinical outcomes. This work sets a foundation for developing clinically-applicable tests that can tackle the diversity of basal-like and triple negative breast cancers using standard formalin-fixed pathology clinical trial materials. The findings presented may guide the selection of breast cancer patients for clinical trial evaluation of existing chemotherapy or emerging therapies. Supplementary material(s) available at: http://hdl.handle.net/2429/81485Medicine, Faculty ofGraduat