Resistance to Targeted Therapy in Breast Cancer

The discoveries of breast cancer molecular subtypes and their deregulated pathways have given rise to the emergence of potential therapeutic targets and treatment options with excellent clinical outcomes. The HER2-amplified breast cancer remains the prototype in which the tyrosine kinase inhibitors are still being used clinically for molecular-targeted breast cancer treatment. Targeted therapy resistance in breast cancer (BC) can result from the proliferation of intrinsic and/or extrinsic instigators leading to relapse after a short remission. Intrinsic mechanisms (acquired before treatment) are a result of genetic mutations that result in a lack of target sensitivity in cancer cells. Extrinsic (acquired) resistance can result from; the emergence of the second proto-oncogene acting as the new driver gene, dysregulated expression of the drug targets as a result of new mutation, and alternations in tumor microenvironment (TME) post-treatment. To overcome the mutations and/or compensatory pathways that impart treatment resistance, often, combinational approaches to treatment are often required. Careful patient selection should be done before the start of targeted therapy to confirm the predictive response beforehand. Newer treatment agents are not without undesired side effects.