Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that cannot be treated with endocrine therapy and Her2-targeted therapy. Although its prevalence among newly diagnosed breast cancers is approximately 12.7%, it accounts for 40% of breast cancer-related mortality. Higher mortality rates among TNBC is partly because of the lack of targeted therapies and the development of resistance to chemotherapy. We discuss several important mechanisms that lead to chemoresistance and focus on important pathways and biological features that can be potentially exploited to develop therapies for TNBC. TNBC is currently defined by the absence of ER, PR, and Her2 and the greatest leap for TNBC would be our ability to characterize them with the presence of ‘x’ proteins. With this review, we intend to highlight the key nodes of TNBC and push the field towards connecting the dots between key features of TNBC and novel drug(s). ABSTRACT: Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management.