Tumour Microenvironment (TME) Targeting as a Promising Therapeutic Strategy in High Risk TNBC Patients

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous sub-type of breast cancer. Within this subtype, a number of other distinct subsets presenting with highly genetically, clinically, pathophysiologically diverse tumors have been recognized. These subsets range from the highly proliferative, invasive and very aggressive BL subtypes, to the low proliferating, indolent tumors with luminal characteristics not only associated with relatively worse prognosis and poor treatment outcomes, but also chemo resistant. Given the global pathological complete response (pCR) for TNBC patients after neoadjuvant chemotherapy (NACT)of only 20 - 30%, the limitation of chemotherapy due to intolerability by majority of patients, new and more effective strategies for improving the treatment outcomes, while at the same time minimizing cytotoxicity, are urgently required. The main objective of this systematic review and metaanalysis was to evaluate the utility of TME as a promising therapeutic target in the high risk TNBC patients. This was done by pooling multiple randomized controlled trials studying the current therapeutic interventions available for this subtype in a single analytic model. Relevant data was systematically searched from research databases such as PubMed, Google Scholar, Science Direct, reviewed and articles selected for this study using a predefined eligibility criterion. The required information was extracted using standardized methods of extraction, analyzed using both narrative and statistical synthesis of the available evidence. The research evidence obtained from the synthesis was organized and summarized using summary tables. Some key results of this study include the finding that addition of TME targeting agents to standard chemotherapy prolongs the overall survival of the patients compared to standard chemotherapy alone. Fundamentally, TME targeting agents were able to achieve not just some of the highest relative risk reductions (e.g. 68% with mTOR Inhibitors), but also very high pCR of up to 88.2% (addition of Carboplatin to the standard NACT). Given the biological complexity, heterogeneity, specificity of TNBC subtypes and TME, this makes TME targeting an attractive strategy for not just optimizing the current chemotherapy interventions, but also minimizing the well-recognized associated cytotoxicity. These findings will have a direct impact in the current treatment practices and management of TNBC and breast cancer in Kenya.