Drug Repositioning and Subgroup Discovery for Precision Medicine Implementation in Triple Negative Breast Cancer

SIMPLE SUMMARY: The heterogeneity of complicated diseases like cancer negatively affects patients’ responses to treatment. Finding homogeneous subgroups of patients within the cancer population and finding the appropriate treatment for each subgroup will improve patients’ survival. In this study, we focus on triple-negative breast cancer (TNBC), where approximately 80% of patients do not entirely respond to chemotherapy. Our aim is to find subgroups of TNBC patients and identify drugs that have the potential to tailor treatments for each group through drug repositioning. After applying our method to TNBC, we found that different targeted mechanisms were suggested for different groups of patients. Our findings could help the research community to gain a better understanding of different subgroups within the TNBC population and can help the drugs to be repurposed with explainable results regarding the targeted mechanism. ABSTRACT: Breast cancer (BC) is the leading cause of death among female patients with cancer. Patients with triple-negative breast cancer (TNBC) have the lowest survival rate. TNBC has substantial heterogeneity within the BC population. This study utilized our novel patient stratification and drug repositioning method to find subgroups of BC patients that share common genetic profiles and that may respond similarly to the recommended drugs. After further examination of the discovered patient subgroups, we identified five homogeneous druggable TNBC subgroups. A drug repositioning algorithm was then applied to find the drugs with a high potential for each subgroup. Most of the top drugs for these subgroups were chemotherapy used for various types of cancer, including BC. After analyzing the biological mechanisms targeted by these drugs, ferroptosis was the common cell death mechanism induced by the top drugs in the subgroups with neoplasm subdivision and race as clinical variables. In contrast, the antioxidative effect on cancer cells was the common targeted mechanism in the subgroup of patients with an age less than 50. Literature reviews were used to validate our findings, which could provide invaluable insights to streamline the drug repositioning process and could be further studied in a wet lab setting and in clinical trials.