Ferroptosis-related gene signature-based subtype identification of triplenegative breast cancer to prioritize treatment strategies

Yongzhen Chen¹Xiaoying Huang²Junqi Wang³Hu Chao¹Zheng Yanan¹Yumeng Wang¹Shuqian Zheng¹Guozhong Ji^1*Qiang You^1*

• ¹Nanjing Medical University, Nanjing, China
• ²University of Macau, Taipa, Macau Region, China
• ³Shenzhen Traditional Chinese Medicine Hospital, Shenzhen ，Guangdong, China

Purpose Ferroptosis, an iron-dependent form of regulated cell death (RCD), had been proved to affect the response to antineoplastic therapies. However, little is known about the role of ferroptosis in chemotherapy and immune checkpoint inhibitors (ICIs) therapy responses, as well as molecular subtype identification of triple-negative breast cancer (TNBC).We performed unsupervised clustering to stratify patients with TNBC in FUSCC TNBC cohort into distinct ferroptosis-related subtypes according to the expression of eight ferroptosis-related genes (FRGs), EMC2, FTH1, HMOX1, LPCAT3, NOX4, SOCS1, BAP1 and ISCU. Gene Ontology (GO) and Gene Set Variation Analysis (GSVA) were conducted to characterize the immune phenotype and enriched pathways of distinct subtypes of TNBC. We constructed the FerrScore model to identify the most promising candidate compounds and predict ICIs therapy benefits for patients with TNBC.We identified two distinct ferroptosis-related subtypes with different overall survival (OS). Patients in cluster 1 exhibit better OS, which have a phenotype of "hot" tumor with abundant immune cell infiltration and higher expression of immune checkpoints compare to cluster 2. We screened Everolimus as the most promising candidate drug for patients with high FerrScore referred to comprehensive factors including CMap score, experimental evidence and clinical trial status. Further, we confirmed FerrScore was a potentially powerful metric to predict anti-PD-L1, anti-PD-1 and anti-PD-1&CTLA-4 ICIs therapy benefits.Ferroptosis reprogrammed the tumor microenvironment (TME), and classified patients into distinct subgroups with significantly different OS. FerrScore was a potentially powerful metric to screen candidate compounds and predict ICIs therapy benefits for patients with TNBC, which prioritized clinical treatment strategies.