Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy

• Published in: EBioMedicine 2021-09, Vol.71, p.103560-103560, Article 103560
• Main Authors: Sha, Rui, Xu, Yaqian, Yuan, Chenwei, Sheng, Xiaonan, Wu, Ziping, Peng, Jing, Wang, Yaohui, Lin, Yanping, Zhou, Liheng, Xu, Shuguang, Zhang, Jie, Yin, Wenjin, Lu, Jinsong
• Format: Article
• Language: English
• Subjects: ACSL4; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor; Biopsy; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Cell Line, Tumor; Coenzyme A Ligases - genetics; Computational Biology; Databases, Genetic; Female; Ferroptosis; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic; GPX4; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Middle Aged; Neoadjuvant chemotherapy; Neoadjuvant Therapy; Neoplasm Staging; Odds Ratio; Pathological complete response; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Prognosis; Research Paper; Treatment Outcome; Young Adult
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2021.103560

Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy. This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression. A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc. This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms. This work was supported by Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908],