Development and Validation of a New Prediction Criteria for Neoadjuvant Chemotherapy Response in Locally Advanced Gastric Cancer Based on Ferroptosis-Related Biomarkers.

BACKGROUND: The efficacy of neoadjuvant chemotherapy (NAC) combined with surgery and postoperative adjuvant chemotherapy in improving the prognosis of locally advanced gastric cancer (LAGC) has been confirmed. Nevertheless, there is still no effective tool to predict the response to NAC in gastric cancer patients. METHODS: This study included a total of 184 patients (118 in the training cohort and 66 in the testing cohort) treated with oxaliplatin + fluorouracil-based NAC from January 2010 to July 2022. Immunohistochemistry staining of biomarkers was carried out on the endoscopy biopsy specimens before receiving treatment. Logistic regression was performed to explore the predictive biomarkers of response to NAC, and internal verification was carried out by using the bootstrap method. RESULT: Ferroptosis increased significantly in NAC-sensitive LAGC. Among the molecular markers related to ferroptosis, Fe(2+), ACSL4, DHODH, GCH1, and FSP1 showed significant differences between the sensitive and nonsensitive groups. Logistic regression analysis revealed Fe(2+), ACSL4, DHODH, and GCH1 as predictors of the efficacy of NAC. A nomogram prediction model was established based on identified biomarkers. The area under the ROC curve (AUC) of the nomogram model was 0.89, which indicated that the prediction results of the model were highly consistent with the actual situation (Hosmer-Lemeshow test p = 0.684). The AUC of the nomogram model in the external validation set (N = 66) was 0.82, indicating that the model has certain predictive ability. CONCLUSION: This study revealed the critical value of biomarkers related to ferroptosis serving as novel predictive biomarkers for patients with LAGC receiving NAC.