Low-density lipoprotein receptor–related protein 1 overexpression as an identifier of brain metastasis and survival for patients with lung cancer.

Abstract

2029 Background: Brain metastasis (BM) is a major cause of mortality in lung cancer. Low-density lipoprotein receptor–related protein 1 (LRP1) has been implicated in tumor invasion and microenvironment regulation; however, its clinical relevance in lung cancer brain metastasis remains unclear. Methods: This retrospective, single-center study included 103 lung cancer patients (including NSCLC and SCLC) diagnosed between January 2013 and February 2025. LRP1 protein expression was evaluated by immunohistochemistry in primary lung tumors and lesions of lung cancer with brain metastasis (unpaired samples). Mean optical density was quantified, and the optimal cutoff for high versus low expression was determined using receiver operating characteristic analysis. Overall survival (OS) and distant metastasis–free survival (DMFS) were assessed using Kaplan–Meier analysis and Cox proportional hazards models, adjusting for pathological type, age, sex, T stage, and N stage. Gene set variation analysis (GSVA), immune cell infiltration analysis (CIBERSORT), and immunotherapy response prediction using TIDE were performed to explore biological characteristics associated with LRP1 expression. Results: LRP1 expression was significantly higher in lung cancer tissues from patients with BM compared with those without BM (P < 0.0001). Among patients with BM, high LRP1 expression was associated with poorer OS (P = 0.0352) and shorter DMFS (P = 0.0183). In multivariable analysis, high LRP1 expression remained independently associated with inferior OS (HR 3.064, 95% CI 1.039–9.034; P = 0.042). GSVA suggested that LRP1-high tumors may be characterized by enrichment of TGF-β, NOTCH, and HEDGEHOG signaling pathways. Immune deconvolution analysis revealed higher infiltration of resting memory CD4⁺ T cells and M0 macrophages in the LRP1-high group. LRP1-low expression was associated with a more favorable predicted response to immunotherapy, as indicated by lower TIDE scores. Conclusions: LRP1 overexpression is associated with brain metastasis, unfavorable survival, and distinct immune features in lung cancer, suggesting its potential value as a prognostic biomarker.