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CBX4 and NOX4 Expression Are Associated With Chemoradiotherapy Response and Overall Survival in Locally Advanced Cervical Squamous Cell Carcinoma

Year: 2026

Type: article

Abstract: BACKGROUND: Tissue biomarkers may improve risk stratification in locally advanced cervical cancer before definitive concurrent chemoradiotherapy (CCRT). We evaluated pretreatment expression of chromobox 4 (CBX4), NADPH oxidase 4 (NOX4), specificity protein 1 (SP1), and copper transporter 1 (CTR1) in relation to CCRT response and overall survival. METHODS: In this retrospective 1:1 matched case-control study, pretreatment biopsies from 40 patients with locally advanced cervical squamous cell carcinoma (20 CCRT-resistant, 20 CCRT-sensitive) were quantified by AI-assisted digital pathology using H-scores. A parsimonious CBX4 + NOX4 logistic model was evaluated by apparent ROC, leave-one-out cross-validation (LOOCV), repeated stratified 5-fold cross-validation, and bootstrap optimism correction. Overall survival analyses were exploratory. RESULTS: CBX4 and NOX4 expression was lower in CCRT-resistant tumors (median H-score: CBX4, 40.47 vs. 79.62; NOX4, 7.00 vs. 53.93; both p < 0.001), whereas SP1 and CTR1 did not differ. Apparent AUCs were 0.840 for CBX4 and 0.843 for NOX4. The two-marker model had an apparent AUC of 0.903, LOOCV AUC 0.845, repeated 5-fold CV AUC 0.854 ± 0.022, and bootstrap-corrected AUC 0.883. High CBX4 and NOX4 expression was associated with better 5-year overall survival; in joint Cox models, hazard ratios per 1-SD increase were 0.31 (95% CI 0.13-0.74) for CBX4 and 0.48 (0.26-0.90) for NOX4. No histochemically detectable copper deposits were observed. CONCLUSIONS: Lower pretreatment CBX4 and NOX4 expression was associated with a CCRT-resistant phenotype and poorer overall survival in this small, response-enriched cohort. Internal resampling suggested discrimination, but same-dataset marker selection may introduce residual optimism and does not establish generalizability. Independent validation in a consecutively recruited cohort is required before clinical application. No mechanisms involving DNA repair, ROS, or chemoradiotherapy sensitivity were established.

Source: Cancer Medicine

DOI: 10.1002/cam4.72402