Combined EGFR / TGF ‐α Expression and Dynamic Plasma EBV DNA Monitoring for Prognostic Stratification in Stage II Nasopharyngeal Carcinoma: A Prospective Cohort Study

BACKGROUND: Risk stratification within anatomically homogeneous stage II nasopharyngeal carcinoma (NPC) remains imprecise. We integrated serial plasma Epstein-Barr virus (EBV) DNA monitoring with pretreatment EGFR/TGF-α immunohistochemistry to evaluate their combined prognostic value. METHODS: Sixty-six prospectively enrolled stage II (T2N0M0) NPC patients received cisplatin-based concurrent chemoradiotherapy (IMRT or VMAT, 66-70 Gy). Plasma EBV DNA was quantified at baseline and at prespecified surveillance intervals (every 2-3 months for the first 2 years, then every 6 months) during 5-year follow-up. EGFR and TGF-α were graded on a four-tier IHC scale (++/+++ = positive). A parsimonious multivariable Cox model with three biologically prespecified covariates (EGFR, TGF-α, post-treatment EBV-abnormal status) and an exploratory EGFR × TGF-α interaction were prespecified; a composite three-tier risk score (0/1/≥ 2 adverse biomarkers) was constructed. RESULTS: Median potential follow-up (reverse Kaplan-Meier) was 58.6 months. EGFR was positive in 60.6%, TGF-α in 53.0%, and pretreatment EBV DNA detectable in 87.9%. Plasma EBV-DNA crossed the 500 copies/mL detection threshold a median of 3.2 months (range, 1.4-5.8) prior to radiologic recurrence in all six serially monitored patients who developed clinical recurrence. Post-treatment EBV-abnormal kinetics (aHR 3.85, 95% CI: 1.60-9.27; p = 0.003) and EGFR positivity (aHR 2.58, 1.08-6.16; p = 0.033) were independent adverse OS prognostic factors; TGF-α showed a non-significant trend (aHR 1.98; p = 0.124). The three-tier composite score discriminated 5-year OS at 100% (low-risk, n = 11), 69.2% (intermediate, n = 26), and 26.4% (high-risk, n = 29; median OS 28.4 months; overall log-rank p < 0.001). CONCLUSION: A parsimonious three-biomarker risk score integrating EGFR/TGF-α expression and post-treatment EBV DNA kinetics provides highly discriminative prognostic stratification in stage II NPC, identifying candidates for both treatment intensification and de-intensification. External validation is warranted.