The Effect of HER3 Expression on Prognosis in EGFR-Mutant Non-Small Cell Lung Cancer: A Retrospective Real-World Study

<i>Background and Objectives</i>: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and remains a leading cause of cancer-related mortality worldwide. EGFR-targeted tyrosine kinase inhibitors (TKIs) have substantially improved outcomes in EGFR-mutant NSCLC; however, primary and acquired resistance continues to limit their long-term efficacy. HER3 (receptor tyrosine-protein kinase ErbB3), a member of the ErbB receptor family, has been implicated in TKI resistance through heterodimerization with EGFR and HER2, leading to downstream PI3K/AKT pathway activation. Despite its biological plausibility as a resistance mediator, the clinical significance of HER3 expression as a prognostic and predictive biomarker in EGFR-mutant NSCLC has not been thoroughly characterized in real-world cohorts. <i>Materials and Methods</i>: This retrospective, single-center study included 52 patients diagnosed with EGFR-mutant NSCLC who received TKI therapy at Afyonkarahisar Health Sciences University between January 2011 and September 2023. HER3 protein expression was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumor tissue sections using the Huabio anti-HER3 antibody (clone PD00-44, 1:2000 dilution). Staining in more than 30% of tumor cells was considered HER3-positive; membranous staining intensity was scored on a 1-3 scale. Progression-free survival (PFS1, PFS2) and overall survival (OS) were analyzed using the Kaplan-Meier method and log-rank test. Statistical significance was set at <i>p</i> < 0.05. <i>Results</i>: Of 52 patients (55.8% female; mean age 64.5 years), 59.6% received chemotherapy and 40.4% received an EGFR TKI as first-line treatment; erlotinib constituted 71.2% of targeted therapies. In the first-line TKI group, HER3-negative patients had a numerically longer median PFS1 compared with HER3-positive patients (14.0 vs. 7.1 months; <i>p</i> = 0.285); however, this difference did not reach statistical significance and should be interpreted with caution given the small sample size. In contrast, among patients receiving first-line chemotherapy, HER3 staining status did not meaningfully affect PFS1 (4.1 vs. 2.5 months; <i>p</i> = 0.063). In second-line treatment, HER3-positive patients who received TKI after prior chemotherapy demonstrated a PFS2 comparable to or slightly exceeding that of HER3-negative patients (21.8 vs. 19.8 months; <i>p</i> = 0.49), suggesting that the sequencing of chemotherapy before TKI may attenuate the adverse effect of HER3 positivity. Median OS was 15.1 months in HER3-negative patients and 12.7 months in HER3-positive patients (<i>p</i> = 0.824); this numerical difference of approximately 3 months did not reach statistical significance and should therefore be interpreted cautiously. Among patients receiving TKI in the first line, HER3-positive patients had a shorter median OS than HER3-negative patients (9.6 vs. 14.2 months), whereas those receiving TKI in the second line showed a trend toward longer OS in HER3-positive patients (20.5 vs. 17.2 months). <i>Conclusions</i>: HER3 expression was associated with reduced first-line TKI efficacy in EGFR-mutant NSCLC, suggesting a possible role for HER3 in primary TKI resistance; however, these findings are exploratory and did not reach statistical significance. The observation that HER3-positive patients who received chemotherapy before TKI demonstrated outcomes comparable to HER3-negative patients raises the hypothesis that treatment sequencing may potentially influence the impact of HER3 positivity, though this requires prospective validation before any clinical conclusions can be drawn. These results suggest that HER3 expression may warrant further investigation as a candidate biomarker for treatment sequencing decisions and as a potential therapeutic target in EGFR-mutant NSCLC. Prospective studies evaluating chemotherapy-TKI sequencing and HER3-directed agents such as patritumab deruxtecan (HER3-DXd) in HER3-positive patients are needed to confirm these preliminary observations.