ACTN4 Gene Amplification and Actinin‐4 Protein Expression for Osimertinib Efficacy in EGFR‐Mutant NSCLC

Actinin‐4 (gene name: ACTN4 ) is an actin‐bundling protein implicated in cancer invasion and metastasis. This study evaluated whether ACTN4 amplification and actinin‐4 protein expression were associated with osimertinib efficacy in epidermal growth factor receptor‐mutant non‐small cell lung cancer. We retrospectively analyzed 63 patients with epidermal growth factor receptor‐mutant non‐small cell lung cancer treated with osimertinib as first‐line treatment. Immunohistochemistry was performed for pretreatment tumor tissues. Actinin‐4 immunohistochemistry positivity was defined as positive staining of ≥ 30% tumor cells. In positive cases, ACTN4 amplification was assessed via fluorescence in situ hybridization. Progression‐free survival and overall survival were compared across groups. Among 63 patients (median age: 73 years, 52 with Eastern Cooperative Oncology Group performance status 0–1, 63 with adenocarcinoma; epidermal growth factor receptor mutations: 19del/L858R/uncommon = 32/24/7), there were 33 and 30 actinin‐4 immunohistochemistry‐positive and actinin‐4 immunohistochemistry‐negative cases, respectively. The propensity score‐weighted overall survival and progression‐free survival were significantly shorter for actinin‐4 immunohistochemistry‐positive patients than for actinin‐4 immunohistochemistry‐negative patients (overall survival: hazard ratio, 2.76; 95% confidence interval, 1.02–7.45; progression‐free survival: hazard ratio, 1.91; 95% confidence interval, 1.03–3.54). Among the 33 actinin‐4 immunohistochemistry‐positive cases, four showed positivity in ACTN4 fluorescence in situ hybridization. Overall survival and progression‐free survival were numerically shorter for patients with ACTN4 positivity than for those with ACTN4 negativity in fluorescence in situ hybridization. The findings suggest that ACTN4 amplification and actinin‐4 protein expression are prognostic markers for poor osimertinib efficacy in epidermal growth factor receptor‐mutant non‐small cell lung cancer.