Rare epidermal growth factor receptor (EGFR) mutations in completely resected stage I lung adenocarcinoma: a real-world study of mutation spectrum, clinicopathological features, and prognosis

Abstract

Background Rare epidermal growth factor receptor (EGFR) mutations are heterogeneous, and their significance after complete resection of stage I lung adenocarcinoma (LUAD) remains unclear. We evaluated the mutation spectrum, clinicopathological correlates, postoperative recurrence patterns, and survival outcomes of a study-defined primary rare EGFR mutation cohort after predefined exclusion of isolated T790M, exon 20 insertion-only disease, and major driver co-alterations. Methods Consecutive patients who underwent R0 resection for pathological stage I LUAD with postoperative EGFR testing at West China Hospital between 2011 and 2024 were retrospectively identified. Rare mutation subtypes, compound mutation patterns, recurrence-free survival (RFS), and overall survival (OS) were assessed. Prognostic factors were evaluated using Cox regression, and outcomes were compared with classical EGFR mutations using 1:2 propensity score matching (PSM). Results Among 1,357 EGFR-positive stage I LUADs, 176 patients formed the primary rare-mutation cohort. The most frequent rare mutation groups were G719X (n=104), L861Q (n=71), and S768I (n=24), with distinct compound mutation patterns. Five-year OS and RFS were 95.8% and 93.5%, respectively. A micropapillary component was associated with shorter RFS in the primary multivariable model [hazard ratio (HR) =4.062, 95% confidence interval (CI): 1.134–14.544; P=0.03]. The unweighted number of pathological high-risk features was associated with RFS (global log-rank P=0.039), whereas adjuvant systemic therapy among stage IB patients and compound rare mutation status were not significantly associated with RFS. After PSM under comparable observed postoperative management, the rare-mutation group had similar OS and a lower recurrence risk than the classical-mutation group. Conclusions After exclusion of isolated T790M and exon 20 insertion-only disease, completely resected stage I LUAD with rare EGFR mutations showed favorable long-term outcomes. Compared with classical mutations, rare mutations were associated with lower recurrence risk and similar OS after treatment-balanced matching. Pathological features, particularly a micropapillary component, may help identify patients at higher risk of recurrence.