Purpose: In early-stage, EGFR mutation–positive (EGFR-M+) non–small cell lung cancer (NSCLC), surgery remains the primary treatment, without personalized adjuvant treatments. We aimed to identify risk factors for recurrence-free survival (RFS) to suggest personalized adjuvant strategies in resected early-stage EGFR-M+ NSCLC. Experimental Design: From January 2008 to August 2020, a total of 2,340 patients with pathologic stage (pStage) IB–IIIA, non-squamous NSCLC underwent curative surgery. To identify clinicopathologic risk factors, 1,181 patients with pStage IB–IIIA, common EGFR-M+ NSCLC who underwent surgical resection were analyzed. To identify molecular risk factors, comprehensive genomic analysis was conducted in 56 patients with matched case–controls (pStage II and IIIA and type of EGFR mutation). Results: Median follow-up duration was 38.8 months (0.5–156.2). Among 1,181 patients, pStage IB, II, and IIIA comprised 577 (48.9%), 331 (28.0%), and 273 (23.1%) subjects, respectively. Median RFS was 73.5 months [95% confidence interval (CI), 62.1–84.9], 48.7 months (95% CI, 41.2–56.3), and 22.7 months (95% CI, 19.4–26.0) for pStage IB, II, and IIIA, respectively (P < 0.001). In multivariate analysis of clinicopathologic risk factors, pStage, micropapillary subtype, vascular invasion, and pleural invasion, and pathologic classification by cell of origin (type II pneumocyte-like tumor cell vs. bronchial surface epithelial cell–like tumor cell) were associated with RFS. As molecular risk factors, the non-terminal respiratory unit (non-TRU) of the RNA subtype (HR, 3.49; 95% CI, 1.72–7.09; P < 0.01) and TP53 mutation (HR, 2.50; 95% CI, 1.24–5.04; P = 0.01) were associated with poor RFS independent of pStage II or IIIA. Among the patients with recurrence, progression-free survival of EGFR-tyrosine kinase inhibitor (TKI) in those with the Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) mutation signature was inferior compared with that of patients without this signature (8.6 vs. 28.8 months; HR, 4.16; 95% CI, 1.28–13.46; P = 0.02). Conclusions: The low-risk group with TRU subtype and TP53 wild-type without clinicopathologic risk factors might not need adjuvant EGFR-TKIs. In the high-risk group, with non-TRU subtype and/or TP 53 mutation, or clinicopathologic risk factors, a novel adjuvant strategy of EGFR-TKI with others, e.g., chemotherapy or antiangiogenic agents needs to be investigated. Given the poor outcome to EGFR-TKIs after recurrence in patients with the APOBEC mutation signature, an alternative adjuvant strategy might be needed.

中文翻译：

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早期 EGFR 突变 NSCLC 患者的临床、病理和分子预后因素

目的：在早期EGFR突变阳性（EGFR-M+）非小细胞肺癌（NSCLC）中，手术仍然是主要治疗方法，无需个性化辅助治疗。我们的目的是确定无复发生存 (RFS) 的危险因素，为切除的早期 EGFR-M+ NSCLC 提出个性化辅助策略。实验设计：2008年1月至2020年8月，共有2,340名病理分期（pStage）IB-IIIA非鳞状NSCLC患者接受了根治性手术。为了确定临床病理危险因素，对 1,181 名接受手术切除的 pStage IB-IIIA、常见 EGFR-M+ NSCLC 患者进行了分析。为了确定分子危险因素，对 56 名匹配病例对照（pStage II 和 IIIA 以及 EGFR 突变类型）的患者进行了全面的基因组分析。结果：中位随访时间为 38。8 个月（0.5–156.2）。在 1,181 名患者中，pStage IB、II 和 IIIA 分别包括 577 名 (48.9%)、331 名 (28.0%) 和 273 名 (23.1%) 受试者。pStage IB、II 和 II 期的中位 RFS 为 73.5 个月 [95% 置信区间 (CI)，62.1–84.9]、48.7 个月（95% CI，41.2–56.3）和 22.7 个月（95% CI，19.4–26.0） IIIA，分别（P＜0.001）。在临床病理危险因素的多变量分析中，分期、微乳头亚型、血管侵犯和胸膜侵犯以及按细胞来源进行的病理分类（II 型肺细胞样肿瘤细胞与支气管表面上皮细胞样肿瘤细胞）与 RFS 相关。作为分子危险因素，RNA 亚型的非终末呼吸单位（非 TRU）（HR，3.49；95% CI，1.72–7.09；P < 0.01）和 TP53 突变（HR，2.50；95% CI， 1.24–5.04；P = 0。01) 与较差的 RFS 相关，与 pStage II 或 IIIA 无关。在复发患者中，具有载脂蛋白 B mRNA 编辑催化多肽样 (APOBEC) 突变特征的患者使用 EGFR 酪氨酸激酶抑制剂 (TKI) 后的无进展生存期低于不具有该特征的患者（8.6 vs. 8.6）。 28.8 个月；HR，4.16；95% CI，1.28–13.46；P = 0.02）。结论：没有临床病理危险因素的 TRU 亚型和 TP53 野生型低危人群可能不需要辅助 EGFR-TKI。在具有非 TRU 亚型和/或 TP 53 突变或临床病理危险因素的高危人群中，需要研究 EGFR-TKI 与其他药物（例如化疗或抗血管生成药物）的新辅助策略。