INTRODUCTION The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging due to intratumor heterogeneity. We aimed to explore a refined stratification mode based on the integrated analysis of ctDNA tracking. METHODS ctDNA was prospectively collected at baseline and every eight weeks in advanced treatment-naïve EGFR-mutant LUAD patients under gefitinib treatment enrolled in a phase II trial, and analyzed using next-generation sequencing of a 168-gene panel. RESULTS Three subgroups categorized by baseline co-mutations: EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%) and EGFR-sensitizing mutations with other driver mutations (24, 13.3%), exhibited distinct progression-free survival (PFS) and overall survival (OS) [PFS 13.2 (11.3-15.2) vs. 9.3 (7.6-10.5) vs. 4.0 (2.4-9.3) months; OS 32.0 (29.2-41.5) vs. 21.7 [(19.3-27.0) vs. 15.5 (10.5-33.7) months], providing evidence for initial stratification. 63.7% of the patients achieved week-8 ctDNA-clearance, with significant difference among three subgroups (74.5% vs. 64.0% vs. 29.4%, P=0.004, fisher's exact test). Patients without week-8 ctDNA-clearance had worse PFS [clearance vs. non-clearance 11.2 (9.9-13.2) vs. 7.4 (5.6-9.6) months, P=0.016, cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, with significant difference in non-p.T790M mutations among three subgroups (7.5% vs. 15.7% vs. 80.0%, P<0.001, fisher's exact test), giving clues to post-line treatment. CONCLUSIONS The patients with baseline co-mutations and ctDNA non-clearance at first visit might require combined therapy due to limited survival benefit of EGFR-TKI monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.

中文翻译：

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基于基线伴随突变和纵向循环肿瘤 DNA 监测的精细分层在吉非替尼治疗下晚期 EGFR 突变肺腺癌中

引言 由于肿瘤内异质性，EGFR 突变型肺腺癌 (LUAD) 的最佳治疗方法仍然具有挑战性。我们旨在探索一种基于 ctDNA 跟踪综合分析的精细分层模式。方法 在接受吉非替尼治疗的接受吉非替尼治疗的晚期 EGFR 突变 LUAD 患者中，在基线和每八周前瞻性收集 ctDNA，并使用 168 个基因组的下一代测序进行分析。结果 按基线共突变分类的三个亚组：EGFR 致敏突变 (59, 32.8%)、EGFR 致敏突变与抑癌突变 (97, 53.9%) 和 EGFR 致敏突变与其他驱动突变 (24, 13.3%) ，表现出不同的无进展生存期 (PFS) 和总生存期 (OS) [PFS 13.2 (11.3-15.2) vs. 9.3 (7.6-10.5) vs. 4.0 (2. 4-9.3) 个月；OS 32.0 (29.2-41.5) 与 21.7 [(19.3-27.0) 与 15.5 (10.5-33.7) 个月]，为初始分层提供了证据。63.7% 的患者实现了第 8 周 ctDNA 清除，三个亚组之间存在显着差异（74.5% vs. 64.0% vs. 29.4%，P=0.004，fisher 精确检验）。没有第 8 周 ctDNA 清除的患者具有更差的 PFS [清除 vs. 未清除 11.2 (9.9-13.2) 个月 vs. 7.4 (5.6-9.6) 个月，P=0.016，cox 回归]，尤其是在第二亚组 [5.8 ( 5.6-11.5) 个月]，提示在治疗期间进行适应性分层的必要性。随访期间，56.0% 和 20.8% 的患者最终携带 p.T790M 和非 p.T790M 突变，三个亚组之间的非 p.T790M 突变差异显着（7.5% vs. 15.7% vs. 80.0%） , P<0.001, 费舍尔精确检验), 为线后治疗提供线索。结论 由于 EGFR-TKI 单药治疗的生存获益有限，首次访视时具有基线共突变和 ctDNA 未清除的患者可能需要联合治疗。我们提出了一种精细化分层模式，用于 EGFR 突变 LUAD 的全程管理。