STK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). Surgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. Among 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1–3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2–4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5–10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6–5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. This analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.

中文翻译：

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STK11/LKB1 改变恶化 KRAS 突变早期非鳞状非小细胞肺癌的不良预后，基于 2 期 IFCT TASTE 试验的结果

STK11/LKB1 突变与 PD-1 轴抑制剂的原发性耐药以及晚期 KRAS 突变肺腺癌的不良预后相关。本研究旨在评估 STK11/LKB1 改变在局限性非鳞状非小细胞肺癌（非鳞状 NSCLC）中的预后意义。对随机辅助 II 期试验（NCT00775385 IFCT-1801 TASTE 试验）中接受完全切除的 IIa、IIb 或 IIIa 期（排除 N2）非鳞状非小细胞肺癌患者的手术样本进行了检查。患者接受标准化疗（培美曲塞顺铂）或基于 EGFR 突变（厄洛替尼）和 ERCC1 表达的个性化治疗。使用靶向 NGS 分析肿瘤分子谱，并与总生存期 (OS) 和无病生存期 (DFS) 相关，并调整相关临床变量。此外，还评估了治疗组之间的相互作用以及术后血浆样本中 OS、PD-L1 表达和肿瘤循环 DNA 的分子变化。在 134 名患者（主要是患有腺癌的男性吸烟者）中，KRAS 突变与较短的 DFS（HR：1.95，95 % CI：1.1–3.4，p = 0.02）和 OS（HR：2.32，95 % CI：1.2–4.6， p = 0.014）。孤立的 STK11/LKB1 突变 (n = 18) 并未显着影响 DFS 或 OS。然而，在 KRAS 突变样本 (n = 53) 中，同时发生 STK11/LKB1 突变的患者 (n = 10) 表现出显着较短的 DFS（HR：3.85，CI：1.5–10.2，p = 0.006），并且 OS 有缩短的趋势（HR：1.80，CI：0.6–5.3，p = 0.28）。未发现 PD-L1 表达、其他基因突变、无进展生存期 (PFS) 或 OS 之间存在关联。该分析强化了 KRAS 突变作为局部非鳞状 NSCLC 复发和生存不良的预测因素。此外，伴随 STK11/LKB1 突变的存在加剧了 KRAS 突变亚群的预后。这些发现强调了这些分子标志物的临床相关性及其对非鳞状非小细胞肺癌治疗策略的潜在影响。