Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada.
Medical Oncology Department, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Sanguinet Street, Montreal, QC, Canada; Department of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, 900 Saint-Denis Street, Montreal, QC, Canada.
Cancer Treat Res Commun. 2023;37:100767. doi: 10.1016/j.ctarc.2023.100767. Epub 2023 Oct 10.
BACKGROUND: PD-L1 expression is used to predict NSCLC response to ICIs, but its performance is suboptimal. The impact of KRAS mutations in these patients is unclear. Studies evaluating co-mutations in TP53, STK11 and KEAP1 as well as the NLR showed that they may predict the benefit of ICIs. PATIENTS & METHODS: This is a retrospective study of patients with NSCLC treated with ICIs at the CHUM between July 2015 and June 2020. OS and PFS were compared using Kaplan-Meier and logrank methods. Co-mutations in TP53, STK11 and KEAP1 as well as the NLR were accounted for. ORR and safety were compared using Wald method. RESULTS: From 100 patients with known KRAS status, 50 were mutated (KRAS). Mutation in TP53, STK11 and KEAP1 were present, and their status known in, respectively, 19/40 (47.5 %), 8/39 (20.5 %) and 4/38 (10.5 %) patients. STK11 and KEAP1 were associated with shorter overall survival when compared with wild type tumors (respectively median OS of 3.3 vs 20.4, p = 0.0001 and 10.1 vs 17.7, p = 0.24). When KRAS status was compounded with STK11/KEAP1, KRAS trended to a better prognosis in STK11+KEAP1 tumors (median OS 21.1 vs 15.8 for KRAS, p = 0.15), but not for STK11+/-KEAP1 tumors. The NLR was strongly impacted by STK11 (6.0vs 3.6, p = 0.014) and TP53 (3.2vs 4.8, p = 0.048), but not by KEAP1 or KRAS mutations. CONCLUSION: STK11 and KEAP1 are adverse predictors of ICI therapy benefit. The NLR is strongly impacted by STK11 but not by KEAP1, suggesting differences in their resistance mechanism. In STK11-KEAP1 tumors, KRAS seem associated with improved survival in NSCLC patients treated with ICIs. MICROABSTRACT: Response of NSCLC to immunotherapy is not easily predictable. We conducted a retrospective study in 100 patients with NSCLC and a known KRAS status. By accounting for different co-mutations, KRAS mutation was found to be associated with a better median overall survival in STK11 and KEAP1 wild-type tumors (21.1 vs 15.8, p = 0.15). NLR was impacted by STK11, but not KEAP1 mutation, suggesting a difference in their resistance mechanism.
背景：PD-L1 表达被用于预测 NSCLC 对免疫检查点抑制剂（ICI）的反应，但表现并不理想。KRAS 突变患者的影响尚不清楚。评估 TP53、STK11 和 KEAP1 共突变以及中性粒细胞与淋巴细胞比值（NLR）的研究表明，它们可能预测 ICI 的获益。
患者与方法：这是一项回顾性研究，纳入了 2015 年 7 月至 2020 年 6 月在 CHUM 接受 ICI 治疗的 NSCLC 患者。采用 Kaplan-Meier 和对数秩检验比较总生存期（OS）和无进展生存期（PFS）。考虑了 TP53、STK11 和 KEAP1 共突变以及 NLR。采用 Wald 方法比较客观缓解率（ORR）和安全性。
结果：在 100 例已知 KRAS 状态的患者中，50 例存在 KRAS 突变（KRAS）。TP53、STK11 和 KEAP1 共突变的情况分别为 19/40（47.5%）、8/39（20.5%）和 4/38（10.5%）。与野生型肿瘤相比，STK11 和 KEAP1 突变与更短的 OS 相关（分别为 3.3 比 20.4，p=0.0001 和 10.1 比 17.7，p=0.24）。当 KRAS 状态与 STK11/KEAP1 复合时，KRAS 在 STK11+KEAP1 肿瘤中呈现更好的预后趋势（KRAS 的中位 OS 分别为 21.1 比 15.8，p=0.15），但在 STK11+/−KEAP1 肿瘤中则不然。NLR 受 STK11（6.0 比 3.6，p=0.014）和 TP53（3.2 比 4.8，p=0.048）强烈影响，但不受 KEAP1 或 KRAS 突变影响。
结论：STK11 和 KEAP1 是 ICI 治疗获益的不良预测因素。NLR 受 STK11 强烈影响，但不受 KEAP1 影响，提示它们的耐药机制不同。在 STK11-KEAP1 肿瘤中，KRAS 似乎与接受 ICI 治疗的 NSCLC 患者的生存改善相关。
微摘要：NSCLC 对免疫治疗的反应不易预测。我们对 100 例 NSCLC 患者进行了回顾性研究，这些患者的 KRAS 状态已知。通过考虑不同的共突变，发现 KRAS 突变与 STK11 和 KEAP1 野生型肿瘤的中位 OS 延长相关（21.1 比 15.8，p=0.15）。NLR 受 STK11 影响，但不受 KEAP1 突变影响，提示它们的耐药机制不同。
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