根据KRAS、TP53、KEAP1和SMARCA4状态，STK11突变与接受一线免疫治疗或化疗免疫治疗的晚期非小细胞肺癌的不良预后相关。
STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status.
作者信息
De Giglio Andrea, De Biase Dario, Favorito Valentina, Maloberti Thais, Di Federico Alessandro, Zacchini Federico, Venturi Giulia, Parisi Claudia, Gustavo Dall'Olio Filippo, Ricciotti Ilaria, Gagliano Ambrogio, Melotti Barbara, Sperandi Francesca, Altimari Annalisa, Gruppioni Elisa, Tallini Giovanni, Gelsomino Francesco, Montanaro Lorenzo, Ardizzoni Andrea
机构信息
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
出版信息
Lung Cancer. 2025 Jan;199:108058. doi: 10.1016/j.lungcan.2024.108058. Epub 2024 Dec 20.
BACKGROUND
The upfront treatment of non-oncogene-addicted NSCLC relies on immunotherapy alone (ICI) or in combination with chemotherapy (CT-ICI). Genomic aberrations such as KRAS, TP53, KEAP1, SMARCA4, or STK11 may impact survival outcomes.
METHODS
We performed an observational study of 145 patients treated with first-line IO or CT-ICI for advanced non-squamous (nsq) NSCLC at our institution tested with an extensive lab-developed NGS panel. The primary objective was to assess the clinical outcomes of STK11-mutated patients. Then, we performed an external validation through the public OAK/POPLAR dataset, including nsq NSCLC patients treated with single-agent ICI or CT.
RESULTS
Most patients were male (59.7 %), former smokers (61.1 %), with ECOG PS 0-1 (84 %), and received first-line CT-IO (58.6 %). 44.8 % had a mutation in KRAS, 21.4 % in KEAP1, 50.3 % in TP53, 13.1 % in SMARCA4, and 14.4 % in the STK11 gene. The mOS was 8 mo. (95 % CI, 5-16.7) for STK11 mutated pts and 17.3 mo. for STK11 wild-type patients (95 % CI, 8.9-24.4) (p = 0.038). TP53 (8.3 vs 17.3), KRAS (9.2 vs 15.9), and KEAP1 (8.9 vs 15.9) mutated patients evidenced a trend for dismal mOS. SMARCA4 status had no impact on mOS. STK11 mutations were detrimental to OS in the univariate (HR 1.74, p = 0.041) and multivariate model (HR 1.97, p = 0.025) after adjusting for sex, age, ECOG PS, treatment (ICI vs CT-ICI), KRAS, KEAP1, TP53, and SMARCA4 status. Genomic alterations did not impact the mPFS in our cohort. Within the OAK/POPLAR dataset, STK11 mutations (60/818 pts) were significantly associated with increased death risk in the univariate (HR 2.01, p < 0.001) and multivariate model (HR 1.66, p = 0.001) after adjusting for age, sex, treatment (ICI vs CT), KRAS, KEAP1, TP53, and SMARCA4 status.
CONCLUSION
STK11 aberrations hampered the mOS of nsq NSCLC patients treated with first-line ICI or CT-ICI. The negative prognostic impact seems to be unrelated to ICI administration.
背景
非致癌基因成瘾性非小细胞肺癌（NSCLC）的初始治疗依赖于单纯免疫疗法（ICI）或与化疗联合（CT-ICI）。KRAS、TP53、KEAP1、SMARCA4或STK11等基因组畸变可能影响生存结果。
方法
我们对在本机构接受一线IO或CT-ICI治疗的145例晚期非鳞状（nsq）NSCLC患者进行了一项观察性研究，这些患者使用广泛的实验室开发的NGS检测板进行了检测。主要目的是评估STK11突变患者的临床结局。然后，我们通过公开的OAK/POPLAR数据集进行了外部验证，该数据集包括接受单药ICI或CT治疗的nsq NSCLC患者。
结果
大多数患者为男性（59.7%），既往吸烟者（61.1%），ECOG PS为0-1（84%），并接受一线CT-IO（58.6%）。44.8%的患者KRAS发生突变，21.4%的患者KEAP1发生突变，50.3%的患者TP53发生突变，13.1%的患者SMARCA4发生突变，14.4%的患者STK11基因发生突变。STK11突变患者的中位总生存期（mOS）为8个月（95%CI，5-16.7），STK11野生型患者为17.3个月（95%CI，8.9-24.4）（p = 0.038）。TP53（8.3对17.3）、KRAS（9.2对15.9）和KEAP1（8.9对15.9）突变患者的mOS有较差趋势。SMARCA4状态对mOS无影响。在调整性别、年龄、ECOG PS、治疗（ICI与CT-ICI）、KRAS、KEAP1、TP53和SMARCA4状态后，STK11突变在单变量（HR 1.74，p = 0.041）和多变量模型（HR 1.97，p = 0.025）中对总生存期有害。基因组改变在我们的队列中不影响中位无进展生存期（mPFS）。在OAK/POPLAR数据集中，在调整年龄、性别、治疗（ICI与CT）、KRAS、KEAP1、TP53和SMARCA4状态后，STK11突变（60/818例患者）在单变量（HR 2.01，p < 0.001）和多变量模型（HR 1.66，p = 0.001）中与死亡风险增加显著相关。
结论
STK11畸变阻碍了接受一线ICI或CT-ICI治疗的nsq NSCLC患者的mOS。负面预后影响似乎与ICI给药无关。
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