Gandhi Malini M, Elkrief Arielle, Moore Catherine Gutierrez, Ricciuti Biagio, Alessi Joao V, Richards Allison L, Tischfield Sam, Williams Jessica, Lamberti Giuseppe, Pecci Federica, Di Federico Alessandro, Makarem Maisam, Johnson Bruce E, Nishino Mizuki, Sholl Lynette M, Schoenfeld Adam J, Awad Mark M
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
J Thorac Oncol. 2025 Jan 27. doi: 10.1016/j.jtho.2025.01.016.
Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in NSCLC, particularly among KRAS-mutant cases. Nevertheless, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized.
Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in cases of nonsquamous NSCLC at Dana-Farber Cancer Institute (DFCI). mRNA and LKB1 protein levels were assessed using The Cancer Genome Atlas. Clinical outcomes were analyzed in patients who received ICI with or without chemotherapy at DFCI and Memorial Sloan Kettering Cancer Center. Analyses of each deletion excluded cases with mutations in that gene.
Among the 3194 cases of nonsquamous NSCLC, 14.7% had STK11 deletion (STK11), 13.5% KEAP1 deletion (KEAP1), and 13.7% SMARCA4 deletion (SMARCA4). These deletions correlated with lower programmed death-ligand 1 expression and higher disease stage, tumor mutational burden, and aneuploidy. STK11, KEAP1, and SMARCA4 each correlated with lower corresponding mRNA expression, and STK11 with lower LKB1 protein expression. Among 767 patients treated with chemoimmunotherapy, these deletions were associated with worse objective response rates (STK11 31% versus 45%, p = 0.005; KEAP1 33% versus 45%, p = 0.03; SMARCA4 29% versus 45%, p = 0.0007), progression-free survival (STK11 hazard ratio [HR] = 1.5, p = 0.0001; KEAP1 HR = 1.4, p = 0.002; SMARCA4 HR = 1.6, p < 0.0001), and overall survival (STK11 HR = 1.7, p < 0.0001; KEAP1 HR = 1.5, p = 0.003; SMARCA4 HR = 1.7, p < 0.0001). The effect of these deletions on chemoimmunotherapy outcomes was comparable to the effect of mutations in these genes. Among 1267 patients treated with ICI alone, these deletions did not impact outcomes in the Memorial Sloan Kettering Cancer Center cohort but were generally associated with worse outcomes in the DFCI cohort among KRAS-mutant cases.
STK11, KEAP1, and SMARCA4 deletions correlate with distinct clinicopathologic features, reduced programmed death-ligand 1 expression, and poor chemoimmunotherapy efficacy in NSCLC.
STK11、KEAP1和SMARCA4基因的突变会使非小细胞肺癌（NSCLC）患者对免疫检查点抑制剂（ICI）的疗效较差，尤其是在KRAS突变的病例中。然而，这些基因缺失的频率、临床病理特征及临床影响尚不清楚。
对达纳-法伯癌症研究所（DFCI）的非鳞状NSCLC病例分析了STK11、KEAP1和SMARCA4基因缺失与临床病理的相关性。使用癌症基因组图谱评估mRNA和LKB1蛋白水平。对在DFCI和纪念斯隆凯特琳癌症中心接受ICI联合或不联合化疗的患者的临床结局进行分析。对每个基因缺失的分析排除了该基因存在突变的病例。
在3194例非鳞状NSCLC病例中，14.7%存在STK11基因缺失（STK11），13.5%存在KEAP1基因缺失（KEAP1），13.7%存在SMARCA4基因缺失（SMARCA4）。这些基因缺失与程序性死亡配体1表达降低及疾病分期更高、肿瘤突变负荷更高和非整倍体相关。STK11、KEAP1和SMARCA4基因缺失均与相应mRNA表达降低相关，STK11基因缺失与LKB1蛋白表达降低相关。在767例接受化疗免疫治疗的患者中，这些基因缺失与较差的客观缓解率相关（STK11为31% 对45%，p = 0.005；KEAP1为33% 对45%，p = 0.03；SMARCA4为29% 对45%，p = 0.0007）、无进展生存期（STK11风险比[HR] = 1.5，p = 0.0001；KEAP1 HR = 1.4，p = 0.002；SMARCA4 HR = 1.6，p < 0.0001）和总生存期（STK11 HR = 1.7，p < 0.0001；KEAP1 HR = 1.5，p = 0.003；SMARCA4 HR = 1.7，p < 0.0001）。这些基因缺失对化疗免疫治疗结局的影响与这些基因的突变的影响相当。在1267例仅接受ICI治疗的患者中，这些基因缺失在纪念斯隆凯特琳癌症中心队列中未影响结局，但在DFCI队列中，在KRAS突变病例中通常与较差的结局相关。
STK11、KEAP1和SMARCA4基因缺失与NSCLC独特的临床病理特征、程序性死亡配体1表达降低及化疗免疫治疗疗效差相关。
