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Abstract：
BACKGROUND: This study aimed to identify the associations between individual KRAS, STK11, KEAP1, or TP53 mutations, as well as the comutation status of these genes, and the tumor mutation burden (TMB) with clinical outcomes of lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICIs).
METHODS: We collected data from patients with lung adenocarcinoma treated with ICIs from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and August 2023. The main endpoints were the treatment response and overall survival (OS).
RESULTS: Among 343 patients with lung adenocarcinoma, 61 (18%), 69 (20%), 41 (12%), and 222 (65%) patients had KRAS, STK11, KEAP1, and TP53 mutations, respectively. An overall objective response was observed in 94 of 338 patients (28%), including 2 (1%) who achieved a complete response and 92 (27%) who achieved a partial response. Patients with STK11, KEAP1, or TP53 mutations had a significantly greater TMB (P<0.001). According to the univariate analysis, the treatment response was significantly correlated with TP53 mutation in both the general (P = 0.041) and KRAS wild-type (P = 0.009) populations. KEAP1 and TP53 mutations were associated with worse OS among assessable patients (hazard ratio (HR) = 2.027, P = 0.002; HR = 1.673, P = 0.007, respectively) and among patients without KRAS mutations (HR = 1.897, P = 0.012; HR = 1.908, P = 0.004, respectively). According to the multivariate analysis, KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were found to be independent factors for OS.
CONCLUSIONS: STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB. TP53 mutation could affect the treatment response to some degree, and both KEAP1 and TP53 mutations resulted in inferior OS in the general patient population and in those with KRAS-wild-type lung adenocarcinoma, indicating that KEAP1 and TP53 mutations might act as prognostic factors for ICI treatment in lung adenocarcinoma patients.
METHODS: We collected data from patients with lung adenocarcinoma treated with ICIs from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and August 2023. The main endpoints were the treatment response and overall survival (OS).
RESULTS: Among 343 patients with lung adenocarcinoma, 61 (18%), 69 (20%), 41 (12%), and 222 (65%) patients had KRAS, STK11, KEAP1, and TP53 mutations, respectively. An overall objective response was observed in 94 of 338 patients (28%), including 2 (1%) who achieved a complete response and 92 (27%) who achieved a partial response. Patients with STK11, KEAP1, or TP53 mutations had a significantly greater TMB (P<0.001). According to the univariate analysis, the treatment response was significantly correlated with TP53 mutation in both the general (P = 0.041) and KRAS wild-type (P = 0.009) populations. KEAP1 and TP53 mutations were associated with worse OS among assessable patients (hazard ratio (HR) = 2.027, P = 0.002; HR = 1.673, P = 0.007, respectively) and among patients without KRAS mutations (HR = 1.897, P = 0.012; HR = 1.908, P = 0.004, respectively). According to the multivariate analysis, KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were found to be independent factors for OS.
CONCLUSIONS: STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB. TP53 mutation could affect the treatment response to some degree, and both KEAP1 and TP53 mutations resulted in inferior OS in the general patient population and in those with KRAS-wild-type lung adenocarcinoma, indicating that KEAP1 and TP53 mutations might act as prognostic factors for ICI treatment in lung adenocarcinoma patients.
摘要：
背景：本研究旨在确定个体KRAS之间的关联，STK11、KEAP1或TP53突变，以及这些基因的合成状态，和肿瘤突变负荷（TMB）与免疫检查点抑制剂（ICIs）治疗的肺腺癌患者的临床结果。
方法：我们从2019年6月至2023年8月的癌症基因组学和高级治疗中心（C-CAT）数据库中收集了使用ICIs治疗的肺腺癌患者的数据。主要终点是治疗反应和总生存期（OS）。
结果：在343例肺腺癌患者中，61（18%），69（20%），41（12%），222例（65%）患者有KRAS，STK11、KEAP1和TP53突变，分别。在338例患者中有94例（28％）观察到总体客观反应，包括2名（1％）获得完全响应和92名（27％）获得部分响应。具有STK11、KEAP1或TP53突变的患者TMB显著增高(P<0.001)。根据单变量分析，在普通人群(P=0.041)和KRAS野生型人群(P=0.009)中,治疗反应与TP53突变显著相关.KEAP1和TP53突变与可评估患者（风险比（HR）=2.027，P=0.002；HR=1.673，P=0.007）和无KRAS突变患者（HR=1.897，P=0.012；HR=1.908，P=0.004）的OS较差相关。根据多变量分析，发现KEAP1（HR=1.890，P=0.008）和TP53（HR=1.735，P=0.011）突变是OS的独立因素。
结论：STK11、KEAP1和TP53突变与高TMB显著相关。TP53突变可在一定程度上影响治疗反应,KEAP1和TP53突变导致一般患者群体和KRAS野生型肺腺癌患者的OS较差，这表明KEAP1和TP53突变可能是肺腺癌患者ICI治疗的预后因素。
方法：我们从2019年6月至2023年8月的癌症基因组学和高级治疗中心（C-CAT）数据库中收集了使用ICIs治疗的肺腺癌患者的数据。主要终点是治疗反应和总生存期（OS）。
结果：在343例肺腺癌患者中，61（18%），69（20%），41（12%），222例（65%）患者有KRAS，STK11、KEAP1和TP53突变，分别。在338例患者中有94例（28％）观察到总体客观反应，包括2名（1％）获得完全响应和92名（27％）获得部分响应。具有STK11、KEAP1或TP53突变的患者TMB显著增高(P<0.001)。根据单变量分析，在普通人群(P=0.041)和KRAS野生型人群(P=0.009)中,治疗反应与TP53突变显著相关.KEAP1和TP53突变与可评估患者（风险比（HR）=2.027，P=0.002；HR=1.673，P=0.007）和无KRAS突变患者（HR=1.897，P=0.012；HR=1.908，P=0.004）的OS较差相关。根据多变量分析，发现KEAP1（HR=1.890，P=0.008）和TP53（HR=1.735，P=0.011）突变是OS的独立因素。
结论：STK11、KEAP1和TP53突变与高TMB显著相关。TP53突变可在一定程度上影响治疗反应,KEAP1和TP53突变导致一般患者群体和KRAS野生型肺腺癌患者的OS较差，这表明KEAP1和TP53突变可能是肺腺癌患者ICI治疗的预后因素。
