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<p>RICTOR, a scaffold protein of the mTORC2 complex, regulates AKT signaling and has been implicated in tumor progression and therapy resistance across multiple cancers. However, the prognostic impact of RICTOR mutations in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma remains unclear. This study aimed to evaluate the clinicopathological, molecular, and survival characteristics of patients with metastatic EGFR-mutant lung adenocarcinoma according to RICTOR mutation status. We retrospectively analyzed 235 patients diagnosed with de novo metastatic lung adenocarcinoma between 2018 and 2024 across three tertiary oncology centers. Patients with targetable oncogenic drivers other than EGFR (ALK, ROS1, HER2, KRAS G12C, BRAF V600E, RET, MET) were excluded. Next-generation sequencing (NGS) was performed using a hybrid-capture panel (Illumina TSO500). Clinical features, co-mutations, treatment responses, and overall survival (OS) were compared between RICTOR-mutant and wild-type subgroups within the EGFR-mutant cohort. Survival analyses employed Kaplan–Meier estimates, log-rank tests, and Cox regression modeling. Of the total cohort, 39 patients (17%) had EGFR-mutant tumors, of whom 15 (38%) carried RICTOR mutations. RICTOR-mutant cases were more likely to be former smokers and presented more frequently with bone and pleural metastases compared with wild type. Treatment patterns and RECIST v1.1 response rates did not significantly differ between groups. Median OS was significantly shorter in RICTOR-mutant versus RICTOR-wild patients (8 vs. 14 months, log-rank <i>p</i> &lt; 0.001). In univariate analysis, RICTOR mutations were associated with inferior OS (HR 2.48, 95% CI 1.73–7.95, <i>p</i> = 0.03), and this association remained significant in multivariate analysis (HR 2.34, 95% CI 1.69–6.75, <i>p</i> = 0.021). Exploratory analyses suggested that RICTOR co-mutations with EGFR exon 19 deletions, exon 18 alterations, or exon 20 alterations were associated with poorer survival outcomes. RICTOR mutations were associated with a high-risk subset of EGFR-mutant metastatic lung adenocarcinoma characterized by more aggressive clinical features and worse survival. These findings suggest the need for prospective validation and support the potential integration of RICTOR status into molecular risk stratification frameworks for precision oncology.</p>

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Prognostic significance of RICTOR mutations in EGFR-mutant metastatic lung adenocarcinoma: a retrospective cohort study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Ali Aytac,
  • Berkay Mehmet Ozata,
  • Ibrahim Halil Erdogdu,
  • Ali Alkan,
  • Ozgur Tanriverdi

摘要

RICTOR, a scaffold protein of the mTORC2 complex, regulates AKT signaling and has been implicated in tumor progression and therapy resistance across multiple cancers. However, the prognostic impact of RICTOR mutations in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma remains unclear. This study aimed to evaluate the clinicopathological, molecular, and survival characteristics of patients with metastatic EGFR-mutant lung adenocarcinoma according to RICTOR mutation status. We retrospectively analyzed 235 patients diagnosed with de novo metastatic lung adenocarcinoma between 2018 and 2024 across three tertiary oncology centers. Patients with targetable oncogenic drivers other than EGFR (ALK, ROS1, HER2, KRAS G12C, BRAF V600E, RET, MET) were excluded. Next-generation sequencing (NGS) was performed using a hybrid-capture panel (Illumina TSO500). Clinical features, co-mutations, treatment responses, and overall survival (OS) were compared between RICTOR-mutant and wild-type subgroups within the EGFR-mutant cohort. Survival analyses employed Kaplan–Meier estimates, log-rank tests, and Cox regression modeling. Of the total cohort, 39 patients (17%) had EGFR-mutant tumors, of whom 15 (38%) carried RICTOR mutations. RICTOR-mutant cases were more likely to be former smokers and presented more frequently with bone and pleural metastases compared with wild type. Treatment patterns and RECIST v1.1 response rates did not significantly differ between groups. Median OS was significantly shorter in RICTOR-mutant versus RICTOR-wild patients (8 vs. 14 months, log-rank p < 0.001). In univariate analysis, RICTOR mutations were associated with inferior OS (HR 2.48, 95% CI 1.73–7.95, p = 0.03), and this association remained significant in multivariate analysis (HR 2.34, 95% CI 1.69–6.75, p = 0.021). Exploratory analyses suggested that RICTOR co-mutations with EGFR exon 19 deletions, exon 18 alterations, or exon 20 alterations were associated with poorer survival outcomes. RICTOR mutations were associated with a high-risk subset of EGFR-mutant metastatic lung adenocarcinoma characterized by more aggressive clinical features and worse survival. These findings suggest the need for prospective validation and support the potential integration of RICTOR status into molecular risk stratification frameworks for precision oncology.