Introduction: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with unique clinicopathologic features and limited therapeutic options. Comprehensive comparisons of genomic profiles and their survival impact between IMA and non-IMA are lacking. This study aimed to evaluate actionable and other clinically significant mutations and their prognostic relevance in IMA versus non-IMA.

Methods: De-identified records of 3,428 patients with primary lung adenocarcinoma and available survival data were retrieved from the Tempus database and stratified by histology into IMA (n=78) and non-IMA (n=3,350) groups. Clinical, biopsy, and molecular characteristics were compared using χ2 and Fisher’s exact tests for categorical variables. Actionable mutations were defined per current NCCN guidelines, including EGFR exon 19, L858R, or G719X mutations, ALK, ROS1, or RET fusions, and ERBB2 alterations. Real-world overall survival (rwOS) was analyzed using Kaplan-Meier curves and Cox proportional hazards models.

Results: IMA showed significantly higher frequencies of KRAS (54% vs. 27%, p < 0.001) and ERBB2 mutations (5.1% vs. 1.6%, p = 0.044) but a lower frequency of EGFR exon 19 deletions (1.3% vs. 9.6%, p = 0.013). Non-IMA patients with actionable mutations had longer median rwOS (35.73 vs. 16.47 months). A similar trend towards improved rwOS was observed for patients with actionable mutations in the IMA cohort (not reached vs. 12.98 months), although the sample size was small (n=14). Additionally, STK11 mutations appeared to be associated with poorer rwOS in non-IMA patients.

Conclusions: IMA exhibits a distinct mutational profile compared with non-IMA, showing differences in both frequency and prognostic impact. While actionable mutations were linked to improved survival in non-IMA, their prognostic value was less evident in IMA. Moreover, STK11 mutations suggested a potentially worse overall survival in non-IMA. Further analyses of clinically significant mutations in a larger IMA cohort will clarify the biological differences underlying these distinct tumor behaviors.

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