Mapping the mutational terrain of lung adenocarcinoma: A Danish cohort study of 880 patients

In this population-based cohort, we examined the prevalence of targetable genomic alterations and characterized KRAS subtypes in relation to co-mutations, PD-L1 expression, treatment, and survival.

A total of 880 patients diagnosed with lung adenocarcinoma in Central Denmark in 2020-2021 underwent reflex next-generation sequencing using a 22-gene panel.

KRAS mutations were present in 383/880 tumors (43.5 %), of which KRAS G12C accounted for 174 cases (19.8 % of the total cohort). Overall, targetable alterations were identified in 327/880 tumors (37.2 %). KRAS G12C mutations were more frequent in females and smokers. KRAS mutations were largely mutually exclusive with other targetable driver alterations. TP53 mutations were more common in KRAS wild-type tumors, whereas non-G12C KRAS mutations were associated with SMAD4 mutations. PD-L1 ≥50 % occurred most frequently in tumors with KRAS G12C. KRAS mutation status was not associated with overall survival in unadjusted analyses. After adjustment for clinical covariates, non-G12C KRAS mutations showed a modest association with increased mortality. Among 628 patients with available treatment data, survival differed across treatment modalities. Among patients receiving systemic first-line treatment (n = 183), survival was significantly better with immune checkpoint inhibitors or targeted therapy than with chemotherapy (p < 0.001). KRAS mutation status was not associated with treatment-specific survival in any treatment group.

Lung adenocarcinomas are characterized by a high prevalence of targetable alterations, with KRAS G12C representing the most frequent alteration. KRAS mutation status showed limited prognostic relevance. These findings support routine molecular testing and integration of genomic and clinical data to guide personalized treatment.