Prognostic impact of targetable driver alterations in resected early-stage lung cancer

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Background: Apart from ALK fusions and the common EGFR mutations, targetable molecular alterations are irrelevant for adjuvant treatment decision making in early-stage non-small cell lung cancer (NSCLC). This retrospective analysis aimed to investigate if there is a difference in recurrence-free survival in stage I–III NSCLC harboring druggable molecular alterations compared to subtypes without targetable molecular alterations. Methods: All consecutive patients who underwent surgery with curative intent for NSCLC (stage I–III) with targetable mutations between January 2015 and December 2020 at three Austrian institutions were identified and compared with tumors without targetable molecular alterations. Tumors with the EGFR-mutated subtype were excluded due to already existing results from prospective trials. Results: One hundred and sixty subjects had tumors with molecular alterations and 355 subjects served as control cohort. There was a higher prevalence of female sex (P<0.001) and never-smokers (P=0.01) among patients with tumors harboring oncogenic driver mutations. The three most common alterations were the KRAS G12C mutation (n=92), ALK fusions (n=21), and the BRAF V600E mutation (n=15). The 1-, 3- and 5-year cumulative incidence of recurrence estimates were 16%, 38% and 46% in patients without molecular alterations and 16%, 38% and 48% in patients with the KRAS G12C mutation and 12%, 33% and 55% in patients with other molecular alterations, respectively (P=0.89). Univariable predictors of an increased recurrence risk were higher tumor stage (P<0.001), receipt of neoadjuvant treatment (P<0.001) and receipt of adjuvant treatment (P=0.03). The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration). Conclusions: NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.

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