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. 2024 Nov 30;13(11):3096-3105.
doi: 10.21037/tlcr-24-433. Epub 2024 Nov 14.

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

Angelika Terbuch  1 , Selma Konjic  1 , Verena Schlintl  1 , Gudrun Absenger  1 , Philipp J Jost  1   2   3 , Jörg Lindenmann  4 , Paul Swatek  4 , Nikolaus John  5 , Teresa John  5 , Robert Wurm  5 , Martin Zacharias  6 , Florian Posch  7 , Maximilian J Hochmair  8   9 , Hannah Fabikan  8   9 , Christoph Weinlinger  8   9 , Oliver Illini  8   9 , Lena Horvath  10 , Gabriele Gamerith  10 , Dominik Wolf  10 , Florian Augustin  11 , Luka Brcic  6
Affiliations

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

Angelika Terbuch et al. Transl Lung Cancer Res. .

Abstract

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.

Keywords: Non-small cell lung cancer (NSCLC); early-stage; molecular alterations; prognosis.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-433/coif). M.J.H. received research grants from Takeda, Roche, Lilly, Merck Sharp & Dohme, AstraZeneca and Bristol-Myers Squibb; received honoraria for lectures and presentations from Daiichi Sankyo, Lilly and Merck Sharp & Dohme and travel support from Amgen, Merck Sharp & Dohme and Bristol Myers Squibb. G.A. received honoraria, payments for advisory boards and travel support from Amgen, AstraZeneca, Roche, Takeda, Pfizer. O.I. received consulting fees from BMS, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly, BMS, Menarini, Merck Sharp & Dohme, Roche, Pfizer; support for attending meetings and/or travel from Eli Lilly, BMS and research grants from Amgen and AstraZeneca outside of the submitted study. A.T. received research grants from AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche Austria and Sanofi-aventis; received honoraria for lectures from Amgen and Merck Shapr & Dohme and travel support from Amgen. G.A. received honoraria and travel support from Amgen, AstraZeneca, Roche, Takeda and Pfizer. L.H. received travel support from Janssen. L.B. received grants from Takeda, AstraZeneca, BMS and Roche; he also received payment for lectures and participated in advisory boards form Invitae, Eli-Lilly, AstraZeneca, Roche, MSD, Merck, BMS, Pfizer, Novartis, Takeda, Janssen; support for attending meeting from Pfizer; he is Int. Secretary-Austrian Society of Pathology, PPS Membership and Awards Committee and Member of the Mesothelioma Committee of IASLC. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Pie chart of molecular alterations (n=160). ALK, anaplastic lymphoma kinase fusions; RET, rearranged during transfection; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma virus; MET, hepatocyte growth factor receptor gene; HER2, human epidermal growth factor receptor 2; NRG1, neuregulin 1.
Figure 2
Figure 2
Cumulative incidence of recurrence according to molecular alteration status (n=515). Curves were obtained with competing risk cumulative incidence estimators treating death-from-other-or-unknown-causes as the competing event of interest. Numbers in brackets represent the number of events within the corresponding year.
Figure 3
Figure 3
Tumor-stage-adjusted cumulative incidence of recurrence according to molecular alteration status (n=513). Curves are predicted cumulative incidences that were obtained from a multivariable Fine & Gray model with two variables (molecular alteration status, tumor stage I/II vs. III/IV). A complete-case-analysis was performed (n=2 missing). The P value is from a post-estimation χ2-test jointly testing the molecular alteration status variable.
Figure 4
Figure 4
Overall survival after recurrence according to molecular alteration status (n=179). Curves were obtained with Kaplan-Meier estimators.
See this image and copyright information in PMC

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