Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC Journal Article
| Authors: | Gandhi, M. M.; Elkrief, A.; Moore, C. G.; Ricciuti, B.; Alessi, J. V.; Richards, A. L.; Tischfield, S.; Williams, J.; Lamberti, G.; Pecci, F.; Di Federico, A.; Makarem, M.; Johnson, B. E.; Nishino, M.; Sholl, L. M.; Schoenfeld, A. J.; Awad, M. M. |
| Article Title: | Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC |
| Abstract: | Introduction: Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in NSCLC, particularly among KRAS-mutant cases. Nevertheless, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized. Methods: Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in cases of nonsquamous NSCLC at Dana-Farber Cancer Institute (DFCI). mRNA and LKB1 protein levels were assessed using The Cancer Genome Atlas. Clinical outcomes were analyzed in patients who received ICI with or without chemotherapy at DFCI and Memorial Sloan Kettering Cancer Center. Analyses of each deletion excluded cases with mutations in that gene. Results: Among the 3194 cases of nonsquamous NSCLC, 14.7% had STK11 deletion (STK11DEL), 13.5% KEAP1 deletion (KEAP1DEL), and 13.7% SMARCA4 deletion (SMARCA4DEL). These deletions correlated with lower programmed death-ligand 1 expression and higher disease stage, tumor mutational burden, and aneuploidy. STK11DEL, KEAP1DEL, and SMARCA4DEL each correlated with lower corresponding mRNA expression, and STK11DEL with lower LKB1 protein expression. Among 767 patients treated with chemoimmunotherapy, these deletions were associated with worse objective response rates (STK11 31% versus 45%, p = 0.005; KEAP1 33% versus 45%, p = 0.03; SMARCA4 29% versus 45%, p = 0.0007), progression-free survival (STK11 hazard ratio [HR] = 1.5, p = 0.0001; KEAP1 HR = 1.4, p = 0.002; SMARCA4 HR = 1.6, p < 0.0001), and overall survival (STK11 HR = 1.7, p < 0.0001; KEAP1 HR = 1.5, p = 0.003; SMARCA4 HR = 1.7, p < 0.0001). The effect of these deletions on chemoimmunotherapy outcomes was comparable to the effect of mutations in these genes. Among 1267 patients treated with ICI alone, these deletions did not impact outcomes in the Memorial Sloan Kettering Cancer Center cohort but were generally associated with worse outcomes in the DFCI cohort among KRAS-mutant cases. Conclusions: STK11, KEAP1, and SMARCA4 deletions correlate with distinct clinicopathologic features, reduced programmed death-ligand 1 expression, and poor chemoimmunotherapy efficacy in NSCLC. © 2025 International Association for the Study of Lung Cancer |
| Keywords: | adult; cancer chemotherapy; controlled study; protein expression; treatment response; aged; middle aged; survival rate; oncoprotein; gene mutation; major clinical study; overall survival; gene deletion; genetics; antineoplastic agent; cd8 antigen; transcription factor foxp3; cd8+ t lymphocyte; cancer immunotherapy; progression free survival; nuclear protein; antineoplastic combined chemotherapy protocols; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; cohort analysis; gene locus; genotype; smoking; transcription factor; immunofluorescence; pathology; protein serine threonine kinase; transcription factors; nuclear proteins; lung tumor; immunotherapy; genomics; immunophenotyping; drug therapy; cytotoxic t lymphocyte antigen 4; aneuploidy; b raf kinase; dna helicases; dna helicase; programmed death 1 ligand 1; programmed death 1 receptor; non small cell lung cancer; tumor microenvironment; copy number variation; activin receptor like kinase 1; clinical outcome; oncogene ret; protein kinase lkb1; stk11 protein, human; procedures; brg1 protein; met gene; chemoimmunotherapy; immune checkpoint inhibitor; high throughput sequencing; kelch like ech associated protein 1; ros1 gene; humans; human; male; female; article; smarca4; non–small cell lung cancer; smarca4 protein, human; tumor mutational burden; stk11; keap1; mrna expression level; protein serine-threonine kinases; kelch-like ech-associated protein 1; keap1 protein, human; amp-activated protein kinase kinases; hydroxymethylglutaryl coenzyme a reductase kinase kinase; functional enrichment analysis |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 20 |
| Issue: | 6 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2025-01-01 |
| Start Page: | 725 |
| End Page: | 738 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2025.01.016 |
| PUBMED: | 39864548 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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