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Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status

2021; Elsevier BV; Volume: 17; Issue: 3 Linguagem: Inglês

10.1016/j.jtho.2021.10.013

1556-1380

Biagio Ricciuti, Kathryn C. Arbour, W. Marston Linehan, Amir Vajdi, Natalie I. Vokes, Lingzhi Hong, Jianjun Zhang, Michael Tolstorukov, Yvonne Y. Li, Liam F. Spurr, Andrew D. Cherniack, Gonzalo Recondo, Giuseppe Lamberti, Xinan Wang, Deepti Venkatraman, Joao V. Alessi, Victor R. Vaz, Hira Rizvi, Jacklynn V. Egger, Andrew J. Plodkowski, S. Khosrowjerdi, Subba R. Digumarthy, Hyesun Park, Nuno Vaz, Mizuki Nishino, Lynette M. Sholl, David A. Barbie, Mehmet Altan, John V. Heymach, Ferdinandos Skoulidis, Justin F. Gainor, Matthew D. Hellmann, Mark M. Awad,

Cancer Immunotherapy and Biomarkers

Abstract Introduction STK11 and KEAP1 mutations ( STK11 mutant [ STK11 MUT ] and KEAP1 MUT ) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11 MUT has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRAS MUT LUAD, its impact on immunotherapy efficacy in KRAS wild-type ( KRAS WT ) LUAD is currently unknown. Whether KEAP1 MUT differentially affects outcomes to PD-(L)1 inhibition in KRAS MUT and KRAS WT LUAD is also unknown. Methods Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS , STK11 , and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS / STK11 and KRAS/KEAP1 comutation status. Results In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22–92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free ( STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall ( STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRAS MUT but not KRAS WT LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRAS MUT , but not in KRAS WT , lung cancers. Conclusions STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRAS MUT but not among KRAS WT LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration.