| Autor: |
S. Scalera, B. Ricciuti, M. Mazzotta, N. Calonaci, J.V. Alessi, L. Cipriani, G. Bon, B. Messina, G. Lamberti, A. Di Federico, F. Pecci, S. Milite, E. Krasniqi, M. Barba, P. Vici, A. Vecchione, F. De Nicola, L. Ciuffreda, F. Goeman, M. Fanciulli, S. Buglioni, E. Pescarmona, B. Sharma, K.D. Felt, J. Lindsay, S.J. Rodig, R. De Maria, G. Caravagna, F. Cappuzzo, G. Ciliberto, M.M. Awad, M. Maugeri-Saccà |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Annals of oncology : official journal of the European Society for Medical Oncology. |
| ISSN: |
1569-8041 |
| Popis: |
KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs.Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation (KEAP1 clonal diploid-subclonal, KEAP1 CD-SC) in the MSK MetTropism cohort (N=2,550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N=237; DFCI N=461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort).Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P=0.001; OS log-rank P0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P=0.006; OS log-rank P=0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features.KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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