141P Immune-related epigenomic and transcriptomic signatures to predict immunotherapy response in NSCLC

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treatment, are subject to abdominoperineal resection (APR), an invasive procedure that significantly impairs quality of life.Genomic analyses could identify new prognostic biomarkers and potential avenues for targeted therapies. Methods:We assessed the prognostic and theragnostic value of pathogenic variants identified in 571 cancer-related genes in surgical samples collected from a multicentric retrospective French cohort of 158 ASCC patients who underwent APR.Results: Alterations in PI3K/AKT/mTOR (43%), chromatin remodeling (48%), and Notch pathways (22%) were frequent in HPV-positive tumors, while HPV-negative tumors (11%) often had variants in cell cycle regulation and genome integrity maintenance genes, like TP53 (59%) and TERT promoter mutations (47%).In patients with HPV-positive tumors, KMT2C (16%) and PIK3CA exon 9/20 pathogenic variants (22%) were associated with poor overall survival (Hazard Ratio (HR) KMT2C ¼ 2.54, 95% CI ¼ 1.25-5.17,p-value ¼ 0.010; HR PIK3CA ¼ 2.43, 95%CI ¼ 1.3-4.56,p-value ¼ 0.006), and progression-free survival (HR KMT2C ¼ 3.38, 95%CI ¼ 1.83-6.26,p-value < 0.001; HR PIK3CA ¼ 1.81, 95%CI ¼ 1.06-3.08,p-value ¼ 0.029) in multivariate analyses.Alterations with theragnostic value in another cancer type (e.g., PIK3CAH1047R or lossof-function variants in homologous repair genes) were detected in 43% of tumors.Conclusions: PIK3CA exon 9/20 and KMT2C pathogenic variants are independent prognostic factors in patients with HPV-positive ASCC treated by APR.Importantly, the high prevalence of alterations with potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.Legal entity responsible for the study: The authors.

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