Methods: We retrospectively analyzed the mutational landscape (excluding Variants of Unknown Significance) in 64 consecutive patients with synchronous mCRC who underwent a comprehensive genomic profiling with the Guardant360 74 gene panel at baseline and at first tumor progression according to UPTR in the context of tumour location and RAS status. The Variant Allele Fraction (VAF%) and the total number of new alterations at first progression were evaluated.Results: 1-The total number of new alterations at first progression was higher in all subgroups for the non UPTR patients (Table ):The median number of metastatic sites at baseline was the same between both subgroups although more irresectable metastatic sites were found in the non UPTR subgroup 2-For Left side + rectum locations either wild-type or mutant, the median VAF% was higher at baseline and at first progression in patients without UPTR as compared with UPTR. This was not the case in the right-side mutant subgroup: Left

0.982). At 94.8% specificity, the sensitivities for detecting advCRA and CRC reached 95.7% and 98.0% (stage 0: 94.1%; stage I: 98.5%), respectively. Promisingly, the detection sensitivity has reached 100% and 97.6% in CRC patients with negative fecal occult or CEA blood test results, respectively. In advCRA subgroup, our model showed high sensitivities for detecting different grades of dysplasia (high: 91.3%, low: 100%) and for pedunculated (92.9%) or sessile adenoma (96.9%). Finally, our model maintained promising performances (mean AUC: 0.985, 92.6% sensitivity at 94.8% specificity) even when sequencing depth was downsampled to 1X.Conclusions: Our integrated predictive model using plasma cfDNA fragmentomic profiles demonstrated an unprecedented detection sensitivity for advCRA and very early-stage CRC, shedding light on more accurate non-invasive colorectal cancer screening in clinical practice.