Clinical/molecular features and prognostic significance of RAS mutant-low versus RAS mutant-high in patients with metastatic colorectal cancer.
Authors: Chibaudel Benoist , Richa Hubert , Carola Elisabeth , Toledano Alain , Dainese Linda , Abdelhamid Mekranter , Martin Anne Lise , Goyer Perrine , Saget Arnaud , Oberlin Olivier , Marijon Hélène , Perez-Staub Nathalie , Iurisci Ida , Gervais Honorine , Ben Romdhane Yosr , Tugler Marie-Hélène , Dupuy Maxime , Awad Sameh , Pujol Pascal , De Gramont Aimery ,   Cancérologie Paris Ouest (CPO)
Published: January 2024

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Background: Addressing tumor heterogeneity is one of the main advantage of liquid biopsy over tissue biopsy, as liquid biopsy is likely to better reflect the global molecular profile (primary tumor site and metastatic disease). Variant Allele Frequency (VAF) represents the fraction of sequencing reads in which a variant is observed. The aim was to evaluate the prognostic value of circulating tumor (ct) VAF for KRAS and NRAS genes in patients with ctRAS mutant metastatic colorectal cancer (MCRC). Methods: Circulating comprehensive genomic profiling using FoundationOne Liquid CDx (FO-Liq) was proposed to patients with histologically proven or highly suspected solid tumor whatever treatment line. FO-Liq is a next generation sequencing panel of 310 cancer related genes and 3 genomic signatures (blood tumor mutational burden (bTMB), microsatellite instability (MSI) and tumor fraction (TF)). The optimal threshold for ctVAF was determined by calculating Harrell’s C discrimination index extended for survival data. The primary endpoint was overall survival (OS). Results: From October 2020 to June 2023, 740 patients were screened for circulating molecular profiling. In the colorectal cohort (N=201), 198 (98.5%) patients had metastatic disease (ctRAS/BRAF wild-type, N=76 (38.4%) ; ctRAS mutant, N=106 (53.5%) and ctBRAF V600E mutant, N=16 (8.1%)). The optimal threshold for ctVAFRAS was 5% (C-index 0.67, 95% CI 0.62-0.73 ; P<0.0001). Among patients with ctRAS mutant MCRC, 43 (40.6%) were ctRAS mutant-Low (VAFRAS<5%) and 63 (59.4%) were ctRAS mutant-High (VAFRAS≥5%). Median follow-up was 18.5 months (95% CI 15.3-34.5). There was a significant increase in the the risk of death for RAS mutant-High compared to RAS mutant-Low (HR 2.81, 95% CI 1.70-4.63; P<0.001). Patients with RAS mutant-low variants had the same prognosis that RAS/BRAF wild-type profile (HR 1.22 ; P=0.573), and patients with RAS mutant-high variants had the same prognosis that BRAF mutant profile (HR 0.82, P=0.563). The factors associated with RAS mutant-High profile were : bTMB-High, TF-High, RAS G12A and G13D variants. MAP kinase, TGFb and Wnt signaling pathways and BRCA1-2 genes were more frequently altered in patients with ctRAS mutant-High tumors. We observed a transient decrease of VAFRAS in second-line setting. Conclusions: The circulating VAF of RAS genes enables to split RAS mutant-Low (favorable prognosis similar to RAS/BRAF wild-type) from RAS mutant-High (poorer prognosis similar to BRAF mutant) metastatic colorectal cancer. These results provide further insights into prognostication and therapeutic strategies in patients with RAS mutant metastatic colorectal cancer.