Beneath the surface of colorectal cancer: Unmasking the evolving nature of (Neo)RAS

Metastatic colorectal cancer (mCRC) remains a major clinical challenge, despite therapeutic advancements. Mutations in KRAS and NRAS (RAS) oncogenes drive resistance to anti-EGFR drugs, necessitating RAS mutational analysis prior to treatment. While tissue biopsy remains the gold standard for molecular profiling, it has limitations such as invasiveness, intra-tumoral heterogeneity, and delayed results. Liquid biopsy (LB), on the other hand, offers a non-invasive alternative by analyzing circulating tumor DNA (ctDNA) and it provides a dynamic view of molecular changes over time. Indeed, ctDNA analysis has expanded the understanding of the mCRC’s molecular landscape, revealing that RAS mutated (MT) subclones undergo both a positive and a negative selection during treatment. This negative selection has been described as the "NeoRAS WT phenomenon." The temporary disappearance of RAS mutations opens "RAS WT windows,” thus making potential candidates for anti-EGFR therapies even patients initially diagnosed as RAS MT. This review examines numerous studies investigating the clinical significance of the “NeoRas WT phenomenon” as a distinct pathological entity. It also highlights the key limitations arising from the variability in study designs, detecting methods and ctDNA shedding rates. The results of ongoing prospective trials are necessary to determine whether NeoRAS WT stands as a reliable marker for guiding anti-EGFR treatment strategies in RAS-mutated patients.