Genomic landscape and survival analysis of ctDNA “neo-RAS wild-type” patients with originally RAS mutant metastatic colorectal cancer

Abstract

BackgroundThe term “neo-RAS wild-type” refers to the switch to RAS wild-type disease in plasma circulating tumor DNA (ctDNA) from originally RAS mutant colorectal cancers. Consistently, the hypothesis to re-determine RAS mutational status in ctDNA at disease progression in RAS mutant mCRC opened to a new perspective for clinically-based selection of patients to be treated with EGFR inhibitors. Currently, the genomic landscape of “neo-RAS wild-type” is unknown. This is a prospective study aimed to investigate clinical and genomic features associated with RAS mutation clearance in a large cohort of RAS mutant mCRC patients who converted to RAS wild- type in liquid biopsy at failure of first-line treatments. Secondary aim was to investigate the long term prognostic significance of “true neo-RAS wild- type”.Patients and methods70 patients with stage IV RAS mutant colorectal cancer were prospectively enrolled. Plasma samples were collected at progression from first-line treatment. RAS/BRAF mutations in plasma were assessed by RT-PCR. In RAS/BRAF wild-type samples, ctDNA was used to generate libraries using a 17 genes panel whose alteration has clinical relevance. To investigate the prognostic significance of RAS mutation clearance, test curves for PFS and OS were represented by Kaplan-Meier estimator plot and Log-rank test.ResultsThe most commonly detected actionable mutations in “neo-RAS wild-type” were: PIK3CA (35.7%); RET (11.9%); IDH1 (9.5%); KIT (7%); EGFR (7%); MET (4.7%); ERBB2 (4.7%); FGFR3 (4.7%). Both OS and post-progression survival were longer in patients with “neo-RAS wild-type” compared to those who remained RAS mutant (p<0.001 for both).ConclusionsDe-novo-targetable mutations occured in a large percentage of “neo-RAS wild-type”, being PIK3CA the most commonly detected. RAS mutation clearance in ctDNA is associated with long- term improvement of overall survival.

Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment

“…Neo RAS -WT is defined as the absence of RAS mutation coupled with trunk mutations of genes such as TP53, APC, or methylated genes (Moati et al 2020 ; Nicolazzo et al 2020 , 2021 ). Nicolazzo et al reported that the most common actionable mutations detected in patients with Neo RAS -WT were PIK3CA (35.7%), RET (11.9%), IDH1 (9.5%), KIT (7%), EGFR (7%), MET (4.7%), ERBB2 (4.7%), and FGFR3 (4.7%) (Nicolazzo et al 2023 ). The prevailing notion is that concurrent genetic alterations serve as corroborative evidence for the presence of tumor DNA in the plasma.…”

“…Recent research suggests that temporal changes may occur in RAS status (Osumi et al 2021 ; Nicolazzo et al 2023 ). In CRC, the condition “Neo RAS wild-type (Neo RAS -WT)” refers to a situation in which a patient initially had a RAS mutation, but after treatment, the status reverted to wild-type (non-mutated).…”

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…RAS proteins are key components of the EGFR signaling pathway, and mutations in these genes lead to constitutive activation of downstream signaling, promoting cell proliferation and survival. Therefore, the presence of RAS mutations is a critical predictive biomarker, guiding treatment decisions and helping to avoid ineffective therapies. , …”

“…Therefore, the presence of RAS mutations is a critical predictive biomarker, guiding treatment decisions and helping to avoid ineffective therapies. 114,115 In addition to RAS mutations, alterations in the BRAF gene, particularly the V600E mutation, are another important genetic event in colorectal cancer. BRAF mutations are observed in approximately 5−10% of colorectal cancer cases and are associated with poor prognosis.…”

Circulating Tumor DNA and Management of Colorectal Cancer

“…The most commonly detected actionable mutations in “neo- RAS wild-type” were: PIK3CA (35.7%), RET (11.9%), IDH1 (9.5%), KIT (7%), EGFR (7%), MET (4.7%), ERBB2 (4.7%), and FGFR3 (4.7%). OS and PFS were longer in patients with “neo- RAS wild-type” compared to those who remained RAS mutant [ 65 ]. Ciardiello et al performed a further analysis of the CAVE and VELO studies, evaluating the percentage of patients with wild-type ctDNA tumors and the association of mutational status with time since the last anti-EGFR drug administration.…”