About RAS Mutation Clearance in Plasma ctDNA From RAS-Mutant Colorectal Cancer Patients

Gazzaniga, Paola; Nicolazzo, Chiara; Caponnetto, S; Cortesi, Enrico

doi:10.1200/po.20.00376

Cited by 2 publications

(3 citation statements)

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“…Since its first description (14), the concept of "neo-RAS wt" in colorectal cancer has gained increasing attention, providing new insights for following targeted treatment selection. In fact, the absence of any clinically relevant mutation of RAS genes in blood has been recently used as a therapeutically exploitable window to change the clinically-based selection of patients to be treated with EGFR inhibitors (7)(8)(9)(10)(11). The rate of RAS mutation clearance in plasma is highly variable, ranging from 8% to 70% of cases according to studies (15).…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon, currently known as "neo-RAS wild-type (wt)", leads to the appearance of a frametime characterized by RAS wt disease in plasma, which has been described in course of treatment and at the time of disease progression, according to studies (4)(5)(6). This observation led to the hypothesis that RAS assessment in ctDNA at disease progression could change the clinically-based selection of patients to be treated with EGFR inhibitors (7)(8)(9)(10)(11). The genomic landscape of actionable alterations in "neo-RAS wt" patients has never been investigated to date.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…We are grateful for your comments on our recent publication 1 that highlighted that nearly 50% of the patients with RAS-mutated metastatic colorectal cancer and prior chemotherapy could display wildtype RAS status in the circulating tumoral DNA (ctDNA), and benefit from the late introduction of an anti-epidermal growth factor receptor (EGFR). 2 We indeed acknowledge that your team had worked in a similar direction, and appropriately cited the report that your group published in 2019.…”

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confidence: 99%