Genomic landscape and survival analysis of ctDNA "neo- wild-type" patients with originally mutant metastatic colorectal cancer.

Background: The term "neo- wild-type" refers to the switch to wild-type disease in plasma circulating tumor DNA (ctDNA) from originally mutant colorectal cancers. Consistently, the hypothesis to re-determine 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- wild-type" is unknown. This is a prospective study aimed to investigate clinical and genomic features associated with mutation clearance in a large cohort of mutant mCRC patients who converted to wild- type in liquid biopsy at failure of first-line treatments. Secondary aim was to investigate the long term prognostic significance of "true neo-- type".

Patients And Methods: 70 patients with stage IV mutant colorectal cancer were prospectively enrolled. Plasma samples were collected at progression from first-line treatment. /BRAF mutations in plasma were assessed by RT-PCR. In /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 mutation clearance, test curves for PFS and OS were represented by Kaplan-Meier estimator plot and Log-rank test.

Results: The most commonly detected actionable mutations in "neo- wild-type" were: (35.7%); (11.9%); (9.5%); (7%); (7%); (4.7%); (4.7%); (4.7%). Both OS and post-progression survival were longer in patients with "neo- wild-type" compared to those who remained mutant (p<0.001 for both).

Conclusions: De-novo-targetable mutations occured in a large percentage of "neo- wild-type", being the most commonly detected. mutation clearance in ctDNA is associated with long- term improvement of overall survival.