Application of liquid biopsies in metastatic gastrointestinal cancer to identify candidate therapeutic targets

Abstract

Background:Next-generation sequencing (NGS) of cell-free tumor DNA (ctDNA) hasgreat potential for liquid biopsy in cancer diagnostics and to identify patients withactionable genomic alteration. This study, a prospective longitudinal study, focused ina cohort of metastatic cancer patients without standard effective active antineoplasticmedical treatment options to establish the rate of patients with actionable genomicalteration and the rate of patients accessing medical treatment. The final objective wasto determine the clinical performance based on non-invasive tumor sequencing.Methods:We collected plasma of 10 metastatic gastrointestinal patients with knownstatus of the RAS genes and microsatellites instability in tumor tissue. CtDNA wasextracted from plasma and genomic alterations were analyzed by Guardant 360(Guardant Health, Biosequence, OncoDNA), a next generation sequencing panel. Thispanel consists of 73 cancer related genes and is able to identify different types ofgenomic alterations. Informed consent was obtained from all patients.Results:We were able to identify 78 somatic mutations in total resulting in a mediannumber of eight somatic mutations per patient. The most common altered genes arewell known tumor suppressor and oncogenes like TP53, APC, KRAS, MYC andEGFR.At least one actionable alteration in plasma cfDNA were detected in eight from the 10patients (80%) but the proportion of patients for which a genomic identified recom-mended therapy was available to effectively initiate the treatment were only 37,5%(3/8). In these patients, the identification of alterations like c-MET amplification,FGFR1 amplification or PIK3CA c.1633G>A (p.E545K) mutation, involved inclinically actionable pathways, allowed the selection of a specific therapy. For the rest ofcases the main causes of non-access to medical treatment associated with a specificmutation were, among others, the advanced pre-treated patient and clinical triallogistical access difficulties.Conclusions:Our findings confirm the percentage of cases with potentially druggableaberrations is similar to other studies using this strategy and emphasizes their clinicalvalue to identify candidate therapeutic targets