Liquid Biopsies in Progressing Metastatic Colorectal Cancer- Application and their Therapeutic Implications According to the RAS Status

Abstract

Introduction The treatment of metastatic colorectal cancer (mCRC) now includes therapy with biological agents inthe first line of treatment. The advances of our knowledge in molecular biology of these tumors allowed the identification of signaling pathways involved in tumorigenesis as potential therapeutic targets. In this field, monoclonal antibodies against epidermal growth factor receptor (anti-EGFR) added to a chemotherapy doublet have demonstrated improved overall survival for these patients. However, mutations in oncogenes NRAS/KRAS are predictive of absence of response to these treatments. Therefore, genotyping in mCRC is essential to personalized treatment. It is known that tumoral heterogeneity and selective pression by targeted therapies can lead to changes in RAS mutational status, along the course of the disease. This opens the possibility of different targeted therapies. Tumor analysis through liquid biopsies allows for the detection of genetic alterations in a less invasive way than common solid tumor biopsy and is currently being validated in different settings, with promising results in mCRC. The main goal of this study was to assess therapeutic implications of Liquid Biopsy (LB) in treatment of progressive mCRC and its potential impact on survival.  Material and methods A retrospective, observational, unicentric study of patients diagnosed with progressive mCRC and who underwent LB after several lines of treatment, was performed. Analysis of patient and tumor characteristics, as well as LB results was performed with descriptive statistics and survival analysis according to Kaplan-Meier methods and COX analysis with STATA/IC software.  Results We included 18 patients on whom LB were performed (median age 61 years; 55% (n=10) men). The median follow-up was 37.4 months. At diagnosis, 12 patients had a KRAS mutation. In the LB reassessment, there was a change in the RAS status in six patients, who initially had a mutation and later showed KRASwt (wild type RAS). LB led to a change in the therapeutic plan in these six patients, allowing the use of anti-EGFR therapy. Progression Free Survival (PFS) and Overall Survival (OS) could not be calculated at this time. Conclusion LB can revolutionize the approach to mCRC by optimizing therapeutic sequencing in a continuum of care strategy. The search for genetic changes over the course of the disease allows a better therapeutic approach to each patient. In the study presented, the realization of LB allowed an increase in therapeutic options in 1/3 of the patients. It is important to continue these studies with larger samples in order to better validate this strategy.