A multi-omic liquid biopsy-based signature as a valuable tool to assess minimal residual disease in localised colorectal cancer

Resumen

The TNM staging system continues to be the most important prognostic factor in colorectal cancer (CRC). For stage II and III CRC patients, the 5-year survival rates after surgery range between 80%-60% and 30%-60%, respectively. It is well established that adjuvant treatment in CRC reduces the risk of death by 10-15% with fluoropyrimidines alone plus a further 4-5% with oxaliplatin-containing combinations in stage III. Despite optimal primary treatment, 30%-50% of patients with colon cancer will relapse, and most of those patients will die from their disease. Carcinoembryonic antigen (CEA) lacks sufficient sensitivity and specificity as a single prognostic test. Likewise, imaging studies are insufficient to detect micrometastases at an early stage. Therefore, the identification of predictive and prognostic markers beyond the TNM system is crucial to define high risk of relapse and to establish potential therapeutic strategies to optimise adjuvant treatment. Circulating tumour DNA (ctDNA), being a popular class of liquid biopsy biomarkers, is the study of molecular alterations of patient's blood. In early stages of CRC, liquid biopsies can easily and non-invasively provide us with information about the presence of minimal residual disease and tumour genotyping, and identify molecular mechanisms of resistance to adjuvant treatment and potential therapeutic molecular targets for CRC. The objective of this project was to examine the prognostic and predictive value of liquid biopsy in 150 patients with stage I-III CRC treated conventionally with surgery and adjuvant chemotherapy. These patients were identified from the Hospital Clínico of Valencia. Genomics, transcriptomics and proteomics data was integrated to define new customised signatures for tissue and plasma biomarkes. Tumor DNA was analyzed by next generation sequencing using a custom 29-gene panel with extended mutational coverage to increase sensitivity. In second instance, we carried out plasma analysis with a proteomic panel mainly related to progression and dissemination of CRC, as well as analysis of previously defined and newly established molecular subtypes. Finally, we evaluated the clinical impact of serial monitoring of ctDNA (ddPCR) in localized CRC patients with newly defined multi-omics subgroups, with the ultimate goal of improving the prognostic assessment as a first step to optimise precision treatment in clinical trials and enhance the survival of CRC patients.