Ricerc@Sapienza

RAS mutations are found in 30 to 50% of metastatic colorectal cancer (mCRC) and determine the ineligibility of affected patients for epidermal growth factor receptor (EGFR)-targeted therapies. Therefore, genotyping colorectal cancer tissue is mandatory in routine practice to personalize the therapeutic approach. The analysis of circulating tumor DNA (ctDNA) in blood samples is a remarkable surrogate of tumor biopsy for mutations detection . We recently demonstrated in a population of mCRC patients serially monitored through plasma ctDNA analysis that the pattern of clonal evolution of RAS mutations is highly heterogeneous, with some tumors retaining and some others losing RAS mutations in plasma at disease progression . This phenomenon, previously reported in other tumor types, supports that RAS mutations are frequently subclonal and that the evolutionary pressure imposed by therapies can result in positive but also negative selection of RAS mutant clones at relapse . To date the mutational landscape of mCRC characterized by loss of RAS mutation at disease progression has never been explored, due to the difficulty to perform re-biopsy on metastatic sites. Aim of the present proposal is to investigate through liquid biopsy other potential driver events in mCRC showing loss of RAS mutations at disease progression by the Next Generation Sequencing (NGS) analysis of ctDNA.