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.
The pattern of clonal evolution of RAS mutations in cancer is highly heterogeneous, with some tumors retaining and some others losing RAS mutations at disease progression . This mixed pattern of positive and negative selection of RAS mutations observed at relapse appears to be related to the selective pressure of treatments.To date , while the mutational landscape of wt RAS metastatic colorectal cancers characterized by appearance of RAS mutation at disease progression has been widely investigated through liquid biopsy, that of mutant RAS cancers losing RAS mutation at relapse has never been exploited.
Being metastatic sites often difficult to be re-biopsed in the clinical practice, genomic profiling from liquid biopsies, specifically circulating tumor DNA, offers potential advantages when compared with tumor tissue based sequencing, being easily collected on almost any patient, including those with tumor lesions that are difficult to biopsy. To date, CRC harboring KRAS mutations are judged as ineligible for anti-EGFR targeted therapies and are doomed to rely on the inhibition of angiogenesis as the only actionable molecular target. Primary resistant tumors, harboring KRAS mutations, appear to be neglected by researchers and the importance of the EGFR pathway, which indeed sustains the disease, is ignored as potential therapeutic target.Recommendations for medical oncologists take no notice of the molecular background of a priori resistant mKRAS CRC and ignore potential strategies to inhibit the addiction of cancer clones to the EGFR pathway. The present proposal, which is aimed to explore relapse-associated mutated key genes in mCRC characterized by negative selection of RAS mutations at relapse might identify additional oncogenic driver mutations with the potential to be exploited for establishing future therapeutic strategies.
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