ctDNA might expand therapeutic options for second line treatment of KRAS mutant mCRC

Abstract

Background: KRAS mutations predict failure of anti-EGFR therapies, thus genotyping colorectal cancer (CRC) is crucial for personalized treatments. Cancer heterogeneity hamper the assessment of KRAS mutational status in tumor tissues, leading to the search for alternative sources of cancer genetic information. ctDNA of patients treated with anti-EGFR drugs exhibit pulsatile levels of KRAS mutations, revealing that the CRC genome adapts dynamically to intermittent EGFR blockade. These data support the use of liquid biopsy to monitor the molecular underpinnings of resistance to anti- EGFR agents. Research has been selectively concentrated on the emergence of resistant clones in the blood of patients with wtKRAS CRC as biomarker of anti-EGFR therapy resistance. Conversely our group demonstrated that patients with metastatic CRC harboring mutated primary tumors, thus not candidate to EGFR inhibitors, frequently have wtKRAS circulating tumor cells in blood. To explain the prevalence of wtKRAS clones in these patients, the generation of hypoxia has been suggested. We aimed to determine if anti-angiogenic drugs might drive the biological evolution of mKRAS clones towards a prevalent wtKRAS disease, by ctDNA. Methods: Ten patients with histologically confirmed mKRAS mCRC candidate to firstline anti angiogenic drugs were prospectively enrolled. To investigate whether wtKRAS clones emerge as dominant under treatments, serial blood draws were performed at baseline and at 3 months months of treatment. IdyllaTM (Biocartis) ctKRAS Mutation Assay was used to track KRAS mutational status in serial ctDNA determinations for each patient. Results: At baseline, KRAS mutational status in ctDNA was found concordant with tumor tissues in all patients analysed. At 3 months,3/10 (30%) of mKRAS CRC patients treated with antiangiogenic drugs switched to wtKRAS ctDNA in peripheral blood. Conclusions: These preliminary data suggest that patients with mKRAS colon cancer not unfrequently switch to a prevalent wtKRAS disease in course of treatment with anti-angiogenic drugs. if confirmed in a large patients population, these results might shift second-line therapeutic options for KRAS mutant mCRC patients from insufficient to promising.