RAS Mutation Conversion in Bevacizumab-Treated Metastatic Colorectal Cancer Patients: A Liquid Biopsy Based Study

Abstract

Liquid biopsies have shown that, in RAS mutant colorectal cancer, the conversion to RAS wild-type * status during the course of the disease is a frequent event, supporting the concept that the evolutionary landscape of colorectal cancer can lead to an unexpected negative selection of RAS mutant clones. The aim of the present study was to clarify whether the negative selection of RAS mutation in plasma might be drug-dependent. For this purpose, we used liquid biopsy to compare the rate of conversion from RAS mutant to RAS wild-type * in two groups of originally RAS mutant mCRC patients: the first treated with chemotherapy alone, while the second was treated with chemotherapy combined with bevacizumab. Serial liquid biopsies were performed at 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4) after starting first line treatments. We found that the only independent variable significantly associated to RAS status conversion was the use of bevacizumab. RAS conversion was not found associated to tumor burden reduction, although bevacizumab-treated patients who converted to RAS wild-type * had a significantly longer PFS compared to patients who remained RAS mutant. The appearance of a “RAS wild-type * window”, mainly in bevacizumab-treated patients, might present them as candidates for second line treatment with anti-EGFR, which was otherwise precluded.

Genomic landscape and survival analysis of ctDNA “neo-RAS wild-type” patients with originally RAS mutant metastatic colorectal cancer

“…Our choice to use a gene panel for detection of only clinically actionable mutations in ctDNA (thus lacking p53, frequently mutated in mCRC) might explain why in 9 cases it was necessary to use a methylation test to confirm the presence of ctDNA. We here report that “neo- RAS wt” occurs mainly in Bevacizumab treated patients, confirming our previous report that Bevacizumab in first-line is as an independent predictor of RAS mutation clearance in ctDNA at PD ( 17 ). Nevertheless, differently from that reported by Sunakawa et al, we disagree in that RAS -mutant colon cancer cells may have changed by intensive treatment, since in our cohort triplet vs doublet was not found associated with RAS mutation conversion.…”

KRAS Mutation Status in Bulgarian Patients with Advanced and Metastatic Colorectal Cancer

“…Tumors with wild-type KRAS status at diagnosis may develop KRAS mutations during treatment, potentially due to acquired resistance to EGFR-directed therapies or due to the development of mutations in the EGFR extracellular domain that prevent therapeutic agent binding [ 25 ]. In this regard, it is interesting to note that the use of antiangiogenic agents in combination with chemotherapy as a first-line treatment may revert RAS -mutated tumors to wild type, allowing patients to receive EGFR inhibitors as a second-line therapy [ 52 , 53 , 54 ]. Liquid biopsy, which is entering recently for screening for RAS mutations, provides a means to monitor the dynamics of the mutational status during the course of therapy [ 55 ].…”

Case Report: Genetic and immune microenvironmental characteristics of a rectal cancer patient with MSS/PD-L1-negative recurrent hepatopulmonary metastasis who achieved complete remission after treatment with PD-1 inhibitor

“…Studies demonstratedthat patients with colorectal cancer who undergo a transformation from mutant to wild-type KRAS have a more favorable survival prognosis ( 9 , 10 ). In CRC, RAS mutant and RAS wild-type cells always coexist in the same tumor microenvironment in a balanced manner, competing for space and resources ( 18 ). Tumors with RAS mutation are under negative selection pressure from chemotherapy or antiangiogenic therapy to support the growth of RAS wild type clones, resulting in their relative increase ( 19 ).…”