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

Chiara Nicolazzo,Gianluigi De Renzi,Salvatore Caponnetto,Valentina Magri,Giuseppe Giannini,Enrico Cortesi,Federica Di Nicolantonio,Francesca Belardinilli,Paola Gazzaniga,Michela De Meo,Annarita Vestri

doi:10.3390/cancers14030802

Abstract

Simple SummaryRecent evidence has been provided that the clonal evolution of mutant RAS colorectal tumors may lead to the negative selection of mutant RAS clones, with the appearance of a time window characterized by the disappearance of RAS mutant clones in plasma. We demonstrate here for the first time that the use of bevacizumab in the first-line treatment is the most significant factor for RAS conversion from mutant to wild type in plasma. The frequent appearance of this “RAS wild-type * window” in patients treated with a first line treatment containing bevacizumab could possibly present them as candidates for second line treatment with anti-EGFR monoclonal antibodies, which are otherwise precluded.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.

Highlights

Activating oncogenic mutations in KRAS and NRAS (RAS) are common in metastatic colorectal cancer, resulting in the constitutive activation of the Ras/Raf/MEK/ERK pathway [1]
Recent studies performed through liquid biopsy have provided evidence that the clonal evolution of RAS mutant CRC may lead to the negative selection of RAS mutant clones, with the appearance of a time window characterized by a RAS wild- type disease in plasma [4,5,6,7,8]
We compared the rate of conversion from RAS mutant to RAS wild-type * in plasma in two groups of originally RAS mutant metastatic colorectal cancer (mCRC) patients: the first treated with chemotherapy alone, while the second was treated with chemotherapy combined with bevacizumab

Summary

Introduction

Activating oncogenic mutations in KRAS and NRAS (RAS) are common in metastatic colorectal cancer (mCRC), resulting in the constitutive activation of the Ras/Raf/MEK/ERK pathway [1]. Some studies are currently investigating the efficacy of anti-EGFR therapy in patients with initially RAS mutant mCRC, who convert to RAS wild-type * in plasma with disease progression [9,10,11]. The aim of the present study was to clarify whether RAS mutation loss in colorectal cancer might be a drug-dependent phenomenon. For this purpose, we compared the rate of conversion from RAS mutant to RAS wild-type * in plasma 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

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