Comparison of Two Blood-Based Genotyping Tests to Investigate the KRAS G12C Mutation in Patients with Non-Small-Cell Lung Cancer at Failure of First-Line Treatments.

Chiara Nicolazzo,Paola Grammatico,Daniele Marinelli,Paola Gazzaniga,Giuseppe Giannini,Alain Gelibter,Francesca Belardinilli,Gianluigi De Renzi,Enrico Cortesi,Irene Bottillo,Simona Pisegna

doi:10.3390/diagnostics11122196

Chiara Nicolazzo, Paola Grammatico + Show 9 more

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https://doi.org/10.3390/diagnostics11122196

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Abstract

Although molecular profiling at diagnosis has traditionally relied on direct sampling of neoplastic tissue, cancer clonal evolution represents a critical obstacle to use primary tissue biopsies to guide clinical decision-making at the time of progressive disease. Liquid biopsies might offer enormous advantages over tissue biopsies, tracking in real-time temporal-based tumor dynamics following each line of treatment. Here, we compared two liquid biopsy assays, specifically real-time polymerase chain reaction and next-generation sequencing, to track the KRAS G12C mutation at onset of progression from previous lines of therapy. The KRAS G12C mutation was acquired at the time of progressive disease in 24% of patients. Furthermore, all patients with KRAS G12C mutation-positive tissue became negative in ctDNA at progressive disease. The presence of other somatic mutations in all these samples confirmed the tumor origin of the circulating DNA. This pilot study suggests that in the assessment of the plasma KRAS G12C mutation as a druggable target, real-time PCR assay Idylla might be a suitable approach to better match patients to interventional biomarker-targeted therapies.

Highlights

Introduction iationsThe rapid evolution of precision medicine in non-small-cell lung cancer (NSCLC) led to an increased demand for biomarkers in a very short timeframe, with molecular testing being mandatory to assign patients to specific treatment groups in precision oncology trials [1]
In the whole patient population, the KRAS G12C mutation was detected in 16% of the patients at the time of first diagnosis
Mutations as therapeutic targets originally detected in the primary tumor tissue might not be present at the time of relapse or, alternatively, might develop at the time of progressive disease (PD), posing a clinical challenge in regards to rebiopsy at the time of PD

Summary

Introduction

The rapid evolution of precision medicine in non-small-cell lung cancer (NSCLC) led to an increased demand for biomarkers in a very short timeframe, with molecular testing being mandatory to assign patients to specific treatment groups in precision oncology trials [1]. 30% of patients with NSCLC have RAS mutations, with 13%. AMG-510 (sotorasib) is a small molecule that selectively and irreversibly targets KRAS G12C through a unique interaction with the P2 pocket, irreversibly locking KRAS in its inactive GDP-bound state [3]. Based on the results of the phase 2 CodeBreaK 100 trial, a new drug application was recently submitted to FDA for sotorasib for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic NSCLC after at least one previous systemic therapy attempt [4].

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