Circulating Tumour DNA Is an Independent Prognostic Biomarker for Survival in Metastatic BRAF or NRAS-Mutated Melanoma Patients.

Guillaume Herbreteau,Gaelle Quéreux,Sandrine Théoleyre,Brigitte Dréno,Anne-Chantal Knol,Marc G Denis,Cécile Frénard,Paul Hofman,Audrey Vallée,Emilie Varey,Amir Khammari

doi:10.3390/cancers12071871

Abstract

Circulating tumour DNA (ctDNA) can be used to identify gene alterations. The purpose of this study was to determine whether the detection of ctDNA, based on the identification of BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma. In total, 68 BRAF or NRAS-mutated stage IV or unresectable stage III metastatic cutaneous melanoma patients were included and tested for the presence of BRAF and NRAS mutations in circulating DNA before treatment initiation, using the Cobas BRAF/NRAS Mutation Test (Roche). The expected mutation was detected in the plasma of 34/68 patients (50% sensitivity). ctDNA detection was associated with AJCC stage, along with the number and nature of metastases. ctDNA was less frequently detected in NRAS-mutated than in BRAF-mutated melanoma (36% and 66%, respectively). At initiation of first-line treatment, ctDNA detection was associated with poor prognosis in Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis (log-rank: p = 0.002 and p < 0.0001, respectively). In multivariate analysis, ctDNA detection was an independent factor of poor prognosis in OS, after adjustment for AJCC stage, number and nature of metastases and gender (HR = 4.384; 95% CI: (1.308; 14.699); p = 0.017).

Highlights

In the era of precision medicine, accurate assessment of cancer prognosis is essential to stratify risks and determine the best treatment option
The presence of a positive sentinel node leads to a lymph node dissection of the invaded area, and subsequently, to adjuvant treatment with anti-PD1 immunotherapy or with BRAF inhibitors (BRAFi), depending on whether the tumour harbours a BRAF codon 600 mutation
As a first line of treatment, BRAF inhibitors are indicated in combination with MEK inhibitors (MEKi) for patients with BRAF-mutated metastatic melanoma (40% of cases)

Summary

Introduction

In the era of precision medicine, accurate assessment of cancer prognosis is essential to stratify risks and determine the best treatment option. The classification of the American Joint Committee on Cancer (AJCC) guides the management of cutaneous melanoma. At AJCC stages I and II (localised extension), treatment is only surgical, with an excellent prognosis. Cancers 2020, 12, 1871 lymph node extension marks a turning point in the disease. The presence of a positive sentinel node leads to a lymph node dissection of the invaded area, and subsequently, to adjuvant treatment with anti-PD1 immunotherapy or with BRAF inhibitors (BRAFi), depending on whether the tumour harbours a BRAF codon 600 mutation. As a first line of treatment, BRAF inhibitors are indicated in combination with MEK inhibitors (MEKi) for patients with BRAF-mutated metastatic melanoma (40% of cases). Immune checkpoint inhibitors (anti-PD1, anti-CTLA4 or a combination of both) constitute a therapeutic alternative, both in BRAF-wildtype and BRAF-mutated patients

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