Reconsidering the turnaround times for BRAF V600 mutation analysis in non-small-cell lung cancer: a molecular diagnosis in one day is achievable for rapid treatment choices

The Editor

Current Oncology

26 November 2018

As reported by Auliac et al.¹, patients with BRAF-mutated non-small-cell lung cancer (nsclc) have particular clinicopathologic features and prognosis. From a treatment point of view, only patients with BRAF V600E–mutated nsclc have been shown to be good responders to the now-approved dabrafenib-plus-trametinib anti-BRAF and anti-MEK bi-therapy. That makes the diagnosis of the BRAF V600E mutation crucial for therapeutic choices at the present time. Turnaround times for molecular tests must be reduced to match with clinical practice and with the therapeutic management of patients with advanced nsclc, especially for patients experiencing acute deterioration. Next-generation sequencing (ngs) methods have revolutionized our capacity to analyze several genes concurrently in the same assay. Nevertheless, the turnaround time for ngs analyses remains long: 1–2 weeks from the prescription to the final result of a molecular analysis. A long turnaround time can delay initiation of appropriate treatment, and efforts must be pursued to obtain as quickly as possible a molecular status usable for treatment choices.

Furthermore, the medicoeconomics of strategies using multiple single-gene-based tests compared with “all in one” ngs-based tests is still debated. For example, in a recent medicoeconomic evaluation in the United States, the cost of sequential tests for KRAS, EGFR, ALK, ROS1, and BRAF was $3,763 ($464, $696, $1,070, $1,127, and $406 respectively), whereas the cost using ngs was $2,860². But the costs vary greatly from one health care system to another.

Besides ngs, alternative methods have been proposed to optimize the workflow of molecular analyses and to obtain a molecular status for the main predictive markers in a single day, such as using fully automated real-time quantitative polymerase chain reaction (rt-pcr) for EGFR mutations or using first-line immunohistochemistry instead of fluorescence in situ hybridization for ALK and ROS1 rearrangements. Fully automated rt-pcr and immunohistochemistry have both been shown to be valuable methods to diagnose BRAF V600E mutations in various cancer subtypes, including nsclc^3,4. VE1 clone-based anti–braf V600E immunohistochemistry has been shown to be a highly sensitive and specific method to detect the braf V600E–mutated protein in nsclc samples, including samples with low tumour content³. The full duration of the immunohistochemistry process takes about 1 day. In France, the cost of analyzing for KRAS and EGFR (€459) combined with alk, ros1, and braf V600E immunohistochemistry (€48 for 1 antibody, but €83 using 3 antibodies: anti-alk, anti-ros1, and anti-braf V600E) is €542, whereas the minimal cost of a ngs analysis is set at €882.9.

A novel approach to the classification of BRAF mutations has distinguished between class i mutations (BRAF V600E and other BRAF V600 mutants), which are responsive to current braf targeting therapies, and class ii and iii mutations (non–BRAF V600 mutants), which do not respond to available therapies⁵. In that manner, there would be a strong rationale to extend the dabrafenib-plus-trametinib therapy to every patient with a BRAF V600–mutated nsclc and, as a consequence, to determine every BRAF V600 mutation and not only BRAF V600E in nsclc samples. That approach would imply favouring molecular analyses rather than VE1 immunohistochemistry testing, which has been highly specific for the braf V600E mutant protein only. The fully automated Idylla rt-pcr method (Biocartis, Mechelen, Belgium) allows for the detection of a BRAF V600 mutation (including BRAF V600E, but also other BRAF V600 mutants) in less than 2 hours from the tumour sample to the final written report, showing great performance in various tumour subtypes, including nsclc, and in various tumor samples, including challenging ones. That rt-pcr method could permit the rapid determination of a BRAF V600 mutation status usable for therapeutic choices in patients with advanced nsclc². The cost of rt-pcr–based KRAS, EGFR, and BRAF testing (€459 for KRAS and EGFR testing and €116 for BRAF testing) combined with alk and ros1 immunohistochemistry (€56 for 2 antibodies) would reached a total cost of €631, which is still lower than the cost of a ngs analysis in France (€882.9).

Given the crucial importance of BRAF testing for the management of patients with advanced nsclc and the various available diagnostic methods with varying turnaround times and costs, the choice of the most appropriate testing strategy to analyze biomarkers, including BRAF V600, in patients with lung cancer should be a decision based on the requirement of the oncology care teams and technical and financial health care conditions, to match with the optimal therapeutic management of patients.