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In this retrospective study, Louveau et al studied the relationship between the detection of mutant V600B BRAF circulating tumour DNA (ctDNA) using an E-ice-COLD-PCR method and clinical outcome in 53 patients with BRAFV600 stage III or IV metastatic melanoma treated with an anti-BRAF therapy (vemurafenib or dabrafenib). Among the 53 patients who had this analysis performed in the first 3 months after initiating the treatment, they found a correlation between the positivity of this test and the progression-free survival (PFS) with a mean PFS of 2.4 versus 4.5 months for positive versus negative V600 ctDNA results. There was no correlation with overall survival, which might be due to the small effective of the cohort.
The authors conclude that early evaluation of ctDNA might become a useful tool to anticipate the duration of response, the expected timing of relapse and further management of the patient.
This is indeed interesting and potentially useful information for patients’ management. Of course, since we now use the combination of anti-BRAF and anti-MEK agents, we would like to know whether the same results will apply to the combination therapy context as it has already been reported in a few patients.1 Second, the kinetics of ctDNA changes might be an important parameter, and we do not know whether a positive test becoming negative was associated with a better outcome in this series. The study does not mention whether the presence and/or the level of ctDNA at baseline was associated with a longer PFS, as it was the case in a large retrospective study2 on more than 800 patients treated with dabrafenib or trametinib for BRAF mutant melanoma. An association between baseline ctDNA and overall survival was also found in this latter analysis.
A recent study on patients with BRAF mutation, who had developed a resistance to anti-BRAF monotherapy and who were treated with the combination of dabrafenib and trametinib, showed that patients with a partial response had a significantly lower copy number of BRAF ctDNA after 2 weeks of treatment than those with no response with a significant decrease of copy number and fraction after 2 weeks of treatment versus baseline.3 Persistent detection of BRAFV600mut ctDNA after 2 weeks of treatment was significantly correlated with a worse progression-free survival (1.8 months (95% CI 1.2 to 2.4) vs 5.9 months (95% CI 4.9 to 6.9), p=0.001). However, in this study, as in the one published here, there was no significant correlation between tumour response or survival and baseline detection of BRAF ctDNA. 4
Several studies reported that re-appearance of BRAF ctDNA could precede a relapse and be seen before clinical or imaging signs. 1 3
Tumour heterogeneity is an important concern in melanoma patients treated with targeted agents, and we know that various tumour clones, selected or emerging under therapy pressure, are leading to secondary resistances. These various clones can also be ‘seen’ in the blood via their circulating mutant DNA, like NRAS or MEK mutations. Indeed, in some melanoma patients treated with anti-BRAF/anti-MEK and developing a resistance resulting from an NRAS mutation can have the ctNRAS mutation detected in the blood and that detection can even precede, in some cases, the diagnosis of relapse. Another recent work reports the detection of various tumour subclones of a KIT mutant melanoma in a patient which could explain why she presented with a dissociated response to an anti-KIT targeted therapy.4
Furthermore, ctDNA analysis can also monitor tumour burden in patients treated with therapies different from anti-BRAF targeting agents like immune checkpoint inhibitors.5
Altogether, detection of ctDNA is a very promising tool that has the advantage to concentrate the tumour genetic heterogeneity in one single compartment: the blood. Several methods are developed, with increasing sensitivity, reliability and handiness. Semiquantitative and quantitative methods are also in development. It is very likely that liquid biopsy allowing detection of various tumour-associated mutations will become a useful and practical mean in the near future that will allow physicians to optimise patients monitoring and treatment readjustment.
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