Poor survival in patients with BRAFV600 high VAF melanoma

Skin cancers

By Mardi Chapman

1 Nov 2023

A high variant allele frequency (VAF) of BRAFV600 mutations on next generation sequencing may be a biomarker of poor prognosis in patients with stage IV metastatic melanoma receiving first line BRAF and MEK inhibitors (BRAFi/MEKi).

A retrospective Italian study of 107 patients used a 41.3% cut-off to dichotomise cases as either low or high VAF.

The BRAFV600E mutation represented the most prevalent variant (76.6%). In addition, 25 cases carried the BRAFV600K substitution.

The study, published in JEADV [link here], found progression-free survival (PFS) was significantly shorter in patients with higher disease burden (HR 2.25), ECOG performance status ≥1 (HR 1.82) and high BRAF VAF >41.3% (HR 1.62).

Overall survival (OS) was also shorter in patients with VAF >41.3% (HR 1.46; 95% CI 0.93–2.29, p = 0.1).

“A statistically significant OS reduction in patients with high VAF was found at univariate analysis [HR 1.6 (95% CI 1.01–2.47, p = 0.04)], but only with borderline significance at multivariate analysis [HR 1.46 (0.93–2.29, p = 0.1)],” it said.

The study also found a significant correlation between VAF and PFS for metastatic sites samples [HR 1.99 (95% CI 1.09–3.67, p < 0.05)] and a trend for primary melanoma (HR 1.86 95% CI 0.79–4.4).

“Furthermore, a trend of significant association with OS was found both for VAF in metastatic sites (HR 1.69, 95% CI 0.9–3.15) and primary melanoma (HR 1.88, 95% CI 0.69–5.1).”

However overall response rate (ORR) was similar in patients with low or high VAF (43.4% v 44.4%; p = 0.3).

“Thus, our data suggest that VAF influences the emergence of secondary resistance without an impact on primary resistance. The first response to BRAFi/MEKi is driven by the presence of BRAFV600 mutation but emergence of clones resistant to BRAFi and MEKi may be partially influenced by VAF,” the investigators said.

They said further studies were warranted to determine whether patients with high VAF should receive alternative treatments.

A Commentary on the research [link here] said BRAF mutation status has been associated with both more aggressive disease and lower melanoma-specific mortality in various studies.

“It is apparent that BRAF-mutant melanomas are a heterogeneous collection of tumours that have proven difficult to treat targeting a single pathway.”

The Commentary, co-authored by Dr Mitchell Stark from the Dermatology Research Centre in the Frazer Institute at the University of Queensland, said that given the superior tolerability and ease of oral administration associated with BRAFi/MEKi treatment over immune-checkpoint inhibitors, a predictive biomarker to guide which patients are more likely to have sustained responses to BRAFi would be clinically valuable.

“Following further validation in prospectively collected BRAF-mutant tumours, BRAF VAF may prove to be a useful prognostic biomarker (if metastatic samples are available), to help determine which BRAF-mutant patients are better candidates for long-term therapy with BRAFi.”

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