Molecular profiling is critical to guide MEK inhibitor use in Erdheim-Chester disease

Abstract

We appreciate the interest of Pegoraro et al. [1] in our study evaluating the impact of MAPK-ERK pathway alterations on the efficacy of MEK inhibitor (MEKi) therapy in Erdheim-Chester Disease (ECD) [2]. Their real-world cohort provides valuable additional data regarding MEKi efficacy in a broader patient population. However, we highlight several key distinctions between their findings and ours.

Firstly, the “wild-type” (WT) cohort reported by Pegoraro et al. [1] does not appear to include patients harboring pathogenic variants outside of the MAPK-ERK pathway, such as CSF1R mutations or resistant BRAF and MEK mutations, which are known drivers of ECD [2,3,4]. In contrast, in our study all patients who did not respond to MEKi harbored either non-MAPK-ERK mutations or a class II BRAF variant. Importantly, these patients subsequently achieved responses to alteration-specific targeted therapies (e.g., pexidartinib for CSF1R mutations). Thus, the presence of alternative oncogenic drivers—rather than the absence of a MAPK-ERK variant—appeared to underlie resistance to MEKi. The Franco-Italian WT subcohort lacks detailed information regarding the sensitivity and depth of the next-generation sequencing (NGS) panels employed. Moreover, their study reports a 20% rate of MAPK-ERK wild-type cases—considerably higher than that reported in other contemporary ECD cohorts [5, 6]—possibly signaling a failure to detect, rather than a true absence of low burden pathogenic MAPK-ERK pathway mutations or a selection bias toward patients with negative NGS who were treated with a MEKi. Crucially, the authors do not report any cases of patients with known non-MAPK-ERK driver alterations who responded to a MEKi. As such, without detailed molecular profiling, it is challenging to definitively conclude that MEKi efficacy is independent of MAPK-ERK pathway mutations.