Abstract
Purpose :
Circulating tumor DNA (ctDNA) is released into the plasma by many cancers and offers clinical applications including non-invasive diagnostics. Histiocytosis results from myelogenous clonal expansion of histiocytes, predominantly driven by mutations in the mitogen-activated protein kinase (MAPK) pathway that are potentially detectable by ctDNA-based sequencing assays. However, ocular-involving histiocytosis is often a diagnostic challenge leading to delayed diagnosis and the need for invasive biopsy of sensitive ocular structures. The purpose of this study is to determine whether sequencing of plasma-derived ctDNA can non-invasively diagnose ocular-involving histiocytosis.
Methods :
Participants: Twenty-four adult patients with ocular-involving histiocytosis and ctDNA sequencing
Design: Single tertiary cancer referral center
Methods: ctDNA was analyzed (via digital droplet PCR for BRAF V600E, and/or next-generation sequencing) and variant allele frequency (VAF) measured at initial presentation to our center, and subsequently as deemed clinically appropriate. Patient demographics, tumor characteristics, and treatment modalities were recorded.
Main Outcome Measure: Plasma-derived ctDNA detectability of pertinent driver mutations of histiocytosis
Results :
At initial presentation of fourteen patients with ocular-involving histiocytosis, sequencing of plasma-derived ctDNA detected driver mutations for histiocytosis (BRAF V600E (10), KRAS (2), ARAF (1), and concurrent MAP2K1/KRAS (1)). Mutations found in cfDNA were 100% concordant in 11/11 patients with mutations identified by solid tumor sequencing. Of ten patients without driver mutation detected in ctDNA, 3 patients had alterations (CBL mutation or kinase fusion) not captured in the ctDNA sequencing assay, 3 were mutation-free even by tumor sequencing; and in 4 patients other tumor sequencing identified mutations (BRAF (2), MAP2K1 (2)) not detected in ctDNA. Detectable ctDNA was significantly more likely in patients with uveal infiltration (p = 0.036).
Conclusions :
In this cohort, plasma-derived ctDNA was detectable and diagnostic in the majority of patients with ocular-involving histiocytosis. This suggests that if ocular histiocytosis is suspected (particularly if involving the uvea), noninvasive plasma-derived ctDNA analysis is a helpful diagnostic tool that may obviate the need to invasively biopsy sensitive ocular structures.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.