Circulating H3K27me3 modified nucleosomes as a biomarker to monitor anti EZH2-based treatment in advanced solid tumour patients: Translational analyses from CAIRE trial

Salani, Francesca; Eccleston, Mark; Palmieri, Lola-Jade; Pernot, Simon; Cousin, Sophie; Masi, Gianluca; Crea, Francesco and Italiano, Antoine (2024). Circulating H3K27me3 modified nucleosomes as a biomarker to monitor anti EZH2-based treatment in advanced solid tumour patients: Translational analyses from CAIRE trial. Cancer Research, 84(6_Suppl.), article no. 5128.



CAIRE is a phase 2 umbrella study which assessed activity of combined anti-EZH2 tazemetostat and anti-PDL1 durvalumab (T+D) in advanced pretreated pancreatic, colorectal and sarcoma cancer patients. The are currently no plasma biomarkers for anti-EZH2 treatment monitoring or outcome. EZH2 catalyzes tri-methylation of Lysine 27 (K27me3) on nucleosomal histone 3 (H3, H3K27me3). Circulating, cell free H3K27me3 modified nucleosomes are thus a potential biomarker for tazemetostat activity. We evaluated the concentration of circulating H3K27me3 modified nucleosomes normalized to H3.1 nucleosomes (the most common isoform of H3) in T+D treated patients, irrespective of the tumor primary site, to determine target engagement during anti-EZH2 treatment. Plasma from patients receiving T+D was collected before the first cycle administration (C1D1), on the following two cycles administration (C2D1, C3D1) and at end of treatment (EOT). H3.1 and H3K27me3 containing nucleosomes were quantified by Nu.Q®-H3.1 and Nu.Q®-H3K27me3 Chemiluminescent Immunoassays. Concentrations are reported as ng/ml and the comparison of their median values at the different timepoints were tested with Kruskal-Wallis and Mann Whitney (independent samples) or Wilcoxon tests (paired samples), with SciPy.stat package (1.6.2). Bonferroni correction was applied to multiple comparisons. Of 197 total samples, 191 were evaluable for both biomarkers (6 higher than top standard after 5x dilution): 69 at C1D1, 63 at C2D1, 50 at C3D1 and 9 at EOT. For 58 patients paired C1D1 and C1D2 levels were available, 46 from C1D1 to C3D1 and 8 from C1D1 to EOT. The normalized Nu.Q®-H3K27me3 C1D1 median value (0.56) was significantly higher than C2D1 (0.31, p: e-12), C3D1 (0.31, p: e-12) and EOT ones (0.28, p: 0.001). Conversely, Nu.Q®-H3.1 levels were similar from C1D1 to C3D1 (range of the medians: 122.16-133.25 ng/ml) and increased at EOT (290.09 ng/ml), but with no significant difference between pairwise timepoints. Regarding paired-samples comparison, the normalized Nu.Q®-H3K27me3 was significantly higher at C1D1 than at C2D1 (p: e-8) and C3D1 (p: e-9) and at EOT (p: 0.02). Conversely, H3.1 concentration was significantly higher at EOT than at C1D1 (p: 0.02), at C2D1 (p: 0.02) and C3D1 (p: 0.05).In conclusion, we described for the first time that normalized circulating nucleosomal H3K27me3 values significantly decrease during T-based treatment in metastatic solid tumor patients, irrespective of the primary disease site, supporting its potential role as a pharmacodynamic biomarker for EZH2 inhibition. Moreover, total nucleosomal H3.1 seems to represent a surrogate of disease burden in metastatic pancreatic, colorectal and sarcoma cancers, as suggested previously in other hematological malignancies.

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