Novel, Minimally Invasive Test Detects Higher Frequency of EZH2 Mutations in Follicular Lymphoma

Parallel testing of both tissue and liquid biopsy samples detects a higher frequency of EZH2 mutations in patients with follicular lymphoma (FL), with significant clinical implications, according to a recent study.

“Recent studies interrogating the genomic background of FL have revealed that all patients carry at least one pathogenic alteration in the components of the epigenetic regulatory system,” wrote Ákos Nagy, MD, HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary, and colleagues, “EZH2 mutations, the third most common epigenetic lesions in this disease, are present in around 25% of cases.”

The authors noted that tissue biopsy-based molecular testing may not capture the full genetic background of a spatially heterogeneous tumor, such as FL. They hypothesized that parallel testing with [liquid biopsy], “the minimally invasive testing of tumor-derived, cell-free DNA in blood plasma,” might yield more thorough results.

They aimed to develop a novel liquid biopsy-based method to detect EZH2 mutations in plasma samples of patients with FL. In order to do this, pre-treatment liquid biopsy and tissue biopsy samples were collected from 112 patients with FL, and they assessed EZH2 mutation status using an in-house-designed multiplex digital droplet PCR approach.

EZH2 mutation frequency was found to be 38.4% (43 out of 112), whereas tissue biopsy-based analysis resulted in only 31.3% (35 out of 112) mutation positivity. Liquid biopsy analysis recovered an additional 8 (7%) patients harboring EZH2 mutations; however, in 5 patients (4.5%), the EZH2 mutation was exclusively detected in the tissue biopsy specimen. Comparing liquid biopsy to tissue biopsy, the specificity, sensitivity, and negative predictive value of the method they used were 89.6%, 88.3%, and 93.2%, respectively. Pre-treatment liquid biopsy EZH2 variant allele frequency (VAF) significantly correlated with EZH2 VAF measured in the corresponding tissue biopsy samples and with FLIPI scores. Although not significant, “a trend could be observed between liquid biopsy EZH2 VAF and histological grade and clinical stage,” the authors observed.

“Here, we have developed a novel, minimally invasive EZH2 mutation detection test,” Nagy and coauthors concluded. “Due to the ability of this approach to resolve spatial heterogeneity, our method detected a higher frequency of EZH2 mutations in FL patients compared to historical data, which further expands the subset of FL patients who would most likely benefit from the recently developed EZH2 inhibitor therapy.”

“The gain-of-function nature of EZH2 mutations triggered successful pharmaceutical small molecular inhibitor development; however, superior effectivity was found in patients harboring EZH2 mutations. Therefore, molecular tests detecting these alterations are of great clinical relevance,” they added.

Source:

Nagy Á, Bátai B, Gróf S, et al. IBCL-222 Parallel Testing of Liquid Biopsy (ctDNA) and Tissue Biopsy Samples Yields Higher Frequency of EZH2 Mutations in Follicular Lymphoma. Clin Lymph, Myel & Leuk. 2022;22 Suppl 2:S386. doi:10.1016/S2152-2650(22)01553-1