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EZH2 Expression Associated With Aggressive Mantle Cell Lymphoma, Study Finds

NEW YORK – Mantle cell lymphoma patients with EZH2 expression may experience more aggressive disease, including a high proliferation rate, poorer overall survival, as well as the presence of aggressive histologic variants and p53 overexpression, a study published on Tuesday in Modern Pathology has shown.

Researchers from the University of Texas MD Anderson Cancer Center assessed EZH2 expression on archived tissue samples from 150 patients with mantle cell lymphoma, using immunohistochemistry and NanoString's multiplex gene expression test, the nCounter PanCancer Pathways Panel.

They found EZH2 expression in 38 percent, or 57 patients' samples. When they compared these patients' medical records with EZH2-negative patients, the researchers found that more EZH2-positive patients compared to EZH2-negative patients had aggressive histologic variants, 65 percent versus 29 percent, respectively. Similarly, EZH2-positive patients were more likely than EZH2-negative patients to have a high Ki-67 proliferation rate, 72 percent versus 19 percent; and p53 overexpression, 43 percent versus 2 percent, respectively.

Patients with aggressive mantle cell lymphoma are characterized by a higher mitotic index and proliferation rate compared to the classic subtype. In the study, researchers found that EZH2 expression in 40 percent or more of cancer cells was associated with the overexpression of cell cycle-related genes, causing the cancer to grow faster.

While there was not a significant difference in median relapse-free survival — 3.8 years for EZH2-positive patients and 2.7 years for EZH2-negative patients — overall survival did differ between the groups. For patients with EZH2-expressing mantel cell lymphoma, median overall survival was 3.9 years compared to 9.4 years for those with EZH2-negative disease.

The difference in overall survival between the two groups persisted regardless of the treatments patients received. EZH2-positive patients on hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with or without rituximab (Genentech/Biogen's Rituxan) had a median overall survival of 5 years versus 11.7 years for EZH2-negative patients. Similarly, those treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab also showed a difference in overall survival between EZH2-positive and -negative groups, 3.5 years versus 5.2 years, respectively.

These data show that EZH2 expression has a greater effect on mantle cell lymphoma progression than expression of other components, such as EED and SUZ12, in the same protein complex. Unlike EZH2 expression, the researchers found that EED and SUZ12 expression did not correlate with either overall survival or relapse-free survival in patients.

Although in multivariate analysis EZH2 expression did not pan out as an independent predictor of overall survival, the researchers suggested that EZH2 expression in combination with a high proliferate rate could identify high-risk mantle cell lymphoma patients. They concluded that EZH2 expression could help with "identification of high-risk mantle cell lymphoma patients, not only in patients with classic histology but with aggressive histology."

In this study, researchers considered the prognostic impact of EZH2 expression in mantle cell lymphoma, but the ability of the biomarker to identify best responders to EZH2 inhibitors may warrant further study. In June 2020, the US Food and Drug Administration approved the first EZH2 inhibitor, tazemetostat (Epizyme's Tazverik), for previously treated patients with relapsed or refractory follicular lymphoma characterized by an EZH2 mutation. At the same time, the agency also approved the drug for all refractory follicular lymphoma patients, regardless of biomarker status, if they lack other treatment options.

The researchers wrote in their paper that the study underlying this approval suggested that EZH2 mutations may not be identifying all follicular lymphoma patients who respond to tazemetostat. They also noted a previous study evaluated EZH2 inhibitors' effect on mantle cell lymphoma cell lines and showed that the treatment led to reduced proliferation and decreased cancer cell survival. The researchers suggested that their study findings along with these previous studies may contain insights into which mantle cell lymphoma patients benefit most from an EZH2 inhibitor.