In patients with localized clear cell renal cell carcinoma (RCC), tumor levels of the oncogenic protein EZH2 (enhancer of zeste homolog 2) were predictive of risk of RCC-specific death, including in patients considered at low or intermediate risk by a standard prognostic model.

Among nearly 2,000 tumors from patients with RCC in three different cohorts, the risks of both all-cause mortality and RCC-specific death were approximately double for patients with tumors that had high expression of EZH2 compared with those whose tumors expressed only low levels, reported Thai Huu Ho, MD, PhD, from the Mayo Clinic in Phoenix, and colleagues.

Among patients deemed to be at low risk according to the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score, high levels of EZH2 were associated with a sixfold increase in risk of death, the investigators wrote (J Clin Oncol. 2017 Oct 4. doi: 10.1200/JCO.2017.73.3238 ).

“With the increasing incidence of small RCC tumors detected by cross-sectional imaging, our study emphasizes the clinical utility of a biomarker that is compatible with a single FFPE [formalin-fixed, paraffin-embedded] slide that accurately predicts risk of RCC death beyond existing clinicopathologic models” they wrote.

EZH2 is a chromatin remodeler, a member of a family of proteins that are involved in epigenetic gene silencing. Although previous studies have explored potential associations between EZH2 expression and RCC outcomes, results have been conflicting, Dr. Ho and associates noted.

In hopes of getting a more definitive picture of the potential role of EZH2 as a prognostic biomarker for RCC, the investigators looked at the association between EZH2 expression and survival in tumors from 532 patients in the Cancer Genome Atlas (CGA) cohort, 122 patients from a University of Texas Southwestern Medical Center (Dallas) cohort, and from 1,338 patients in a Mayo Clinic cohort.

In a model adjusted for age and SSIGN score, patients in the CGA cohort whose tumors had high levels of EZH2 expression had a hazard ratio (HR) for worse overall survival of 1.54 (P less than .028) compared with patients with low expression. Respective HRs for overall survival in the UT Southwestern and Mayo Cohorts were 2.16 (P = .034) and 1.43 (P = .00026).

When the researchers looked at RCC-specific survival in patients in the Mayo cohort, they found that those with the highest levels of EZH2 expression had a twofold risk for death vs. those with the lowest levels (HR 1.97, P less than .001).

They also found that patients with a low-risk SSIGN score who had high levels of EZH2 protein expression had an HR for RCC-specific death of 6.14, and that patients with intermediate-risk SSIGN scores has an HR for RCC-related death of 2.12 (P less than .001 for both comparisons).

The investigators noted that EZH2 enzymatic activity in RCC could potentially be targeted by EZH2 inhibitors such as tazemetostat .

“Further studies are required to determine how to better incorporate molecular biomarkers with prognostic information into surveillance guidelines and adjuvant clinical trials,” they concluded.

The study was supported by the Mayo Clinic, Gerstner Family Career Development Award, National Cancer Institute, and Cancer Prevention Research Institute of Texas. Dr. Ho and seven coauthors reported no relationships to disclose. The remaining investigators reported relationships with various companies.


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