ZEB2 Biomarker May Improve TNM Risk-Stratification in CRC

Assessing the transcription factor ZEB2 (zinc finger E-box binding homeobox 2) as part of TNM staging for colorectal cancer could improve physician’s ability to appropriately risk-stratify patients, according to the results of a study published in JAMA Network Open.

Expression of ZEB2 in patients in the study was associated with worse oncologic outcomes and distant recurrence.

“Addition of the ZEB2 score to nomograms composed of conventional TNM and histologic factors increased sensitivity and specificity of TNM, resulting in improved risk-stratification in 14 of every 100 patients assessed,” wrote researcher Rahul Sreekumar, MD, of Cancer Research UK Centre, and colleagues. “Detection of this molecular marker by immunohistochemical analysis is a simple and reproducible method for detecting a mesenchymal phenotype.”

According to the study, previous research has suggested an association between a mesenchymal phenotype and increased risk for disease recurrence and micrometastases. Sreekumar and colleagues investigated the epithelial to mesenchymal transition–inducing transcription factor ZEB2 as a biomarker in patients with colorectal cancer who had undergone curative surgery.

In a test cohort of 126 patients, 41.3% of tumors were nuclear ZEB2 positive. In a validation cohort of 210 patients, 49.5% of tumors were ZEB2 positive. In both groups, ZEB2 expression was associated with a significant reduction in overall survival (OS) and disease-free survival.

Specifically, in the test cohort, ZEB2 expression was linked with lymph node metastases and a higher-stage disease. The mean OS in ZEB2-positive patients was 43.8 months compared with 60.4 months in negative patients (P = .02). The mean disease-free survival was 48 months in ZEB2-positive patients compared with 60.5 months in negative patients (P = .005). ZEB2 expression was an independent biomarker of OS and disease-free survival.

In the validation cohort, the mean OS was 47 months for patients positive for ZEB2 expression compared with 53.9 months for negative patients (P = .02). The mean disease-free survival was 44.6 months in ZEB2-positive patients compared with 57.6 months in negative patients (P = .001). Again, ZEB2 expression was an independent biomarker of OS and disease-free survival.

“Addition of ZEB2 expression to nomograms composed of conventional TNM risk factors improved the ability to identify patients at high-risk of recurrence demonstrated by the improvement in concordance index in both test (0.73–0.77) and validation (0.82–0.87) cohorts,” the researchers reported.

In an invited commentary, Joceline V. Vu, MD, Ana De Roo, MD, and Karin M. Hardiman, MD, PhD, of Michigan Medicine, noted that the lack of biomarkers in colorectal cancer has made risk-stratification “imprecise” and has led to an over or undertreatment of certain subpopulations of patients.

“The study by Sreekumar et al identified a promising biomarker that better stratifies prognosis, but its clinical utility remains undetermined,” they wrote. “Risk-stratification is important, but the true clinical utility of biomarkers is in guiding treatment. For ZEB2 and other biomarkers, future work should address whether currently available therapies can modify outcomes in ZEB2-positive patients. Understanding whether outcomes for patients with ZEB2-positive CRC are altered by receipt of adjuvant chemotherapy could help elucidate whether it is ultimately a marker of poor outcomes or whether it will have true clinical utility.”