The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients: A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy.

ABSTRACT

OBJECTIVE: Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy. MATERIALS AND METHODS: The EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases). RESULTS: EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups. CONCLUSIONS: A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.