TY - JOUR
T1 - The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients
T2 - A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy
AU - Saigusa, Natsuki
AU - Hirai, Hideaki
AU - Tada, Yuichiro
AU - Kawakita, Daisuke
AU - Nakaguro, Masato
AU - Tsukahara, Kiyoaki
AU - Kano, Satoshi
AU - Ozawa, Hiroyuki
AU - Kondo, Takahito
AU - Okami, Kenji
AU - Togashi, Takafumi
AU - Sato, Yukiko
AU - Urano, Makoto
AU - Kajiwara, Manami
AU - Shimura, Tomotaka
AU - Fushimi, Chihiro
AU - Shimizu, Akira
AU - Okamoto, Isaku
AU - Okada, Takuro
AU - Suzuki, Takayoshi
AU - Imanishi, Yorihisa
AU - Watanabe, Yoshihiro
AU - Sakai, Akihiro
AU - Ebisumoto, Koji
AU - Sato, Yuichiro
AU - Honma, Yoshitaka
AU - Yamazaki, Keisuke
AU - Ueki, Yushi
AU - Hanazawa, Toyoyuki
AU - Saito, Yuki
AU - Takahashi, Hideaki
AU - Ando, Mizuo
AU - Kohsaka, Shinji
AU - Matsuki, Takashi
AU - Nagao, Toshitaka
N1 - Publisher Copyright:
Copyright © 2022 Saigusa, Hirai, Tada, Kawakita, Nakaguro, Tsukahara, Kano, Ozawa, Kondo, Okami, Togashi, Sato, Urano, Kajiwara, Shimura, Fushimi, Shimizu, Okamoto, Okada, Suzuki, Imanishi, Watanabe, Sakai, Ebisumoto, Sato, Honma, Yamazaki, Ueki, Hanazawa, Saito, Takahashi, Ando, Kohsaka, Matsuki and Nagao.
PY - 2022/2/3
Y1 - 2022/2/3
N2 - 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.
AB - 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.
KW - EZH2
KW - H3K27me3
KW - HER2
KW - androgen receptor
KW - combined androgen blockade (CAB)
KW - prognosis
KW - salivary duct carcinoma
KW - therapeutic effect
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U2 - 10.3389/fonc.2021.779882
DO - 10.3389/fonc.2021.779882
M3 - Article
AN - SCOPUS:85124839811
SN - 2234-943X
VL - 11
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 779882
ER -