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

Natsuki Saigusa; Hideaki Hirai; Yuichiro Tada; Daisuke Kawakita; Masato Nakaguro; Kiyoaki Tsukahara; Satoshi Kano; Hiroyuki Ozawa; Takahito Kondo; Kenji Okami; Takafumi Togashi; Yukiko Sato; Makoto Urano; Manami Kajiwara; Tomotaka Shimura; Chihiro Fushimi; Akira Shimizu; Isaku Okamoto; Takuro Okada; Takayoshi Suzuki; Yorihisa Imanishi; Yoshihiro Watanabe; Akihiro Sakai; Koji Ebisumoto; Yuichiro Sato; Yoshitaka Honma; Keisuke Yamazaki; Yushi Ueki; Toyoyuki Hanazawa; Yuki Saito; Hideaki Takahashi; Mizuo Ando; Shinji Kohsaka; Takashi Matsuki; Toshitaka Nagao

doi:10.3389/fonc.2021.779882

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

Front Oncol. 2022 Feb 3:11:779882. doi: 10.3389/fonc.2021.779882. eCollection 2021.

Authors

Natsuki Saigusa¹, Hideaki Hirai¹, Yuichiro Tada², Daisuke Kawakita³, Masato Nakaguro⁴, Kiyoaki Tsukahara⁵, Satoshi Kano⁶, Hiroyuki Ozawa⁷, Takahito Kondo⁸, Kenji Okami⁹, Takafumi Togashi¹⁰, Yukiko Sato¹¹, Makoto Urano¹², Manami Kajiwara¹, Tomotaka Shimura¹³, Chihiro Fushimi², Akira Shimizu⁵, Isaku Okamoto⁵, Takuro Okada⁵, Takayoshi Suzuki⁶, Yorihisa Imanishi⁷, Yoshihiro Watanabe⁷, Akihiro Sakai⁹, Koji Ebisumoto⁹, Yuichiro Sato¹⁰, Yoshitaka Honma¹⁴, Keisuke Yamazaki¹⁵, Yushi Ueki¹⁵, Toyoyuki Hanazawa¹⁶, Yuki Saito¹⁷, Hideaki Takahashi¹⁸, Mizuo Ando¹⁹, Shinji Kohsaka²⁰, Takashi Matsuki²¹, Toshitaka Nagao¹

Affiliations

¹ Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan.
² Department of Head and Neck Oncology and Surgery, International University of Health and Welfare, Mita Hospital, Tokyo, Japan.
³ Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
⁴ Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.
⁵ Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan.
⁶ Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁷ Department of Otorhinolaryngology Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.
⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan.
⁹ Department of Otolaryngology Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan.
¹⁰ Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
¹¹ Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
¹² Department of Diagnostic Pathology Bantane Hospital Fujita Health University, School of Medicine, Nagoya, Japan.
¹³ Department of Otolaryngology, Showa University Fujigaoka Hospital, Yokohama, Japan.
¹⁴ Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁵ Department of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
¹⁶ Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
¹⁷ Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.
¹⁹ Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
²⁰ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
²¹ Department of Otorhinolaryngology, Head and Neck Surgery, Kitasato University School of Medicine, Kanagawa, Japan.

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.

Keywords: EZH2; H3K27me3; HER2; androgen receptor; combined androgen blockade (CAB); prognosis; salivary duct carcinoma; therapeutic effect.

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.