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

被引：13

作者：

Saigusa, Natsuki ^{[1
]}

Hirai, Hideaki ^{[1
]}

Tada, Yuichiro ^{[2
]}

Kawakita, Daisuke ^{[3
]}

Nakaguro, Masato ^{[4
]}

Tsukahara, Kiyoaki ^{[5
]}

Kano, Satoshi ^{[6
,7
]}

Ozawa, Hiroyuki ^{[8
]}

Kondo, Takahito ^{[9
]}

Okami, Kenji ^{[10
]}

Togashi, Takafumi ^{[11
]}

Sato, Yukiko ^{[12
]}

Urano, Makoto ^{[13
]}

Kajiwara, Manami ^{[1
]}

Shimura, Tomotaka ^{[14
]}

Fushimi, Chihiro ^{[2
]}

Shimizu, Akira ^{[5
]}

Okamoto, Isaku ^{[5
]}

Okada, Takuro ^{[5
]}

Suzuki, Takayoshi ^{[6
,7
]}

Imanishi, Yorihisa ^{[8
]}

Watanabe, Yoshihiro ^{[8
]}

Sakai, Akihiro ^{[10
]}

Ebisumoto, Koji ^{[10
]}

Sato, Yuichiro ^{[11
]}

Honma, Yoshitaka ^{[15
]}

Yamazaki, Keisuke ^{[16
]}

Ueki, Yushi ^{[16
]}

Hanazawa, Toyoyuki ^{[17
]}

Saito, Yuki ^{[18
]}

Takahashi, Hideaki ^{[19
]}

Ando, Mizuo ^{[20
]}

Kohsaka, Shinji ^{[21
]}

Matsuki, Takashi ^{[22
]}

Nagao, Toshitaka ^{[1
]}

机构：

[1] Tokyo Med Univ, Dept Anat Pathol, Tokyo, Japan

[2] Int Univ Hlth & Welf, Mita Hosp, Dept Head & Neck Oncol & Surg, Tokyo, Japan

[3] Nagoya City Univ, Dept Otorhinolaryngol Head & Neck Surg, Grad Sch Med Sci, Nagoya, Aichi, Japan

[4] Nagoya Univ Hosp, Dept Pathol & Lab Med, Nagoya, Aichi, Japan

[5] Tokyo Med Univ, Dept Otorhinolaryngol Head & Neck Surg, Tokyo, Japan

[6] Hokkaido Univ, Dept Otolaryngol Head & Neck Surg, Fac Med, Sapporo, Hokkaido, Japan

[7] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan

[8] Keio Univ, Dept Otorhinolaryngol Head & Neck Surg, Sch Med, Tokyo, Japan

[9] Tokyo Med Univ, Dept Otorhinolaryngol Head & Neck Surg, Hachioji Med Ctr, Tokyo, Japan

[10] Tokai Univ, Dept Otolaryngol Head & Neck Surg, Sch Med, Isehara, Kanagawa, Japan

[11] Niigata Canc Ctr Hosp, Dept Head & Neck Surg, Niigata, Japan

[12] Japanese Fdn Canc Res, Canc Inst Hosp, Dept Pathol, Tokyo, Japan

[13] Fujita Hlth Univ, Sch Med, Dept Diagnost Pathol, Bantane Hosp, Nagoya, Aichi, Japan

[14] Showa Univ, Dept Otolaryngol, Fujigaoka Hosp, Yokohama, Kanagawa, Japan

[15] Natl Canc Ctr, Dept Head & Neck, Esophageal Med Oncol, Tokyo, Japan

[16] Niigata Univ, Grad Sch Med & Dent Sci, Dept Otolaryngol Head & Neck Surg, Niigata, Japan

[17] Chiba Univ, Grad Sch Med, Dept Otolaryngol Head & Neck Surg, Chiba, Japan

[18] Univ Tokyo, Fac Med, Dept Otolaryngol Head & Neck Surg, Tokyo, Japan

[19] Yokohama City Univ, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Yokohama, Kanagawa, Japan

[20] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Otorhinolaryngol Head & Neck Surg, Okayama, Japan

[21] Natl Canc Ctr, Div Cellular Signaling, Tokyo, Japan

[22] Kitasato Univ, Dept Otorhinolaryngol Head & Neck Surg, Sch Med, Sagamihara, Kanagawa, Japan

来源：

FRONTIERS IN ONCOLOGY | 2022年 / 11卷

基金：

日本学术振兴会;

关键词：

salivary duct carcinoma; EZH2; androgen receptor; HER2; combined androgen blockade (CAB); prognosis; therapeutic effect; HISTONE METHYLTRANSFERASE; DEPRIVATION THERAPY; PROTEIN EZH2; OPEN-LABEL; POLYCOMB; RECEPTOR; TAZEMETOSTAT; CANCER; METHYLATION; MALIGNANCY;

D O I：

10.3389/fonc.2021.779882

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

ObjectiveSalivary 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 MethodsThe 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). ResultsEZH2 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. ConclusionsA 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.

引用

页数：16

共 4 条

[1] Differential Expression of EZH2 and H3K27me3 in Oral Verrucous Carcinoma and Oral Verrucous Hyperplasia
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Kitkumthorn, Nakarin
Srimaneekarn, Natchalee
Bumalee, Dusit
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HEAD & NECK PATHOLOGY, 2021, 15 (02) : 408 - 415
[2] Aberrant overexpression of EZH2 and H3K27me3 serves as poor prognostic biomarker for esophageal squamous cell carcinoma patients
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Gu, Lina
Cao, Yu
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[3] The Expression of Cyclin D1, VEGF, EZH2, and H3K27me3 in Atypical Teratoid/Rhabdoid Tumors of the CNS: A Possible Role in Targeted Therapy
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Suri, Vaishali
Sharma, Mehar C.
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APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY, 2016, 24 (10) : 729 - 737
[4] Expression of the epigenetic H3K27me3 modifier genes KDM6A and EZH2 in patients with upper tract urothelial carcinoma
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Zhang, Jin-Xia
Wang, Shu-Fang
Zhang, Yu
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ONCOLOGY LETTERS, 2020, 20 (06)

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