Morphological and molecular biological research aimed at personalized medicine of patients with salivary duct carcinoma

• Project/Area Number: 19K16568
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Hirai Hideaki 東京医科大学, 医学部, 助教 (00770744)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 唾液腺導管癌 / androgen receptor (AR) / HER2 / PD-1 / PD-L1 / EZH2 / adipophilin / FASN / Androgen receptor (AR) / PD1 / Adipophilin / 癌免疫微小環境 / androgen receptor

Outline of Research at the Start

我々は切除不能・再発転移を示す唾液腺導管癌に対し抗HER2療法とアンドロゲン遮断療法の臨床試験を施行し、68％と42％の高い奏効率を得た。療効果を予測するバイオマーカーの解明が望まれるが、検討した報告はない。また、多くの癌腫で免疫チェックポイント阻害剤の有用性が明らかになっているが、唾液腺癌の領域で基礎的な解析はほとんどなされていない。本研究では、新規治療を施行した症例を含む約300例のSDCについて、病理組織学的検討、免疫組織化学的検索、遺伝子解析を行い、抗HER2療法とアンドロゲン遮断療法における治療効果予測因子を探索すると共に、免疫逃避分子機構の解明とそれに基づく治療法開発を行う。

Outline of Final Research Achievements

In this study, we analyzed salivary duct carcinoma (SDC) cases including patient treated with HER2- or AR-targeted therapy, and investigated predictive factors of these therapies and tumor immune microenvironment. A high expression of EZH2 in SDC was a predictor of a poor efficacy of AR-targeted therapy. A high expression of adipophilin, lipid metabolism-related protein, was associated with an aggressive histopathology and unfavorable prognosis. Furthermore, in tumor immune microenvironment, SDC cases with high PD-L1 expression showed aggressive histological features and a poor prognosis.

Academic Significance and Societal Importance of the Research Achievements

今回の研究で唾液腺導管癌（SDC）の予後因子や治療効果予測因子の一部が明らかになったことは、高悪性度腫瘍でかつ標準治療が確立していないSDCの治療戦略構築の一助になるものと考えられる。また、免疫微小環境のうちPD-1とPD-L1の臨床病理学的意義を明らかにしたことは、PD-1阻害薬をはじめとする免疫療法をSDCの治療に導入するにあたって有意義な基礎的データとなるであろう。

Research Products

• [Journal Article] PD-L1 Expression and Survival Rates Using TPS and CPS for Nivolumab-treated Head-and-Neck Cancer (2022)
  • Author(s): ITO TATSUYA、OKAMOTO ISAKU、TOKASHIKI KUNIHIKO、SATO HIROKI、OKADA TAKURO、YAMASHITA GAI、NAGAO TOSHITAKA、HIRAI HIDEAKI、SAIGUSA NATSUKI、TSUKAHARA KIYOAKI
  • Journal Title: Anticancer Research Volume: 42 Issue: 3 Pages: 1547-1554
  • DOI: 10.21873/anticanres.15628
  • Peer Reviewed
• [Journal Article] 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 (2022)
  • Author(s): Saigusa N, Hirai H, Kohsaka S, et al.
  • Journal Title: Front Oncol Volume: 11 Pages: 779882-779882
  • DOI: 10.3389/fonc.2021.779882
  • Peer Reviewed / Open Access
• [Journal Article] A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome with Recurrent Olfactory Neuroblastoma (2021)
  • Author(s): Abe Hironori、Suwanai Hirotsugu、Kambara Nodoka、Sano Koji、Shikuma Junpei、Akaoka Hiroaki、Kanazawa Akira、Hirai Hideaki、Miwa Takashi、Nagao Toshitaka、Odawara Masato
  • Journal Title: Internal Medicine Volume: 60 Issue: 1 Pages: 105-109
  • DOI: 10.2169/internalmedicine.2897-19
  • NAID: 130007965297
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Predictive and Prognostic Biomarker Identification in a Large Cohort of Androgen Receptor-Positive Salivary Duct Carcinoma Patients Scheduled for Combined Androgen Blockade (2021)
  • Author(s): Lassche Gerben、Tada Yuichiro、van Herpen Carla M. L.、Jonker Marianne A.、Nagao Toshitaka、Saotome Takashi、Hirai Hideaki、Saigusa Natsuki、Takahashi Hideaki、Ojiri Hiroya、van Engen-Van Grunsven Adriana C. H.、Schalken Jack A.、Fushimi Chihiro、Verhaegh Gerald W.
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3527-3527
  • DOI: 10.3390/cancers13143527
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of epithelioid schwannoma arising from the parotid gland (2021)
  • Author(s): KARUBE Kohei、HIRAI Hideaki、HONDA Shogo、TASAKI Koichiro、MIYAKE Shinji、NAGAO Toshitaka
  • Journal Title: The Journal of the Japanese Society of Clinical Cytology Volume: 60 Issue: 6 Pages: 359-364
  • DOI: 10.5795/jjscc.60.359
  • NAID: 130008135976
  • ISSN: 0387-1193, 1882-7233
  • Peer Reviewed
• [Journal Article] Sialadenoma Papilliferum of the Bronchus (2021)
  • Author(s): Nakaguro Masato、Mino-Kenudson Mari、Urano Makoto、Ogawa Ikuko、Honda Yumi、Hirai Hideaki、Tanigawa Maki、Sukeda Aoi、Kajiwara Naohiro、Ohira Tatsuo、Ikeda Norihiko、Mikami Yoshiki、Tada Yuichiro、Ikeda Jun-Ichiro、Matsubayashi Jun、Faquin William C.、Sadow Peter M.、Nagao Toshitaka
  • Journal Title: American Journal of Surgical Pathology Volume: Publish Ahead of Print Issue: 5 Pages: 662-671
  • DOI: 10.1097/pas.0000000000001657
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Diagnostic Utility of RAS Q61R Mutation-specific Immunohistochemistry in Epithelial-Myoepithelial Carcinoma (2021)
  • Author(s): Nakaguro Masato、Tanigawa Maki、Hirai Hideaki、Yamamoto Yoshinari、Urano Makoto、Takahashi Reisuke H.、Sukeda Aoi、Okumura Yuki、Honda Shogo、Tasaki Koichiro、Shimizu Akira、Tsukahara Kiyoaki、Tada Yuichiro、Matsubayashi Jun、Faquin William C.、Sadow Peter M.、Nagao Toshitaka
  • Journal Title: American Journal of Surgical Pathology Volume: Publish Ahead of Print Issue: 7 Pages: 885-894
  • DOI: 10.1097/pas.0000000000001673
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neck dissection prolongs survival in patient with stage IVC hypopharyngeal carcinoma with mixed responses to nivolumab (2020)
  • Author(s): Ito Tatsuya、Sato Hiroki、Tsujikawa Takahiro、Hirai Hideaki、Okamoto Isaku、Miyake Keitaro、Nagao Toshitaka、Tsukahara Kiyoaki
  • Journal Title: Auris Nasus Larynx Volume: - Issue: 2 Pages: 322-326
  • DOI: 10.1016/j.anl.2020.02.014
  • Peer Reviewed
• [Journal Article] 母指対立障害をきたした正中神経より生じたlipomatosis of nerveの1例(原著論文/症例報告) (2020)
  • Author(s): 間渕隼矢、平井秀明
  • Journal Title: 関東整形災害外科学会雑誌 Volume: 51 Pages: 392-396
  • Peer Reviewed
• [Journal Article] 切迫窒息を呈した縦隔腫瘍合併妊娠の1例 (2020)
  • Author(s): 菊地孝行、平井秀明
  • Journal Title: 東京産科婦人科学会会誌 Volume: 69 Pages: 649-653
  • Peer Reviewed
• [Journal Article] Multicentre, retrospective study of the efficacy and safety of nivolumab for recurrent and metastatic salivary gland carcinoma (2020)
  • Author(s): Niwa Kazutomo、Kawakita Daisuke、Nagao Toshitaka、Takahashi Hideaki、Saotome Takashi、Okazaki Masashi、Yamazaki Keisuke、Okamoto Isaku、Hirai Hideaki、Saigusa Natsuki、Fushimi Chihiro、Okazaki Shin-ichi、Matsui Hirooki、Iwaki Sho、Matsuki Takashi、Tsukahara Kiyoaki、Oridate Nobuhiko、Tada Yuichiro
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 16988-16988
  • DOI: 10.1038/s41598-020-73965-6
  • Peer Reviewed / Open Access
• [Journal Article] Association between clinical symptoms and post‐mortem neuropathology in dementia with Lewy bodies (2020)
  • Author(s): Kaneko Yoshitsugu、Hirao Kentaro、Serisawa Shuntaro、Kanetaka Hidekazu、Shimizu Soichiro、Hirai Hideaki、Shishido‐Hara Yukiko、Umahara Takahiko、Sakurai Hirofumi、Hanyu Haruo
  • Journal Title: Geriatrics & Gerontology International Volume: 20 Issue: 3 Pages: 261-262
  • DOI: 10.1111/ggi.13853
  • Peer Reviewed / Open Access
• [Journal Article] Central pathology review of salivary gland adenoid cystic carcinoma (2020)
  • Author(s): Ueda K、Murase T、Nagao T、Kusafuka K、Urano M、Yamamoto H、Nakaguro M、Taguchi K、Masaki A、Hirai H、Kawakita D、Tsukahara K、Hato N、Nagao T、Fujimoto Y、Sakurai K、Hanai N、Kano S、Onitsuka T、Okami K、Nibu K、Tada Y、Kawata R、Inagaki H
  • Journal Title: Head & Neck Volume: X Issue: 8 Pages: 1721-1727
  • DOI: 10.1002/hed.26081
  • Peer Reviewed
• [Journal Article] Prognostic Implication of Histopathologic Indicators in Salivary Duct Carcinoma (2020)
  • Author(s): Nakaguro Masato、Sato Yukiko、Tada Yuichiro、Kawakita Daisuke、Nagao Toshitaka et al.
  • Journal Title: The American Journal of Surgical Pathology Volume: 44 Issue: 4 Pages: 526-535
  • DOI: 10.1097/pas.0000000000001413
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma. (2020)
  • Author(s): Hideaki Hirai, et al.
  • Journal Title: Virchows Archiv Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm (2019)
  • Author(s): Nakaguro Masato、Urano Makoto、Ogawa Ikuko、Hirai Hideaki、Yamamoto Yoshinari、Yamaguchi Hiroshi、Tanigawa Maki、Matsubayashi Jun、Hirano Hiroshi、Shibahara Junji、Tada Yuichiro、Tsuzuki Toyonori、Okada Yasuo、Sato Yuichiro、Ikeda Kenichiro、Sukeda Aoi、Honda Yumi、Mikami Yoshiki、Nagao Toshitaka
  • Journal Title: Histopathology Volume: 76 Issue: 3 Pages: 411-422
  • DOI: 10.1111/his.13990
  • Peer Reviewed / Open Access
• [Presentation] 唾液腺導管癌においてEZH2高発現は複合アンドロゲン遮断療法の効果不良予測因子になりうる (2021)
  • Author(s): 平井 秀明, 三枝 奈津季, 浦野 誠, 中黒 匡人, 佐藤 由紀子, 塚原 清彰, 加納 里志, 近藤 貴仁, 大上 研二, 小澤 宏之, 富樫 孝文, 川北 大介, 多田 雄一郎, 長尾 俊孝, SDC多施設共同研究会
  • Organizer: 日本唾液腺学
• [Presentation] 頭頸部癌の病理とゲノム異常 唾液腺導管癌の臨床病理・治療と遺伝子異常 (2020)
  • Author(s): 平井秀明
  • Organizer: 第109回日本病理学会総会
  • Invited
• [Presentation] Histopathology of poorly differentiated gastric adenocarcinoma of solid type, and its clinicopathological significance (2019)
  • Author(s): Hideaki Hirai
  • Organizer: SciTech Biomed-Cancer Sciences 2019
  • Int'l Joint Research / Invited
• [Presentation] 唾液腺導管癌の分子病理学的新知見 (2019)
  • Author(s): 平井秀明
  • Organizer: 第108回日本病理学会総会、コンパニオンミーティング
  • Invited
• [Presentation] Diagnostic Yield of HRAS Mutations in Epithelial Myoepithelial Carcinoma Exhibiting a Broad Histopathological Spectrum (2019)
  • Author(s): Makoto Urano, Masato Nakaguro, Hideaki Hirai, Maki Tanigawa, Kiyoaki Tsukahara, Yuichiro Tada, Toshitaka Nagao
  • Organizer: UNITED STATES & CANADIAN ACADEMY OF PATHOLOGY
  • Int'l Joint Research
• [Book] 唾液腺/口腔・歯原性腫瘍 (2019)
  • Author(s): 長尾俊孝、平井秀明
  • Total Pages: 400
  • Publisher: 中山書店
  • ISBN: 9784521742724