Investigation of molecular markers for prediction of the highly aggressive breast cancers that show clinically progressive disease during neoadjuvant chemotherapy

• Project/Area Number: 25430144
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: National Defense Medical College
• Principal Investigator: TSUDA HITOSHI 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, 病態病理学, 教授 (70217321)
• Research Collaborator: Yoshida Masayuki 国立がん研究センター中央病院, 病理科・臨床検査科 ; Kinoshita Takayuki 国立がん研究センター中央病院, 乳腺外科, 科長 ; Tamura Kenji 国立がん研究センター中央病院, 乳腺・腫瘍内科, 科長 ; Ono Makiko 国立がん研究センター中央病院, 乳腺・腫瘍内科 ; Tanabe Yuko 国立がん研究センター中央病院, 乳腺・腫瘍内科
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 乳癌 / 化学療法抵抗性 / 上皮間葉移行 / トリプルネガティブ乳癌 / 術前化学療法 / 臨床的病状進行 / バイオマーカー / 免疫組織化学 / ゲノム / 化生を伴う癌 / 化学療法効果予測 / 化生癌

Outline of Final Research Achievements

Using surgically resected tumor specimens from 22 TNBCs that showed cPD during NAC (cPD group) and 80 TNBCs that did not receive NAC (control group), we performed histopathologic and immunohistochemical (IHC) analyses of 11 molecules relevant to epithelial-mesenchymal transition (EMT), basal-like, molecular apocrine or other features. Metaplastic features and high proliferation on histology and positive cytokeratin 5/6, ZEB1, TWISTNB, vimentin, and HMGB1 and negative androgen receptor (AR) by IHC were more frequent in the cPD than in the control. By an unsupervised hierarchical cluster analysis incorporating these 11 molecules, the 102 TNBCs were divided into two major clusters and seven subclusters that appeared to correspond to intrinsic subtype, cPD status, histological type, and clinical outcome. The combinations of high proliferation, metaplastic features, and statuses of some EMT and basal-like markers and AR appeared to characterize the TNBCs that showed cPD after NAC.

Research Products

• [Journal Article] Prognostic significance of progesterone receptor expression in estrogen-receptor positive, HER2-negative, node-negative invasive breast cancer with a low Ki-67 labeling index (2017)
  • Author(s): Makiko Ono, Hitoshi Tsuda, Masayuki Yoshida, Chikako Shimizu, Takayuki Kinoshita, Kenji Tamura
  • Journal Title: Clin Breast Cancer Volume: 17 Issue: 1 Pages: 41-47
  • DOI: 10.1016/j.clbc.2016.06.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic and predictive values of PD-1 and PD-L1 expression among patients who received neoadjuvant chemotherapy in early breast cancer (2017)
  • Author(s): Atsuko Kitano, Makiko Ono, Masayuki Yoshida, Emi Noguchi, Akihiko Shimomura, Tatsunori Shimoi, Mayu Yonokawa, Kan Yonemori, Chikako Shimizu, Takayuki Kinoshita, Yasuhiro Fujiwara, Hitoshi Tsuda, Kenji Tamura
  • Journal Title: ESMO Open Volume: 2 Issue: 2 Pages: e000150-e000150
  • DOI: 10.1136/esmoopen-2016-000150
  • Peer Reviewed / Open Access
• [Journal Article] Histopathological and immunohistochemical characteristics of triple-negative breast cancers that showed clinically progressive disease during neoadjuvant chemotherapy (2017)
  • Author(s): Yuko Tanabe, Hitoshi Tsuda, Masayuki Yoshida, Harukaze Yamamoto, Makoto Kodaira, Mayu Yunokawa, Kan Yonemori, Chikako Shimizu, Seiichiro Yamamoto, Takayuki Kinoshita, Yasuhiro Fujiwara, Kenji Tamura
  • Journal Title: Cancer Sci Volume: in press Issue: 7 Pages: 1520-1529
  • DOI: 10.1111/cas.13274
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic impact of discordance in hormone receptor status between primary and recurrent sites in the patients with recurrent breast cancer (2016)
  • Author(s): Sho Shiino, Takayuki Kinoshita, Masayuki Yoshida, Kenjiro Jimbo, Sota Asaga, Shin Takayama, Hitoshi Tsuda
  • Journal Title: Clin Breast Cancer Volume: 16 Issue: 4 Pages: e133-e140
  • DOI: 10.1016/j.clbc.2016.05.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinicopathological predictive factors of ipsilateral and contralateral events in ductal carcinoma in situ after initial surgical therapy (2016)
  • Author(s): Nobuko Tamura, Hitoshi Tsuda, Junko Suzuki, Kenjiro Jimbo, Sota Asaga, Takashi Hojo, and Takayuki Kinoshita
  • Journal Title: Breast Cancer Volume: 23 Issue: 3 Pages: 510-518
  • DOI: 10.1007/s12282-015-0595-x
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic impact of discordance in hormone receptor status between primary and recurrent sites in the patients with recurrent breast cancer (2016)
  • Author(s): Sho Shiino, Takayuki Kinoshita, Masayuki Yoshida, Kenjiro Jimbo, Sota Asaga, Shin Takayama, and Hitoshi Tsuda
  • Journal Title: Clin Breast Cancer Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expression of ribophorin II (RPN2) in human breast cancer (2015)
  • Author(s): Makiko Ono, Hitoshi Tsuda, Takayuki Kobayashi, Fumitaka Takeshita, Ryou-u Takahashi, Kenji Tamura, Sadako Akashi-Tanaka, Tomoyuki Moriya, Tamio Yamasaki, Takayuki Kinoshita, Junji Yamamoto, Yasuhiro Fujiwara, and Takahiro Ochiya
  • Journal Title: Pathology International Volume: 65 Issue: 6 Pages: 301-308
  • DOI: 10.1111/pin.12297
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prognostic impact of Ki-67 labeling indices with three different cut-off values and histological and nuclear grades in hormone-receptor- positive, HER2-negative, node-negative invasive breast cancers. (2015)
  • Author(s): Makiko Ono, Hitoshi Tsuda, Mayu Yunokawa, Kan Yonemori, Chikako Shimizu, Masashi Ando, Kenji Tamura, Takayuki Kinoshita, Yasuhiro Fujiwara
  • Journal Title: Breast Cancer Volume: (in press) Issue: 2 Pages: 141-152
  • DOI: 10.1007/s12282-013-0464-4
  • Peer Reviewed
• [Journal Article] Clinicopathological predictive factors of ipsilateral and contralateral events in ductal carcinoma in situ after initial surgical therapy (2015)
  • Author(s): Nobuko Tamura, Hitoshi Tsuda, Junko Suzuki, Kenjiro Jimbo, Sota Asaga, Takashi Hojo, Takayuki Kinoshita
  • Journal Title: Breast Cancer Volume: in press
  • Peer Reviewed
• [Journal Article] Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer (2014)
  • Author(s): Kenji Hashimoto, Hitoshi Tsuda, Fumiaki Koizumi, Chikako Shimizu, Kan Yonemori, Masashi Ando, Makoto Kodaira, Mayu Yunokawa, Yasuhiro Fujiwara, Kenji Tamura
  • Journal Title: Annals of Oncology Volume: 25 Issue: 10 Pages: 1973-1979
  • DOI: 10.1093/annonc/mdu247
  • Peer Reviewed
• [Journal Article] Nucleostemin expression in invasive breast cancer (2014)
  • Author(s): Takayuki Kobayashi, Kenkichi Masutomi, Kenji Tamura, Tomoyuki Moriya, Tamio Yamasaki, Yasuhiro Fujiwara, Junji Yamamoto, Osamu Matsubara, Hitoshi Tsuda
  • Journal Title: BMC Cancer Volume: 14(1) Issue: 1 Pages: 215-215
  • DOI: 10.1186/1471-2407-14-215
  • Peer Reviewed
• [Presentation] Immune system pathway activation for prediction of the response to neoadjuvant chemotherapy in triple-negative breast cancer (2017)
  • Author(s): Takeshi Sawada, Riet Hilhorst, Savithri Rangarajan, Masayuki Yoshida, Kenji Tamura, Rinie van Beuningen, Rob Ruijtenbeek, Hitoshi Tsuda, Fumiaki Koizumi
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: Washington D. C., U. S. A.
  • Year and Date: 2017-04-01
  • Int'l Joint Research
• [Presentation] 臓器別シンポジウム：乳がん治療のゲノム個別化を促進する．乳癌の微小免疫環境と治療感受性について (2015)
  • Author(s): 津田均、田辺裕子、木下貴之、田村研治
  • Organizer: 第53回日本癌治療学会
  • Place of Presentation: 京都
  • Year and Date: 2015-10-29
  • Invited
• [Presentation] 乳がん再発に関与するLong Non-coding RNAの探索 (2015)
  • Author(s): 竹下文隆、小野麻紀子、高橋陵宇、津田均、田村研治、落谷孝広
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 術前化学療法抵抗性トリプルネガティブ乳癌におけるHMGB1 発現の検討 (2015)
  • Author(s): 田辺裕子、津田 均、吉田正行、木下貴之、公平 誠、 温泉川真由、山本春風、米盛勧、清水千佳子、藤原康弘、田村研治
  • Organizer: 第23回日本乳癌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-02
• [Presentation] Tumor-infiltrating lymphocyte and cytoplasmic HMG1 expression in triple-negative breast cancers that progress during neoadjuvant chemotherapy (2015)
  • Author(s): Yuko Tanabe, Hitoshi Tsuda, Masayuki Yoshida, Makoto Kodaira, Mayu Yunokawa, Kan Yonemori, Harukaze Yamamoto, Chikako Shimizu, Yasuhiro Fujiwara, Kenji Tamura
  • Organizer: St Gallen Breast Cancer Symposium 2015
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-03-18 – 2015-03-21
• [Presentation] 術前化学療法中に病状進行を認めるトリプルネガティブ乳癌の臨床病理所見の検討 (2014)
  • Author(s): 田辺裕子、津田均、吉田正行、木下貴之、橋本淳、公平誠、温泉川真由、米盛勧、山本春風、清水千佳子、藤原康弘、田村研治
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Histopathologic and immunohistochemical findings in triple-negative breast cancers showing clinical progressive disease during neoadjuvant chemotherapy (2014)
  • Author(s): Yuko Tanabe, Hitoshi Tsuda, Masayuki Yoshida, Makoto Kodaira, Mayu Yunokawa, Kan Yonemori, Harukaze Yamamoto, Chikako Shimizu, Yasuhiro Fujiwara, Kenji Tamura
  • Organizer: The 50th Annual Meeting of American Society of Clinical Oncology (2014 ASCO Meeting)
  • Place of Presentation: San Antonio, TX, U.S.A.
  • Year and Date: 2014-05-30 – 2014-06-03
• [Book] 乳癌診療のための分子病理エッセンシャル (2016)
  • Author(s): 津田 均、田村研治、木下貴之
  • Total Pages: 304
  • Publisher: 南山堂