Optimization of breast cancer treatment by using stromal reaction

• Project/Area Number: 15K10067
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Japanese Foundation for Cancer Research (2017-2018); Kyorin University (2015-2016)
• Principal Investigator: UENO TAKAYUKI 公益財団法人がん研究会, 有明病院 乳腺外科, 部長 (40452362)
• Research Collaborator: SAKURAI chie
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: オートファジー / アポトーシス / 内分泌療法 / 化学内分泌療法 / 間質応答 / エネルギー代謝 / 血管新生 / 抗癌治療

Outline of Final Research Achievements

We found that endocrine therapy by an aromatase inhibitor (reduction in estrogen) induced autophagy but reduced apoptosis, a form of cell death. On the other hand, a chemoendocrine therapy containing endocrine therapy and oral chemotherapy (cyclophosphamide) induced not only autophagy but also apoptosis. Furthermore, tumors with stromal autophagy showed poorer response to endocrine therapy than tumors without stromal autophagy, which was not observed in chemoendocrine therapy.

Academic Significance and Societal Importance of the Research Achievements

間質のオートファジーは内分泌療法の治療反応性に影響するが、化学内分泌療法の治療反応性には影響しないことより、間質の状態を評価することにより、より効果的な治療選択が可能となると考えられる。また、治療における間質の変化をモニタリングすることにより、化学療法や分子標的治療を追加するなどの新たな治療戦略に結びつくと考えられる。とくに、術前内分泌療法後の間質の状態を評価することにより、その後の予後や追加治療の必要性が判断できる可能性があり、乳がんの予後改善につながると考えられる。

Research Products

• [Journal Article] Changes in Recurrence Score by neoadjuvant endocrine therapy of breast cancer and their prognostic implication (2019)
  • Author(s): Ueno Takayuki、Saji Shigehira、Masuda Norikazu、Iwata Hiroji、Kuroi Katsumasa、Sato Nobuaki、Takei Hiroyuki、Yamamoto Yutaka、Ohno Shinji、Yamashita Hiroko、Hisamatsu Kazufumi、Aogi Kenjiro、Sasano Hironobu、Toi Masakazu
  • Journal Title: ESMO Open Volume: 4 Issue: 1 Pages: e000476-e000476
  • DOI: 10.1136/esmoopen-2018-000476
  • Peer Reviewed / Open Access
• [Journal Article] Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR. (2019)
  • Author(s): Ueno T, Masuda N, Kamigaki S, Morimoto T, Saji S, Imoto S, Sasano H, Toi M.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 4 Pages: 984-984
  • DOI: 10.3390/ijms20040984
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone receptor expression in proliferating cancer cells of hormone receptor-positive breast cancer. (2018)
  • Author(s): Ueno T, Saji S, Chiba T, Kamma H, Isaka H, Itoh H, Imi K, Miyamoto K, Tada M, Sasano H, Toi M, Imoto S.
  • Journal Title: Tumour Biol. Volume: 40 Issue: 10 Pages: 1-10
  • DOI: 10.1177/1010428318811025
  • Peer Reviewed / Open Access
• [Journal Article] A multicenter phase II trial of neoadjuvant letrozole plus low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer (JBCRG-07): therapeutic efficacy and clinical implications of circulating endothelial cells. (2018)
  • Author(s): Ueno T, Masuda N, Kamigaki S, Morimoto T, Akiyama F, Kurosumi M, Tsuda H, Mikami Y, Tanaka S, Morita S, Toi M.
  • Journal Title: Cancer Med. Volume: - Issue: 6 Pages: 1516-1516
  • DOI: 10.1002/cam4.1516
  • NAID: 120006496947
  • Peer Reviewed / Open Access
• [Journal Article] Impact of clinical response to neoadjuvant endocrine therapy on patient outcome: a follow-up study of JFMC34-0601 multicentre prospective neoadjuvant endocrine trial. (2018)
  • Author(s): Ueno T, Saji S, Masuda N, Kuroi K, Sato N, Takei H, Yamamoto Y, Ohno S, Yamashita H, Hisamatsu K, Aogi K, Iwata H, Yamanaka T, Sasano H, Toi M.
  • Journal Title: ESMO Open. Volume: - Issue: 2 Pages: e000314-e000314
  • DOI: 10.1136/esmoopen-2017-000314
  • Peer Reviewed / Open Access
• [Journal Article] A phase I/II pharmacokinetics/pharmacodynamics study of irinotecan combined with S-1 for recurrent/metastatic breast cancer in patients with selected UGT1A1 genotypes (the JBCRG-M01 study). (2017)
  • Author(s): Ishiguro H, Saji S, Nomura S, Tanaka S, Ueno T, Onoue M, Iwata H, Yamanaka T, Sasaki Y, Toi M.
  • Journal Title: Cancer Med. Volume: - Issue: 12 Pages: 1258-1258
  • DOI: 10.1002/cam4.1258
  • Peer Reviewed / Open Access
• [Journal Article] Pathway level alterations rather than mutations in single genes predict response to HER2 targeted therapies in the neo-ALTTO trial. (2017)
  • Author(s): Shi W, Jiang T, Nuciforo P, Hatzis C, Holmes E, Harbeck N, Sotiriou C, Pena L, Loi S, Rosa DD, Chia S, Wardley A, Ueno T, Rossari J, Eidtmann H, Armour A, Piccart-Gebhart M, Rimm DL, Baselga J, Pusztai L.
  • Journal Title: Ann Oncol. Volume: 28 Issue: 1 Pages: 128-135
  • DOI: 10.1093/annonc/mdw434
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The lack of increases in circulating endothelial progenitor cell as a negative predictor for pathological response to neoadjuvant chemotherapy in breast cancer patients. (2017)
  • Author(s): Sunao Tanaka, Takayuki Ueno, Hiroshi Ishiguro, Satoshi Morita & Masakazu Toi
  • Journal Title: npj Precision Oncology Volume: 1 Issue: 1 Pages: 6-6
  • DOI: 10.1038/s41698-017-0006-1
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy. (2016)
  • Author(s): Ueno T, Saji S, Sugimoto M, Masuda N, Kuroi K, Sato N, Takei H, Yamamoto Y, Ohno S, Yamashita H, Hisamatsu K, Aogi K, Iwata H, Imoto S, Sasano H, Toi M
  • Journal Title: BMC Cancer Volume: 16 Issue: 1 Pages: 230-230
  • DOI: 10.1186/s12885-016-2270-9
  • NAID: 120005973398
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characteristic gene expression profiles of human fibroblasts and breast cancer cells in a newly developed bilateral coculture system. (2015)
  • Author(s): Ueno T, Utsumi J, Toi M, Shimizu K
  • Journal Title: Biomed Res Int. Volume: 2015 Pages: 960840-960840
  • DOI: 10.1155/2015/960840
  • NAID: 120005745649
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Neoadjuvant hormone therapy による治療最適化 (2018)
  • Author(s): 上野貴之
  • Organizer: 第26回日本乳癌学会学術総会
  • Invited
• [Presentation] Updates on the clinical utility of 21-gene assay recurrence score (Oncotype DX). (2017)
  • Author(s): Takayuki Ueno
  • Organizer: Organisation for Oncology and Translational Research 13th Annual Conference
  • Int'l Joint Research / Invited
• [Presentation] Tailored neoadjuvant endocrine therapy and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer. (2017)
  • Author(s): Norikazu Masuda, Nobuaki Sato, Takashi Morimoto, Takayuki Ueno, et al.
  • Organizer: 2017 San Antonio Breast Cancer Symposiusm
  • Int'l Joint Research
• [Presentation] Circulating tumor cells: their clinical application and therapeutic potential (2016)
  • Author(s): Takayuki Ueno
  • Organizer: The 14th Asian Breast Disease Association Meeting & Symposium
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-02
  • Int'l Joint Research / Invited
• [Presentation] 単一細胞レベルでのバイオマーカー探索 (2016)
  • Author(s): 上野貴之
  • Organizer: 第24回 日本乳癌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-16
  • Invited
• [Presentation] Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues (2016)
  • Author(s): Takayuki Ueno, Hirotsugu Isaka, Hiroki Itoh, Kaisuke Miyamoto, Manami Kitamura, Shigeru Imoto
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues (2016)
  • Author(s): Takayuki Ueno, Hirotsugu Isaka, Hiroki Itoh, Kentaro Imi, Kaisuke Miyamoto, Manami Kitamura, Shigeru Imoto
  • Organizer: The 4th International Conference of Federation of Asian Clinical Oncology
  • Place of Presentation: Xiamen, China
  • Int'l Joint Research
• [Presentation] Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues (2015)
  • Author(s): Takayuki Ueno, Hirotsugu Isaka, Hiroki Itoh, Kentaro Imi, Kaisuke Miyamoto, Manami Kitamura, Shigeru Imoto
  • Organizer: 3rd International Conference of Federation of Asian Clinical Oncology
  • Place of Presentation: 京都
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] ER陽性乳癌組織におけるER発現とKi67発現の腫瘍内heterogeneityの解析 (2015)
  • Author(s): 上野貴之、伊東大樹、伊美建太郎、宮本快介、北村真奈美、井本滋
  • Organizer: 第23回日本乳癌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-02
• [Presentation] pCR再考 (2015)
  • Author(s): 上野貴之
  • Organizer: 第23回日本乳癌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-02
  • Invited