Clinical validation of microenvironmental control related to malignant trait acquisition of triple negative breast cancer

• Project/Area Number: 17K10559
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Osaka City University
• Principal Investigator: Kashiwagi Shinichiro 大阪市立大学, 大学院医学研究科, 講師 (80637017)
• Co-Investigator(Kenkyū-buntansha): 藤田 寿一 大阪市立大学, 大学院看護学研究科, 准教授 (30212187) ; 高島 勉 大阪市立大学, 大学院医学研究科, 講師 (80336776)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: トリプルネガティブ乳癌 / 腫瘍微小環境 / 腫瘍免疫 / Precision medicine / 癌 / トランスレーショナルリサーチ / 免疫学 / 病理学 / 外科

Outline of Final Research Achievements

It has been clarified that the evaluation of host tumor microenvironment (TME) plays an important role in predicting prognosis and therapeutic effect in cancer treatment. The applicant examined the dynamic changes of TME from the viewpoints of epithelial-mesenchymal transition (EMT), tumor hypoxia, cancer metabolism competition and tumor immune response, and clarified the factors, plasticity and heterogeneity related to the changes. In this study, we evaluated tumor-infiltrating lymphocytes (TILs) for dynamic changes in TIME due to modification of drug therapy and metastasis/recurrence, and revealed that the CD8/FOXP3 ratio is a useful marker. We also developed a new evaluation index called RCB-TILs that combines TILs with Residual Cancer Burden (RCB), which is a residual tumor after neoadjuvant chemotherapy.

Academic Significance and Societal Importance of the Research Achievements

申請者らは，本研究のテーマである『TNBCの悪性形質獲得に関わる微小環境制御の臨床的検証』についてEMTや腫瘍免疫，内分泌感受性の側面から探究をすすめ，国内外に発信した．そして実臨床への応用可能なTNBCの新たな治療戦略の構築を目的とした基礎研究・臨床研究を推進している．薬物療法前後や原発巣/転移巣の標本を使用するなど癌微小環境を動的に捉え，これらに変化を及ぼす癌間質の関与や腫瘍免疫の誘導などを検証した．本研究により癌微小環境は動的な変化を示し，その分子機構にEMTや免疫環境が関与していることを明らかにした．

Research Products

• [Journal Article] The effect of smoking on biological change of recurrent breast cancer. (2020)
  • Author(s): Takada K, Kashiwagi S, Asano Y, Goto W, Kouhashi R, Yabumoto A, Morisaki T, Fujita H, Shibutani M, Takashima T, Hirakawa K, Ohira M.
  • Journal Title: Journal of Translational Medicine Volume: 18 Issue: 1 Pages: 153-153
  • DOI: 10.1186/s12967-020-02307-x
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of sentinel lymph node metastasis using the platelet-to-lymphocyte ratio in T1 breast cancer. (2020)
  • Author(s): Takada K, Kashiwagi S, Asano Y, Goto W, Kouhashi R, Yabumoto A, Morisaki T, Shibutani M, Takashima T, Fujita H, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 40 Issue: 4 Pages: 2343-2349
  • DOI: 10.21873/anticanres.14202
  • Peer Reviewed / Open Access
• [Journal Article] The effects of eribulin on breast cancer microenvironment identified using eribulin-resistant breast cancer cell lines. (2020)
  • Author(s): Goto W, Kashiwagi S, Asano Y, Takada K, Takahashi K, Fujita H, Takashima T, Shibutani M, Amano R, Tomita S, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 39 Issue: 8 Pages: 4031-4041
  • DOI: 10.21873/anticanres.13559
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical outcomes of recombinant human-soluble thrombomodulin treatment for disseminated intravascular coagulation in solid Tumors. (2019)
  • Author(s): Kashiwagi S, Asano Y, Takahashi K, Shibutani M, Amano R, Tomita S, Hirakawa K, Ohira M.
  • Journal Title: Anticancer research Volume: 39 Issue: 5 Pages: 2259-2264
  • DOI: 10.21873/anticanres.13342
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic value of quality of life scores in breast cancer patients undergoing preoperative chemotherapy. (2019)
  • Author(s): Takada K, Kashiwagi S, Fukui Y, Goto W, Asano Y, Morisaki M, Takashima T, Hirakawa K, Ohira M.
  • Journal Title: BJS Open Volume: 3 Issue: 1 Pages: 38-47
  • DOI: 10.1002/bjs5.50108
  • Peer Reviewed / Open Access
• [Journal Article] Clinical verification of the relationship between smoking and the immune microenvironment of breast cancer (2019)
  • Author(s): Takada Koji、Kashiwagi Shinichiro、Asano Yuka、Goto Wataru、Takahashi Katsuyuki、Fujita Hisakazu、Takashima Tsutomu、Tomita Shuhei、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: Journal of Translational Medicine Volume: 17 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12967-019-1773-y
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the occurrence of new lesions on the survival of patients who undergo chemotherapy for metastatic colorectal cancer. (2019)
  • Author(s): Shibutani M, Maeda K, Nagahara H, Fukuoka T, Matsutani S, Kashiwagi S, Hirakawa K, Ohira M.
  • Journal Title: Molecular and Clinical Oncology Volume: 10 Pages: 285-292
  • DOI: 10.3892/mco.2018.1778
  • Peer Reviewed
• [Journal Article] Study on the progression types of cancer in patients with breast cancer undergoing eribulin chemotherapy and tumor microenvironment (2018)
  • Author(s): Kashiwagi S, Tsujio G, Asano Y, Goto W, Takada K, Takahashi K, Morisaki T, Fujita H, Takashima T, Tomita S, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Journal of translational Medicine Volume: 16 Issue: 1 Pages: 54-54
  • DOI: 10.1186/s12967-018-1443-5
  • Peer Reviewed / Open Access
• [Journal Article] Mesenchymal?epithelial Transition and Tumor Vascular Remodeling in Eribulin Chemotherapy for Breast Cancer (2018)
  • Author(s): Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Hatano T, Tanaka S, Takashima T, Tomita S, Motomura H, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 38 Issue: 1 Pages: 401-410
  • DOI: 10.21873/anticanres.12236
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of the treatment response to pre-operative chemotherapy in breast cancer by the checkpoint protein expression (2018)
  • Author(s): Asano Y, Kashiwagi S, Goto W, Takada K, Takahashi K, Morisaki T, Fujita H, Takashima T, Tomita S, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Journal of translational Medicine Volume: 16 Issue: 1 Pages: 87-87
  • DOI: 10.1186/s12967-018-1458-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prediction of Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer by Subtype Using Tumor-infiltrating Lymphocytes (2018)
  • Author(s): Asano Y, Kashiwagi S, Goto W, Takada K, Takahashi K, Hatano T, Takashima T, Tomita S, Motomura H, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 38 Issue: 4 Pages: 2311-2321
  • DOI: 10.21873/anticanres.12476
  • Peer Reviewed / Open Access
• [Journal Article] Predictive value of improvement in the immune tumour microenvironment in patients with breast cancer treated with neoadjuvant chemotherapy (2018)
  • Author(s): Goto Wataru、Kashiwagi Shinichiro、Asano Yuka、Takada Koji、Takahashi Katsuyuki、Hatano Takaharu、Takashima Tsutomu、Tomita Shuhei、Motomura Hisashi、Ohsawa Masahiko、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: ESMO Open Volume: 3 Issue: 6 Pages: e000305-e000305
  • DOI: 10.1136/esmoopen-2017-000305
  • Peer Reviewed / Open Access
• [Journal Article] Predictive value of lymphocyte-to-monocyte ratio in the preoperative setting for progression of patients with breast cancer (2018)
  • Author(s): Goto Wataru、Kashiwagi Shinichiro、Asano Yuka、Takada Koji、Takahashi Katsuyuki、Hatano Takaharu、Takashima Tsutomu、Tomita Shuhei、Motomura Hisashi、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1137-1137
  • DOI: 10.1186/s12885-018-5051-9
  • Peer Reviewed / Open Access
• [Journal Article] Eribulin promotes antitumor immune responses in patients with locally advanced or metastatic breast cancer. (2018)
  • Author(s): Goto W, Kashiwagi S*, Asano Y, Takada K, Morisaki T, Fujita H, Takashima T, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 38 Issue: 5 Pages: 2929-2938
  • DOI: 10.21873/anticanres.12541
  • Peer Reviewed / Open Access
• [Journal Article] Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab, trastuzumab, and docetaxel for advanced HER2-positive breast cancer (2018)
  • Author(s): Takada Koji、Kashiwagi Shinichiro、Goto Wataru、Asano Yuka、Takahashi Katsuyuki、Takashima Tsutomu、Tomita Shuhei、Ohsawa Masahiko、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: Journal of Translational Medicine Volume: 16 Issue: 1 Pages: 86-86
  • DOI: 10.1186/s12967-018-1460-4
  • Peer Reviewed / Open Access
• [Journal Article] Possibility of avoiding axillary lymph node dissection by immune microenvironment monitoring in preoperative chemotherapy for breast cancer (2018)
  • Author(s): Takada Koji、Kashiwagi Shinichiro、Goto Wataru、Asano Yuka、Takahashi Katsuyuki、Fujita Hisakazu、Takashima Tsutomu、Tomita Shuhei、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: Journal of Translational Medicine Volume: 16 Issue: 1 Pages: 318-318
  • DOI: 10.1186/s12967-018-1692-3
  • Peer Reviewed / Open Access
• [Journal Article] Significance of re-biopsy for recurrent breast cancer in the immune tumour microenvironment (2018)
  • Author(s): Takada Koji、Kashiwagi Shinichiro、Goto Wataru、Asano Yuka、Takahashi Katsuyuki、Hatano Takaharu、Takashima Tsutomu、Tomita Shuhei、Motomura Hisashi、Ohsawa Masahiko、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: British Journal of Cancer Volume: 119 Issue: 5 Pages: 572-579
  • DOI: 10.1038/s41416-018-0197-4
  • Peer Reviewed / Open Access
• [Journal Article] Novel evaluation scale for QOL (QOL-ACD-BP) in preoperative chemotherapy for breast cancer (2018)
  • Author(s): Takada Koji、Kashiwagi Shinichiro、Goto Wataru、Asano Yuka、Takahashi Katsuyuki、Morisaki Tamami、Takashima Tsutomu、Tomita Shuhei、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 144 Issue: 8 Pages: 1547-1559
  • DOI: 10.1007/s00432-018-2670-0
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of HER family (HER1-4) expression as a biomarker in combination therapy with pertuzumab, trastuzumab and docetaxel for advanced HER2-positive breast cancer. (2018)
  • Author(s): Takada K, Kashiwagi S*, Goto W, Asano Y, Morisaki T, Fujita H, Takashima T, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 38 Issue: 4 Pages: 2285-2294
  • DOI: 10.21873/anticanres.12473
  • Peer Reviewed / Open Access
• [Journal Article] Mesenchymal epithelial transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer (2018)
  • Author(s): Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Takashima T, Noda S, Onoda N, Tomita S, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: Anticancer Research Volume: 38 Pages: 401-410
  • Peer Reviewed
• [Journal Article] Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. (2017)
  • Author(s): Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, Takashima T, Onoda N, Tomita S, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: PLoS ONE Volume: 12 Issue: 2 Pages: e0170634-e0170634
  • DOI: 10.1371/journal.pone.0170634
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of predictive markers of the therapeutic effect of eribulin chemotherapy for locally advanced or metastatic breast cancer (2017)
  • Author(s): Kashiwagi S, Fukushima W, Asano Y, Goto W, Takada K, Noda S, Takashima T, Onoda N, Ohsawa M, Hirakawa K, Ohira M.
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 604-604
  • DOI: 10.1186/s12885-017-3598-5
  • Peer Reviewed / Open Access
• [Presentation] 乳癌術前化学療法における免疫微小環境のダイナミックモニタリング (2019)
  • Author(s): 柏木伸一郎, 浅野有香, 高田晃次, 後藤 航, 森崎珠実, 野田 諭, 高島 勉, 小野田尚佳, 平川弘聖, 大平雅一
  • Organizer: 第119回 日本外科学会定期学術集会
• [Presentation] メタボロミクスを用いたエリブリン特異的薬剤特性の検証 (2018)
  • Author(s): 柏木伸一郎, 浅野有香, 後藤 航, 高田晃次, 森崎珠実, 野田 諭, 高島 勉, 小野田尚佳, 平川弘聖, 大平雅一
  • Organizer: 第26回 日本乳癌学会学術総会