Development of treatment strategy based on stromal reaction in hormone recepotr-positive breast cancer

• Project/Area Number: 19H03721
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Japanese Foundation for Cancer Research
• 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)
• Co-Investigator(Kenkyū-buntansha): 戸井 雅和 京都大学, 医学研究科, 教授 (10207516) ; 清谷 一馬 公益財団法人がん研究会, がんプレシジョン医療研究センター 免疫ゲノム医療開発プロジェクト, 主任研究員 (30433642) ; 杉本 昌弘 東京医科大学, 医学部, 教授 (30458963) ; LOW SIEWKEE 公益財団法人がん研究会, がんプレシジョン医療研究センター リキッドバイオプシーシステム開発グループ, 主任研究員 (40634720)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2019: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 間質応答 / 内分泌療法 / 分子標的治療 / 三次元培養 / 間質反応 / CDK4/6 / バイオインフォ―マティクス / バイオインフォーマティクス

Outline of Research at the Start

現在の乳がんの治療戦略は、がん細胞のみの性質に基づいて決定されており、間質細胞に対する生物学的評価は利用されていない。しかし、間質の状態により予後や治療反応性が異なることより、間質反応を含めた治療戦略が必要である。
我々が確立した三次元共培養系を用い、エストロゲン涸渇下やシクロホスファミド、CDK4/6阻害薬添加条件で、親細胞と内分泌耐性細胞を比較することにより、各間質細胞の治療反応性や耐性に関与する候補分子を同定する。さらに血液検体を用いた免疫応答、遺伝子変異と治療反応性について検討を行い、AIとバイオインフォーマティクスを用いて統合的に解析し、間質特性に基づいた治療戦略を提案する。

Outline of Final Research Achievements

A bilateral co-culture system for cancer cells and stromal cells has been established. The response to endocine therapy (estrogen depletion) and concomitant use of mTOR inhibitors was investigated using breast cancer cell lines and mammary gland-derived fibroblasts. Gene expression profiles were analyzed by RNA sequencing of cells and metabolomic analysis of metabolites in culture supernatant was perfomed. Candidate molecules and candidate signaling pathways that may be involved in the therapeutic effect of hormone therapy were analyzed, as well as molecules and pathways that may be involved in the therapeutic effects of everolimus and resistance to treatment.
A clinical trial of preoperative endocrine therapy plus CDK4/6 inhibitor was completed and the results were reported at the international conference.

Academic Significance and Societal Importance of the Research Achievements

ホルモン受容体陽性乳がんの予後は他のサブタイプと比べると良好といわれているが、実際には術後５年以上たった段階で再発するような場合も多く（晩期再発）、さらなる治療の改善が必要となっている。ホルモン療法は乳がんの微小環境を変化させる治療であることから、乳がんのみでなく、微小環境も合わせて治療対象とすることにより、より効果的な治療が可能になると考えられる。我々は、生体内に近い環境で乳がん細胞と間質細胞を共培養することができる３次元培養システムを開発し、ホルモン療法や分子標的治療の効果に影響する分子やパスウェイの解析を行った。これらの結果は、より効果的な乳がん治療に結び付くと考えられる。

Research Products

• [Journal Article] Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR (2022)
  • Author(s): Ueno Takayuki, Kitano Shigehisa, Masuda Norikazu, Ikarashi Daiki, Yamashita Makiko, Chiba Tomohiro, Kadoya Takayuki, Bando Hiroko, Yamanaka Takashi, Ohtani Shoichiro, Nagai Shigenori, Nakayama Takahiro, Takahashi Masato , Saji Shigehira, Aogi Kenjiro, Velaga Ravi,...Toi Masakazu
  • Journal Title: BMC Medicine Volume: 20 Issue: 1 Pages: 136-145
  • DOI: 10.1186/s12916-022-02332-1
  • Peer Reviewed / Open Access
• [Journal Article] Biomarkers of neoadjuvant/adjuvant endocrine therapy for ER-positive /HER2-negative breast cancer (2020)
  • Author(s): Ueno T
  • Journal Title: Chin Clin Oncol Volume: 9 Issue: 3 Pages: 35-41
  • DOI: 10.21037/cco-20-165
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of gene mutation in ctDNA analysis for hormone receptor-positive metastatic breast cancer. (2020)
  • Author(s): Tomoko Shibayama、Siew-Kee Low、Makiko Ono、Takayuki Kobayashi、Kokoro Kobayashi、Ippei Fukada、Yoshinori Ito、Takayuki Ueno、Shinji Ohno、Yusuke Nakamura、Shunji Takahashi
  • Journal Title: Breast Cancer Research and Treatment Volume: 180 Issue: 2 Pages: 331-341
  • DOI: 10.1007/s10549-019-05512-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treating HR+/HER2- breast cancer in premenopausal Asian women: Asian Breast Cancer Cooperative Group 2019 Consensus and position on ovarian suppression (2019)
  • Author(s): Yeo Winnie、Ueno Takayuki、Lin Ching-Hung、Liu Qiang、Lee Kyung-Hun、Leung Roland、Naito Yoichi、Park Yeon Hee、Im Seock-Ah、Li Huiping、Yap Yoon Sim、Lu Yen-Shen
  • Journal Title: Breast Cancer Research and Treatment Volume: 177 Issue: 3 Pages: 549-559
  • DOI: 10.1007/s10549-019-05318-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Contrasting Epidemiology and Clinicopathology of Female Breast Cancer in Asians vs the US Population (2019)
  • Author(s): Lin Ching-Hung、Yap Yoon Sim、Lee Kyung-Hun、Im Seock-Ah、Naito Yoichi、Yeo Winnie、Ueno Takayuki、Kwong Ava、Li Huiping、Huang Shu-Min、Leung Roland、Han Wonshik、Tan Benita、Hu Fu-Chang、Huang Chiun-Sheng、Cheng Ann-Lii、Lu Yen-Shen、The Asian Breast Cancer Cooperative Group
  • Journal Title: JNCI: Journal of the National Cancer Institute Volume: 111 Issue: 12 Pages: 1298-1306
  • DOI: 10.1093/jnci/djz090
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer (2022)
  • Author(s): Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun She Minamiguchi, Yosuke Yamada , Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, ....., Masakazu Toi
  • Organizer: 2022 San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] International retrospective cohort study of locoregional and systemic therapy in oligometastatic breast cancer (OLIGO-BC1) (2020)
  • Author(s): Ueno, T., Imoto, S., Futamura, M., Toi, M., Fujiwara, Y., Im, Y. H., Im, S. A., Ahn, S. G., Lee, J. E., Park, Y. H., Wang, K., Bi, X., Liu, G., Sim, S. H., Takao, S., Saito-Oba, M., Kitagawa, Y., Nishimura, M.
  • Organizer: 2020 ASCO Virtual Scientific Program
  • Int'l Joint Research
• [Presentation] 新たな時代に期待する”ホルモンと癌” (2020)
  • Author(s): 上野貴之
  • Organizer: 第20回関東ホルモンと癌研究会
  • Invited
• [Presentation] Role of multigene assays to guide decisions for neoadjuvant therapy (2019)
  • Author(s): Ueno, T.
  • Organizer: Global Breast Cancer Conference
  • Int'l Joint Research / Invited