定量ctDNA解析の切除可能境界膵癌に対する術前治療の効果と手術適応判定への応用

• Project/Area Number: 19K08433
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: 水野 伸匡 愛知県がんセンター(研究所), がん予防研究分野, 研究員 (80399592)
• Co-Investigator(Kenkyū-buntansha): 井本 逸勢 愛知県がんセンター(研究所), 分子遺伝学分野, 副所長兼分野長 (30258610) ; 高橋 進一郎 国立研究開発法人国立がん研究センター, 東病院, 部長 (50505914)
• Project Period (FY): 2019-04-01 – 2025-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: Borderline resectable膵癌 / ctDNA / 附随研究 / リキッドバイオプシー / KRAS / 術前化学療法 / 化学放射線療法 / 組織学的奏効

Outline of Research at the Start

切除可能境界(BR)膵癌は主要動脈に半周未満で接触・浸潤し、切除しても高率に顕微鏡的癌遺残となる。KRASは膵癌の90%以上で変異を認め血中循環腫瘍(ct)DNA量は腫瘍量の特異的マーカーとなり得る。BR膵癌に対する術前治療(NAC)のGEM+nab-PTXとS-1併用放射線療法のランダム化比較試験の附随研究として、NAC前後および術後にctDNA中KRAS変異量をデジタルPCRの一つであるddPCR法で解析する。主評価項目を切除標本の組織学的奏功とし、ctDNA中KRAS変異量と手術結果を比較し、画像診断では困難であるNAC後の手術適応判定におけるctDNA解析の妥当性・有用性を検討する。

Outline of Annual Research Achievements

膵癌はUICC-TNM分類第8版によってStage IからIVに分類される。Stage IおよびIIの多くは切除可能であるが、Stage IIIおよびStage IVは切除不能な進行膵癌であり、Stage IIIは「局所進行膵癌 (LAPC)」、Stage IVは「遠隔転移を伴う膵癌」となる。切除可能境界 (borderline resectable, BR)膵癌は腹腔動脈幹 (CA)や上腸間膜動脈 (SMA)に180度未満で接触・浸潤し、切除しても高率に顕微鏡的癌遺残（R1）となるカテゴリーである。化学療法や化学放射線療法（CRT）など、様々な術前治療 (NAC)の臨床試験が実施されているが、NAC後の画像診断では正確な手術適応の判断が困難である。KRASは膵癌の90%以上で変異を認め、循環血漿中(ct)DNAの変異KRAS量は腫瘍量の特異的マーカーとなり得る。BR膵癌を対象とした術前GEM+nab-PTXとS-1併用放射線療法のランダム化比較第2/3相試験であるGABARNANCE試験の附随研究として、本研究課題ではctDNA中変異KRAS解析のBR膵癌NAC後の手術適応決定への応用を目的に、NACの効果と切除標本における奏功を予測する新規バイオマーカーとしての血中KRAS変異解析と周術期アウトカムを比較する。1) NAC前、2) NAC後、3) 手術のできた症例では切除後の3ポイントで血漿10　mLを採取する。本研究の成果は、BR膵癌のみならず、化学療法後のコンバージョン手術を考慮する膵癌への外挿により、膵癌全体の予後改善に資するバイオマーカーの開発に寄与することが期待される。

Current Status of Research Progress

4: Progress in research has been delayed.

Reason

COVID-19感染拡大に伴う診療および研究の制約と、本体試験に用いる薬剤の供給停止のため。

Strategy for Future Research Activity

これまでのデータの解析を検討する。

Research Products

• [Journal Article] Effect of systemic inflammatory response on induction chemotherapy followed by chemoradiotherapy for locally advanced pancreatic cancer: an exploratory subgroup analysis on systemic inflammatory response in JCOG1106 (2023)
  • Author(s): Mizuno Nobumasa, et al.
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 53 Issue: 8 Pages: 704-713
  • DOI: 10.1093/jjco/hyad044
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer (2023)
  • Author(s): Umemoto Kumiko、Mizuno Nobumasa、et al.
  • Journal Title: British Journal of Cancer Volume: 128 Issue: 8 Pages: 1603-1608
  • DOI: 10.1038/s41416-023-02189-y
  • Peer Reviewed / Open Access
• [Journal Article] FOLFIRINOX in Pancreatic Cancer: Risk Factors for Febrile Neutropenia and Severe Neutropenia ? Nationwide Study Analysis (2023)
  • Author(s): TODAKA AKIKO、SASAKI MITSUHITO、UENO HIDEKI、GOTO TAKUMA、MUROHISA GOU、MIZUNO NOBUMASA、OZAKA MASATO、KOBAYASHI SATOSHI、UESUGI KAZUHIRO、KOBAYASHI NORITOSHI、HAYASHI HIDEYUKI、SUDO KENTARO、OKANO NAOHIRO、HORITA YOSUKE、KAMEI KEIKO、NANAMI SHOKO、BOKU NARIKAZU
  • Journal Title: Anticancer Research Volume: 43 Issue: 9 Pages: 4115-4123
  • DOI: 10.21873/anticanres.16601
  • Peer Reviewed
• [Journal Article] Clinical Practice Guidelines for Pancreatic Cancer 2022 from the Japan Pancreas Society: a synopsis (2023)
  • Author(s): Takuji Okusaka, Masafumi Nakamura, Masahiro Yoshida, Masayuki Kitano, Yoshinori Ito, Nobumasa Mizuno, Keiji Hanada, Masato Ozaka, Chigusa Morizane, Yoshifumi Takeyama, Toshio Fujisawa et. al
  • Journal Title: International Journal of Clinical Oncology Volume: 28 Issue: 4 Pages: 493-511
  • DOI: 10.1007/s10147-023-02317-x
  • Peer Reviewed / Open Access
• [Journal Article] A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407) (2023)
  • Author(s): Ozaka Masato、Mizuno Nobumasa、et al.
  • Journal Title: European Journal of Cancer Volume: 181 Pages: 135-144
  • DOI: 10.1016/j.ejca.2022.12.014
  • Peer Reviewed / Open Access
• [Journal Article] Germline variants in cancer-predisposing genes in pancreatic cancer patients with a family history of cancer (2022)
  • Author(s): Terashima Takeshi、Morizane Chigusa、Ushiama Mineko、Shiba Satoshi、Takahashi Hideaki、Ikeda Masafumi、Mizuno Nobumasa、Tsuji Kunihiro、Yasui Kohichiroh、Azemoto Nobuaki、Satake Hironaga、Nomura Shogo、Yachida Shinichi、Sugano Kokichi、Furuse Junji
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 52 Pages: 1105-1114
  • DOI: 10.1093/jjco/hyac110
  • Peer Reviewed
• [Journal Article] Postoperative Treatment of Resectable Pancreatic Cancer With Positive Peritoneal Lavage Cytology: A Multicentre Retrospective Study (2022)
  • Author(s): Todaka A, Nara S, Motoi F, Morinaga S, Toshiyama R, Higuchi R, Konishi M, Shirakawa H, Tsumura H, Okuyama H, Nagano H, Shioji K, Sugimachi K, Asagi A, Mizuno N, Furuse J
  • Journal Title: Anticancer Res Volume: 42 Issue: 2 Pages: 893-902
  • DOI: 10.21873/anticanres.15547
  • Peer Reviewed
• [Journal Article] Endoscopic duodenal stent placement versus gastrojejunostomy for unresectable pancreatic cancer patients with duodenal stenosis before introduction of initial chemotherapy (GASPACHO study): a multicenter retrospective study (2022)
  • Author(s): Azemoto N, Ueno M, Yanagimoto H, Mizuno N, Kawamoto Y, Maruki Y, Watanabe K, Suzuki R, Kaneko J, Hisada Y, Sato H, Kobayashi S, Miyata H, Furukawa M, Mizukami T, Miwa H, Ohno Y, Tsuji K, Tsujimoto A, Nagano H, Okuyama H, Asagi A, Okano N, Ishii H, Morizane C, Ikeda M, Furuse J.
  • Journal Title: Jpn J Clin Oncol Volume: 52 Issue: 2 Pages: 134-142
  • DOI: 10.1093/jjco/hyab194
  • Peer Reviewed
• [Journal Article] Impact of Renal Function on S-1 + Radiotherapy for Locally Advanced Pancreatic Cancer: An Integrated Analysis of Data From 2 Clinical Trials (2021)
  • Author(s): Kobayashi S, Ueno M, Ogawa G, Fukutomi A, Ikeda M, Okusaka T, Sato T, Ito Y, Kadota T, Ioka T, Sugimori K, Sata N, Nakamori S, Shimizu K, Mizuno N, Ishii H, Furuse J.
  • Journal Title: Pancreas Volume: 50 Issue: 7 Pages: 965-971
  • DOI: 10.1097/mpa.0000000000001879
  • Peer Reviewed
• [Journal Article] Tolerability of Nab-Paclitaxel Plus Gemcitabine as Adjuvant Setting in Japanese Patients With Resected Pancreatic Cancer (2021)
  • Author(s): Ueno, M., S. Morinaga, Y. Hashimoto, K. Umemoto, N. Sasahira, A. Saiura, Y. Seyama, G. Honda, T. Ioka, H. Takahashi, A. Miyamoto, S. Nakamori, M. Unno, T. Takadate, N. Mizuno, Y. Shimizu, H. Ueno, M. Sugiyama, A. Fukutomi, S. Shimizu, T. Okusaka and J. Furuse
  • Journal Title: Pancreas Volume: 50 Issue: 1 Pages: 83-88
  • DOI: 10.1097/mpa.0000000000001702
  • Peer Reviewed / Open Access
• [Journal Article] FOLFIRINOX in advanced pancreatic cancer patients with the double-variant type of UGT1A1 *28 and *6 polymorphism: a multicenter, retrospective study (2021)
  • Author(s): Umemoto Kumiko、Takahashi Hideaki、Morizane Chigusa、Yamada Ikuhiro、Shimizu Satoshi、Shioji Kazuhiko、Yoshida Yukio、Motoya Masayo、Mizuno Nobumasa、Kojima Yasushi、Terashima Takeshi、Uesugi Kazuhiro、Ueno Makoto、Furuse Junji、Akimoto Tetsuo、Ikeda Masafumi
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 87 Issue: 3 Pages: 397-404
  • DOI: 10.1007/s00280-020-04206-w
  • Peer Reviewed / Open Access
• [Journal Article] Randomized phase II study of chemoradiotherapy with versus without induction chemotherapy for locally advanced pancreatic cancer: Japan Clinical Oncology Group trial, JCOG1106 (2020)
  • Author(s): Ioka, T., J. Furuse, A. Fukutomi, J. Mizusawa, S. Nakamura, N. Hiraoka, Y. Ito, H. Katayama, M. Ueno, M. Ikeda, K. Sugimori, N. Okano, K. Shimizu, H. Yanagimoto, T. Okusaka, M. Ozaka, A. Todaka, S. Nakamori, K. Tobimatsu, N. Sata, Y. Kawashima, A. Hosokawa, T. Yamaguchi, H. Miyakawa, H. Hara, N. Mizuno and H. Ishii
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 51 Issue: 2 Pages: 235-243
  • DOI: 10.1093/jjco/hyaa198
  • Peer Reviewed
• [Journal Article] FOLFIRINOX as second-line chemotherapy for advanced pancreatic cancer: A subset analysis of data from a nationwide multicenter observational study in Japan (2020)
  • Author(s): Kobayashi Noritoshi、Omae Katsuhiro、Horita Yosuke、Ueno Hideki、Mizuno Nobumasa、Uesugi Kazuhiro、Sudo Kentaro、Ozaka Masato、Hayashi Hideyuki、Okano Naohiro、Kamei Keiko、Yamaguchi Atsushi、Kobayashi Satoshi、Suzuki Shuhei、Ishihara Shin、Uchiyama Takashi、Todaka Akiko、Fukutomi Akira
  • Journal Title: Pancreatology Volume: 20 Issue: 7 Pages: 1519-1525
  • DOI: 10.1016/j.pan.2020.07.006
  • Peer Reviewed
• [Journal Article] Phase II clinical trial of gemcitabine plus oxaliplatin in patients with metastatic pancreatic adenocarcinoma with a family history of pancreatic/breast/ovarian/prostate cancer or personal history of breast/ovarian/prostate cancer (FABRIC study) (2020)
  • Author(s): Okano, N., C. Morizane, S. Nomura, H. Takahashi, H. Tsumura, H. Satake, N. Mizuno, K. Tsuji, K. Shioji, A. Asagi, K. Yasui, S. Kitagawa, T. Kashiwada, A. Ishiguro, M. Kanai, M. Ueno, T. Ogura, S. Shimizu, K. Tobimatsu, M. Motoya, K. Nakashima, M. Ikeda, T. Okusaka and J. Furuse
  • Journal Title: International Journal of Clinical Oncology Volume: 25 Issue: 10 Pages: 1835-1843
  • DOI: 10.1007/s10147-020-01721-x
  • Peer Reviewed / Open Access
• [Journal Article] Phase I/II Study: Experience with the Late Onset of Acute Pancreatitis after the Start of Chemotherapy with Gemcitabine Plus nab-Paclitaxel for Metastatic Pancreatic Cancer. (2019)
  • Author(s): Ueno M, Nagashima F, Ueno H, Ikeda M, Ohkawa S, Mizuno N, Ioka T, Omuro Y, Nakajima TE, Furuse J
  • Journal Title: Intern Med Volume: 58 Issue: 4_suppl Pages: 2957-2962
  • DOI: 10.1200/jco.2020.38.4_suppl.695
  • NAID: 130007728769
  • Peer Reviewed
• [Journal Article] Influence of initial dose intensity on efficacy of FOLFIRINOX in patients with advanced pancreatic cancer. (2019)
  • Author(s): Kobayashi S, Ueno M, Omae K, Kuramochi H, Terao M, Mizuno N, Ozaka M, Ueno H, Uesugi K, Kobayashi N, Kobayashi M, Todaka A, Fukutomi A.
  • Journal Title: Oncotarget Volume: 10 Issue: 19 Pages: 1775-1784
  • DOI: 10.18632/oncotarget.26633
  • Peer Reviewed
• [Presentation] Randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer (JCOG1407). (2021)
  • Author(s): Ozaka M, Ueno M, Ishii H, Mizusawa J, Katayama H, Kataoka T, Okusaka T, Ikeda M, Miwa H, Kaneko S, Maesono T, Mizuno N, Yamamoto T, Kawamoto Y, Todaka A, Kamata K, Hisano T, Fujimori N, Furuse J.
  • Organizer: ASCO2021
  • Int'l Joint Research
• [Presentation] Utility of circulating tumor DNA (ctDNA) versus tumor tissue clinical sequencing for enrolling patients (pts) with advanced non-colorectal (non-CRC) gastrointestinal (GI) cancer to matched clinical trials: SCRUM-Japan GI-SCREEN and GOZILA combined analysis. (2020)
  • Author(s): Ohba A, Nakamura Y, Taniguchi H, Ikeda M, Bando H, Mizuno N, Kato K, Morizane C, Nishina T, Ueno M, Furuse J, Hara H, Denda T, Kawakami H, Esaki T, Moriwaki T, Yasui H, Komatsu Y, Yoshino T, Ohtsu A.
  • Organizer: ASCO2020 virtual
  • Int'l Joint Research
• [Presentation] Multicenter retrospective observational study of pancreatic cancer with positive peritoneal lavage cytology intended for surgical resection. (2020)
  • Author(s): Todaka A, Nara S, Motoi F, Morinaga S, Hama N, Higuchi R, Konishi M, Shirakawa H, Tsumura H, Okuyama H, Matsui H, Shioji K, Sugimachi K, Asagi A, Mizuno N, Fukutomi A, Furuse J.
  • Organizer: 2020 Gastrointestinal Cancers Symposium
  • Int'l Joint Research
• [Presentation] Phase II trial of GEMOX for the advanced pancreatic cancer with family/personal history of HBOC related cancer. (2019)
  • Author(s): 津村英隆, 森実千種, 野村尚吾, 高橋秀明, 岡野尚弘, 水野伸匡, 佐竹悠良, 辻国広, 塩路和彦, 浅木彰則, 安居幸一郎, 宮川浩之, 石黒敦, 小倉孝氏, 上野誠, 飛松和俊, 寺島健志, 池田公史, 奥坂拓志, 古瀬純司.
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] 切除不能局所進行膵癌:化学療法と化学放射線療法 局所進行切除不能膵癌に対するFOLFIRINOX療法 多施設共同観察研究結果報告 (2019)
  • Author(s): 松本逸平, 亀井敬子, 大前勝弘, 鈴木修平, 松岡英彦, 水野伸匡, 尾阪将人, 上野秀樹, 小林智, 上杉和寛, 小林真里奈, 戸高明子, 福冨晃.
  • Organizer: 第50回日本膵臓学会大会