遺伝子変異陽性肺癌におけるheterogeneityが治療効果に与える影響の解明

• Project/Area Number: 18K07271
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Wakayama Medical University
• Principal Investigator: 赤松 弘朗 和歌山県立医科大学, 医学部, 講師 (10646582)
• Co-Investigator(Kenkyū-buntansha): 山本 信之 和歌山県立医科大学, 医学部, 教授 (60298966) ; 洪 泰浩 和歌山県立医科大学, 医学部, 准教授 (80426519)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Granted (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: リキッドバイオプシー / EGFR遺伝子変異 / 非小細胞肺癌 / 分子標的治療薬 / heterogeneity

Outline of Annual Research Achievements

多施設共同研究（WJOG8114LTR試験）において腫瘍組織あるいは末梢血検体から抽出した腫瘍由来DNA（tumor-derived, cell-free DNA；以下、cfDNA）については、EGFR感受性・耐性遺伝子に関する高感度法（digital PCR法）を用いた解析結果を論文投稿し、採択された（Akamatsu H, Koh Y, Lung Cancer 2019)。この中では、治療開始後4週時点でのcfDNA減衰の有無が長期予後に影響する事を示している。一方でcf DNAでの増悪予測はCTなどの画像における増悪に比して感度が優れるという事は示せなかった。解析時点での増悪症例がそれ程多くない事もあり、増悪予測ツールとしてのcf DNAの意義については今後も検討していく余地があると考えている。また、本研究の副次的解析として、exon19欠失の詳細なバリアントについて次世代シーケンサを用いて解析し、これらの差異がEGFR阻害剤の有効性に影響を与えるのかについて検討し現在論文投稿中である。
当院で行ってきた前向き観察研究に関しては63例の症例集積が済んでおり、ほぼ全例に対して複数ポイントでの検体採取とDNA抽出を終えた。また1年目の研究実績として、高感度次世代シーケンサーによる検出系確立のため、観察研究に登録された中の12例についてAVENIO ctDNA Surveillance Kitを用い、既に当科で既に確立したdigital PCRとの比較を行った。結果、EGFR遺伝子変異についてそれぞれ12例・11例で変異が検出され、少なくともdigital PCRと同程度の感度を有する事を確認した。今後治療成績との突合せを経て、当初の目的である高感度次世代シーケンサーを用いた解析を予定している。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

当院での前向き観察研究については予定された80例の症例登録のうち既に63例の登録が済み、うち12例については高感度次世代シーケンサーを用いた検出形の確立を済ましている。

Strategy for Future Research Activity

本年度も引き続き残りの症例集積を進めていくとともに、まずは前半時点で登録された症例を中心に解析を進めていく。一方で登録症例の中には、現時点の観察期間では十分な増悪が確認されていないものがあることから、こまめなフォローアップが必要である。

Research Products

• [Journal Article] Clinical significance of monitoring EGFR mutation in plasma using multiplexed digital PCR in EGFR mutated patients treated with afatinib (West Japan Oncology Group 8114LTR study). (2019)
  • Author(s): Akamatsu H, Yasuhiro Koh, Isamu Okamoto, Daichi Fujimoto, Akihiro Bessho, Koichi Azuma, Satoshi Morita, Nobuyuki Yamamoto, Kazuhiko Nakagawa
  • Journal Title: Lung Cancer. Volume: 131 Pages: 128-133
  • DOI: 10.1016/j.lungcan.2019.03.021
  • Peer Reviewed / Open Access
• [Journal Article] A Phase II Study of Nivolumab in Patients With Advanced Non-small-cell Lung Cancer who Responded to Prior PD-1/L1 Inhibitors: West Japan Oncology Group 9616L (WJOG9616L). (2019)
  • Author(s): Akamatsu H, Teraoka S, Koh Y, Yamanaka T, Yamamoto N, Nakagawa K.
  • Journal Title: Clinical Lung Cancer Volume: 20 Pages: 139-141
  • DOI: 10.1016/j.cllc.2018.12.001
  • Peer Reviewed / Open Access
• [Journal Article] A Phase II Study of Gefitinib With Concurrent Thoracic Radiotherapy in Patients With Unresectable, Stage III Non-small-cell Lung Cancer Harboring EGFR Mutations (WJOG6911L). (2019)
  • Author(s): Akamatsu H, Harada H, Tokunaga S, Yoshimura N, Ikeda H, Oizumi S, Sugimoto N, Takano T, Murakami H, Nishimura Y, Yamamoto N, Nakagawa K.
  • Journal Title: Clinical Lung Cancer Volume: 20
  • DOI: 10.1016/j.cllc.2018.08.017
  • Peer Reviewed / Open Access
• [Journal Article] Heterogeneous Expression of Programmed Death Receptor-ligand 1 on Circulating Tumor Cells in Patients With Lung Cancer. (2019)
  • Author(s): Koh H, Yagi S, Akamatsu H, Kanai K, Hayata A, Tokudome N, Akamatsu K, Higuchi M, Kanbara H, Nakanishi M, Ueda H, Yamamoto N.
  • Journal Title: Clinical Lung Cancer Volume: 印刷中
  • DOI: 10.1016/j.cllc.2019.03.004
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA. (2019)
  • Author(s): Otsubo K, Sakai,K, Takeshita M, Harada D, Azuma K, Ota K, Akamatsu H, Goto K, Horiike A, Kurata T, Nakagaki N, Nosaki K, Iwama E, Nakanishi Y, Nishio N, Okamoto I.
  • Journal Title: The Oncologist Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status. (2019)
  • Author(s): Nakashima K, Kimura M, Akamatsu H, Daga H, Imai H, Taira T, Ko R, Hisamatsu Y, Nishino K, Sugimoto T, Miyashita Y, Takahashi T.
  • Journal Title: Jpn J Clin Oncol Volume: 印刷中
  • DOI: 10.1093/jjco/hyz041
  • Peer Reviewed
• [Journal Article] Carboplatin Plus Nab-paclitaxel in Performance Status 2 Patients With Advanced Non-small-cell Lung Cancer. (2019)
  • Author(s): Nakashima K, Akamatsu H, Murakami H, Niwa T, Iwamoto Y, Ozawa Y, Yokoyama T, Shoda H, Yamamoto N, Yoshioka H, Masuda K, Naito T, Mori K, Takahashi T.
  • Journal Title: Anticancer Res. Volume: 39 Pages: 1463-1468
  • DOI: 10.21873/anticanres.13263
  • Peer Reviewed
• [Journal Article] The impact of high PD-L1 expression on the surrogate endpoints and clinical outcomes of anti-PD-1/PD-L1 antibodies in non-small cell lung cancer. (2019)
  • Author(s): Ito K, Miura S, Sakaguchi T, Murotani K, Horita N, Akamatsu H, Uemura K, Morita S, Yamamoto N.
  • Journal Title: Lung Cancer Volume: 128 Pages: 113-119
  • DOI: 10.1016/j.lungcan.2018.12.023
  • Peer Reviewed
• [Journal Article] Randomized Phase III Study of Cisplatin With Pemetrexed and Cisplatin With Vinorelbine for Completely Resected Nonsquamous Non-Small-Cell Lung Cancer: The JIPANG Study Protocol. (2018)
  • Author(s): Akamatsu H, Koh Y, Ozawa Y, Fujimoto D, Hata A, Katakami N, Tomii K, Shimokawa T, Yamamoto N.
  • Journal Title: Clin Lung Cancer Volume: 19
  • DOI: 10.1016/j.cllc.2018.08.001
  • Peer Reviewed / Open Access
• [Journal Article] Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer: AURA3 trial. (2018)
  • Author(s): Akamatsu H, Katakami N, Okamoto I, Kato T, Kim YH, Imamura F, Shinkai M, Hodge RA, Uchida H, Hida T.
  • Journal Title: Lung Cancer Volume: 109 Pages: 1930-1938
  • DOI: 10.1111/cas.13623
  • NAID: 120006496875
  • Peer Reviewed / Open Access
• [Journal Article] EGFR mutation analysis for prospective patient selection in AURA3 phase III trial of osimertinib versus platinum-pemetrexed in patients with EGFR T790M-positive advanced non-small-cell lung cancer. (2018)
  • Author(s): John T, Akamatsu H, Delmonte A, Su WC, Lee JS, Chang GC, Huang X, Jenkins S, Wu YL.
  • Journal Title: Lung Cancer Volume: 126 Pages: 133-138
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Exploration of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors based on plasma analysis by digital polymerase chain reaction and next-generation sequencing. (2018)
  • Author(s): Iwama E, Sakai K, Azuma K, Harada D, Nosaki K, Hotta K, Nishio M, Kurata T, Fukuhara T, Akamatsu H, Goto K, Shimose T, Kishimoto J, Nakanishi Y, Nishio K, Okamoto I.
  • Journal Title: Cancer Science Volume: 109 Pages: 3921-3933
  • DOI: 10.1111/cas.13820
  • Peer Reviewed / Open Access
• [Journal Article] Erlotinib Plus Bevacizumab Phase II Study in Patients with Advanced Non-small-Cell Lung Cancer (JO25567): Updated Safety Results. (2018)
  • Author(s): Kato T, Seto T, Nishio M, Goto K, Yamamoto N, Okamoto I, Tao L, Yu W, Khaznadar T, Tajima K, Shibata M, Seki A, Yamamoto N
  • Journal Title: Drug Saf Volume: 41 Pages: 229-237
  • DOI: 10.1007/s40264-017-0596-0
  • Peer Reviewed / Open Access
• [Journal Article] Real world treatment and outcomes in EGFR mutation-positive non-small cell lung cancer: Long-term follow-up of a large patients cohort. (2018)
  • Author(s): 6.Okamoto I, Morita S, Tashiro N, Imamura F, Inoue A, Seto T, Yamamoto N, Ohe Y, Nakagawa K, Fukuoka M
  • Journal Title: Lung Cancer Volume: 117 Pages: 14-19
  • DOI: 10.1016/j.lungcan.2018.01.005
  • NAID: 120006454679
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. (2018)
  • Author(s): 9.Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T:
  • Journal Title: Lung Cancer Volume: 121 Pages: 37-40
  • DOI: 10.1016/j.lungcan.2018.04.015
  • Peer Reviewed / Open Access
• [Journal Article] Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LuX-Lung 6, and LUX-Lung 7 Trials. (2018)
  • Author(s): Wu YL, Sequist LV, Tan EH, Geater SL, Orlov S, Zhang L, Lee KH, Tsai CM, Kato T, Barrios CH, Schuler M, Hirsh V, Yamamoto N, O’Byrne K, Boyer M, Mok T, Peil B, Marten A, Chih-Hsin Yang J, Paz-Ares L, Park K
  • Journal Title: Clinical Lung Cancer Volume: 19
  • DOI: 10.1016/j.cllc.2018.03.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Predictive impact of sequential evaluation of PD-L1-expressing circulating tumor cells in NSCLC patients treated with nivolumab. (2018)
  • Author(s): Koh Y, Akamatsu H, Mori K, Kanai K, Hayata A, Tokudome N, Higuchi M, Akamatsu K, Nakanishi M, Ueda H, Yamamoto N
  • Organizer: American Association for Cancer Research Annual Meeting
  • Int'l Joint Research
• [Presentation] Predictive values of serum protein levels in advanced non-small-cell lung cancer patients treated with nivolumab. (2018)
  • Author(s): Oyanagi J, Koh Y, Akamatsu H, Kanai K, Hayata A, Tokudome N, Akamatsu K, Nakanishi M, Ueda H, Yamamoto N:
  • Organizer: American Association for Cancer Research Annual Meeting
• [Presentation] 肺癌診療ガイドライン改訂の要点 (2018)
  • Author(s): 赤松弘朗
  • Organizer: 第58回日本呼吸器学会学術講演会
  • Invited
• [Presentation] 肺癌薬物療法アップデート 肺がんの薬物療法 (2018)
  • Author(s): 赤松弘朗
  • Organizer: 第16回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] がん免疫療法ガイドライン改訂版 (2018)
  • Author(s): 赤松弘朗
  • Organizer: 第16回日本臨床腫瘍学会学術集会
  • Invited
• [Book] 肺癌診療ガイドライン 2018年版 第5版 (2018)
  • Author(s): 赤松弘朗、山本信之、他
  • Total Pages: 420
  • Publisher: 金原出版
  • ISBN: 9784307203913
• [Book] がん免疫療法ガイドライン 第2版 (2018)
  • Author(s): 赤松弘朗、山本信之、他
  • Total Pages: 162
  • Publisher: 金原出版
  • ISBN: 9784307101950