Translational research to evaluate the resistant mechanism of anti-HER2 antibody by using immunohistochemistry and next-generation sequencing in HER2-positive gastric patients.

• Project/Area Number: 17K15010
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor diagnostics
• Research Institution: Research Institute for Clinical Oncology, Saitama Cancer Center
• Principal Investigator: Takahashi Naoki 埼玉県立がんセンター(臨床腫瘍研究所), 病院 消化器内科, 医長 (20744204)
• Research Collaborator: Sawada Takeshi ; Sasaki Yasushi ; Iwasa Satoru
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 胃癌 / HER2 / ハーセプチン / trastuzumab / gastric cancer / HER2陽性胃癌 / 免疫染色 / 次世代シークエンサー

Outline of Final Research Achievements

Trastuzumab is an active HER2 targeted drug and approved for HER2-positive GC patients. The mechanism of the resistance to trastuzumab is unclear and there were few reports to evaluate the RTKs protein expression and genetic alterations by using tumor tissues during the treatment. Our study indicated that HER2 expression disappeared during the treatment of trastuzumab in 42% of HER2-positve GC patients. In addition, the frequency of patinets with high IGF-1R expression statistically increased after treatment. Somatic mutations such as KRAS and BRAF were observed in a part of patients. Although these mutations was reported as the resistance to several molecular target drugs, HER2-positive patients with these mutations achieved response to trastuzumab in our study. HER2 copy number was also evaluated by digital PCR. High copy number of HER2 at pre-treatment was associated with good response of trastuzumab and long duration of the treatment with trastuzumab.

Academic Significance and Societal Importance of the Research Achievements

本研究は、転移性胃癌に対するハーセプチン治療中における腫瘍細胞のタンパク発現ならびに遺伝子変化を評価した。これらの腫瘍細胞におけるタンパク発現や遺伝子変化は、分子標的治療薬の治療効果を予測するマーカーとなったり、新たな治療標的として新たな治療開発に繋がる重要な知見となる。HER2発現のみならず、HER2以外のタンパク発現や、癌関連遺伝子も、ハーセプチン治療中に変化が認められている。本研究で得られたたんぱく発現や遺伝子変化のプロファイルは、今後、血液を用いたcfDNAによる網羅的遺伝子解析や新たな治療開発に発展させることが可能であり、学術的ならびに社会的意義は大きいと考える。

Research Products

• [Journal Article] Genome-wide Discovery of a Novel Gene-expression Signature for the Identification of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma. (2019)
  • Author(s): Sonohara F, Gao F, Iwata N, Kanda M, Koike M, Takahashi N, Yamada Y, Kodera Y, Wang X, Goel A.
  • Journal Title: Ann Surg. Volume: 269 Issue: 5 Pages: 879-886
  • DOI: 10.1097/sla.0000000000002622
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A comprehensive methylation signature identifies lymph node metastasis in esophageal squamous cell carcinoma. (2019)
  • Author(s): Roy R, Kandimalla R, Sonohara F, Koike M, Kodera Y, Takahashi N, Yamada Y, Goel A.
  • Journal Title: Int J Cancer Volume: 144 Issue: 5 Pages: 1160-1169
  • DOI: 10.1002/ijc.31755
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptomic expression profiling identifies ITGBL1, an epithelial to mesenchymal transition (EMT)-associated gene, is a promising recurrence prediction biomarker in colorectal cancer. (2019)
  • Author(s): Matsuyama T, Ishikawa T, Takahashi N, Yamada Y, Yasuno M, Kawano T, Uetake H, Goel A.
  • Journal Title: Mol Cancer Volume: 18 Issue: 1 Pages: 19-19
  • DOI: 10.1186/s12943-019-0945-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome-wide discovery and identification of a novel miRNA signature for recurrence prediction in stage II and III colorectal cancer. (2018)
  • Author(s): Kandimalla R, Gao F, Matsuyama T, Ishikawa T, Uetake H, Takahashi N, Yamada Y, Becerra CR, Kopetz S, Wang X, Goel A.
  • Journal Title: Clin Cancer Res Volume: 印刷中 Issue: 16 Pages: 3867-3877
  • DOI: 10.1158/1078-0432.ccr-17-3236
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer (2018)
  • Author(s): Shigeyasu Kunitoshi、Okugawa Yoshinaga、Toden Shusuke、Miyoshi Jinsei、Toiyama Yuji、Nagasaka Takeshi、Takahashi Naoki、Kusunoki Masato、Takayama Tetsuji、Yamada Yasuhide、Fujiwara Toshiyoshi、Chen Leilei、Goel Ajay
  • Journal Title: JCI Insight Volume: 3 Issue: 12 Pages: 99976-99976
  • DOI: 10.1172/jci.insight.99976
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Prospective, Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory, KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial). (2018)
  • Author(s): Akiyoshi K, Hamaguchi T, Yoshimura K, Takahashi N, Honma Y, Iwasa S, Takashima A, Kato K, Yamada Y, Onodera H, Takeshita S, Yasui H, Sakai G, Akatsuka S, Ogawa K, Horita Y, Nagai Y, Shimada Y.
  • Journal Title: Clin Colorectal Cancer. Volume: 17 Issue: 1 Pages: e83-e89
  • DOI: 10.1016/j.clcc.2017.10.004
  • Peer Reviewed
• [Journal Article] Patterns of Relapse after Definitive Chemoradiotherapy in Stage II/III (Non-T4) Esophageal Squamous Cell Carcinoma. (2018)
  • Author(s): Sudo K, Kato K, Kuwabara H, Sasaki Y, Takahashi N, Shoji H, Iwasa S, Honma Y, Okita NT, Takashima A, Hamaguchi T, Yamada Y, Ito Y, Itami J, Fukuda T, Tobinai K, Boku N.
  • Journal Title: Oncology. Volume: 94（1） Issue: 1 Pages: 47-54
  • DOI: 10.1159/000480515
  • Peer Reviewed
• [Journal Article] Asymptomatic Pancreatic Metastasis from Renal Cell Carcinoma Diagnosed 21 Years after Nephrectomy. (2017)
  • Author(s): Zianne M, Takahashi N, Tsujibata A, Miwa K, Goto Y, Matano Y.
  • Journal Title: Case Rep Gastrointest Med. Volume: 2017 Pages: 2017-2017
  • DOI: 10.1155/2017/8765264
  • Peer Reviewed / Open Access
• [Journal Article] Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study. (2017)
  • Author(s): Saka H, Kitagawa C, Kogure Y, Takahashi Y, Fujikawa K, Sagawa T, Iwasa S, Takahashi N, Fukao T, Tchinou C, Landers D, Yamada Y.
  • Journal Title: Invest New Drugs. 2017 Aug;35(4):451-462. Volume: 35 Issue: 4 Pages: 451-462
  • DOI: 10.1007/s10637-016-0416-x
  • Peer Reviewed
• [Journal Article] CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 ‘gene desert’, serve as important prognostic biomarkers in colorectal cancer (2017)
  • Author(s): Ozawa T, Matsuyama T, Toiyama Y, Takahashi N, Ishikawa T, Uetake H, Yamada Y, Kusunoki M, Calin G, Goel A.
  • Journal Title: Annals of Oncology. Volume: 28 Issue: 8 Pages: 1882-1888
  • DOI: 10.1093/annonc/mdx248
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of Response to Chemotherapy between Ovarian and Extraovarian Metastasis of Gastric Cancer (2017)
  • Author(s): Ishimoto U, Nakamura S, Sasaki Y, Takahashi N, Iwasa S, Honma Y, Okita N, Takashima A, Kato K, Hamaguchi T, Boku N.
  • Journal Title: Gan To Kagaku Ryoho. Volume: 44 Pages: 233-237
  • Peer Reviewed
• [Presentation] Comparison of HER2 expression by immunohistochemistry and HER2 copy number by digital PCR in tumor tissue during treatment with trastuzumab in the prospective cohort of metastatic HER2-positive gastric cancer patients. (2019)
  • Author(s): Naoki Takahashi, Satoru Iwasa, Tomohiro Matsushima, Shoichi Miyazawa, Satoshi Shimizu, Yosuke Kumekawa, Takako Yoshii, Masako Asayama, Hiroki Hara.
  • Organizer: ASCO-GI 2019
  • Int'l Joint Research
• [Presentation] Plasma Levels of Pirnas as Biomarkers for Prognosis and Predicting Tumor Recurrence in Colorectal Cancer Patients (2017)
  • Author(s): Ozawa T, Toiyama Y, Takahashi N, Nagasaka T, Fujiwara T, Yamada Y, Kusunoki M, Watanabe T, Goel A.
  • Organizer: DDW 2017
  • Int'l Joint Research
• [Presentation] Genome-wide discovery and identification of a novel microrna signature for recurrence prediction in colorectal cancer (2017)
  • Author(s): Kandimalla R, Gao F, Matsuyama T, Ishikawa T, Uetake H, Takahashi N, Yamada Y, Becerra CR, Kopetz S, Wang X, Goel A.
  • Organizer: AACR 2017
  • Int'l Joint Research
• [Presentation] ITGBL1 is a novel epithelial mesenchymal transition-associated prognostic biomarker in colorectal cancer (2017)
  • Author(s): Takatoshi Matsuyama, Toshiaki Ishikawa, Naoki Takahashi, Yasuhide Yamada, Masamichi Yasuno, Tatsuyuki Kawano, Hiroyuki Uetake, and Ajay Goel
  • Organizer: AACR 2017
  • Int'l Joint Research
• [Presentation] 663PChange in the molecular profile of tumor tissues during treatment with trastuzumab, as analyzed by next-generation sequencing and immunohistochemistry: A multicenter prospective biomarker study on HER2-positive gastric cancer (2017)
  • Author(s): Takahashi N, Iwasa S, Sawada T, Sasaki Y, Taniguchi H, Oda I, Honda T, Kojima Y, Hara H, Honma Y, Takashima A, Kato K, Hamaguchi T, Yamada Y.
  • Organizer: ESMO 2017
  • Int'l Joint Research