Annual Report 2018

Department of Gastrointestinal Oncology

Takayuki Yoshino, Toshihiko Doi, Takashi Kojima, Kouhei Shitara, Nozomu Fuse, Hiroya Taniguchi, Yasutoshi Kuboki, Akihito Kawazoe, Daisuke Kotani, Yoshiaki Nakamura, Masataka Yagisawa

Introduction

 In 2018, approximately 790 gastrointestinal (GI) cancer patients were treated by staff oncologists and skilled residents in the Department of GI Oncology, which focuses on optimal chemotherapy W/ or W/O radiation for the treatment of GI cancers.

The Team and What We Do

 Inter-divisional tumor board conferences with the Surgical/Radiation Oncology Divisions are held regularly to review the current treatment for each patient and to discuss further treatment strategies. Our activities for each type of GI cancer in 2018 are shown in Table 1 (Number). There are ongoing clinical trials which consist of 49 Phase I trials including globally first-in-class (FIC), first-in-human (FIH), investigational new drugs (INDs), 21 Phase II/III clinical trials in order to approve the INDs, and 19 investigatorinitiated clinical trials (IITs). In addition, young skilled residents in their early 30s have become principal investigators for several IITs.

Table 1. Number of new patients

Activities

1. Phase I

 Our Department has focused more on early stage clinical development of INDs. The number of patients enrolled for phase 1 trials have been increasing recently, especially studies for immunomodulating agents. Furthermore, new types of cancer therapy such as antibody drug conjugate (ADC) or cell therapies using chimeric antigen receptor (CAR)-T cells, and bispecific T-cell engager antibody (BiTE) - a complex formed with antibodies against CD3 and antibodies against tumor cell surface antigens - will be more focused on solid tumors including GI tumors.

2. Esophageal Cancer (EC)

 As a single institutional clinical study, the Phase I trial of definitive chemoprotontherapy in patients with clinical stage I/II/III esophageal carcinoma was completed. The Phase I trial of oncolytic virus and pembrolizumab is going. A phase Ib/II study to investigate the safety, efficacy, and proof-of-concept (POC) of Anti PDL1 antibody monotherapy following radical chemoradiotherapy in patients with inoperable locally advanced esophageal squamous cell cancer has been started.

3. Gastric Cancer (GC)

 Immune monitoring studies have been conducted to evaluate several immunological properties or to clarify a possible resistance mechanism after PD-1 blockade. Several research projects in collaboration with pharmaceutical companies are ongoing. The results of the phase 1 trial of anti-CD4 depleting antibody IT1208, the phase 1 trial of nivolumab plus regorafenib and phase 2 of TAS114+S1 for gastric cancer were reported. The enrollment in phase 1 of TAS116 and nivolumab and phase 2 of lenvatinib plus pembrolizumab was completed. The phase 1 study of disulfiram as an anti-macrophage treatment in combination with anti-PD1 for gastric cancer is ongoing. Finally, the phase 1 trial of photoimmunotherapy plus anti-PD1 therapy will be started soon.

4. Colorectal Cancer (CRC)

 We have been conducting our initiative SCRUM-Japan platform, which is a nationwide cancer genome screening system using tumortissue (GI-SCREEN), and circulating tumor DNA-based NGS screening (GOZILA project). Utilizing these screening systems, the umbrella type of IITs for metastatic CRC patients with HER2 amplification, BRAF V600E mutation, BRAF non-V600E mutation, MET amplification are on-going. IITs for tumor-agnostic metastatic cancer patients with HER2 amplification or FGFR alterations detected by Guardant360 will soon start. The clinical evaluation studies of cell-free tumor DNA-based RAS gene testing by BEAMing technology and of a newly developed MSI testing kit were completed.

Education

 Our residents study the latest evidence-based medicine and apply this knowledge pragmatically to enhance care for patients with GI cancers, and eventually obtain qualifications as comprehensive GI oncologists through daily practice and direct training from our staff. Accordingly, our staff actively provide numerous valuable opportunities to polish their chemotherapy skills, especially in collaboration with the Department of Experimental Therapeutics as well as diagnostic & therapeutic endoscopies in collaboration with the Department of Digestive Endoscopy. We regularly hold board meetings discussing tumors and frequently hold face-toface meetings with experts in different fields. We instruct them on how to conduct valuable clinical trials, help them attend international academic conferences, and explain the best way to present academic meetings and work on many highimpact articles in scholarly journals. To date, our department has helped many residents to become 'true' skilled GI oncologists who play major roles at leading cancer centers across the country.

Future prospects

 We continue to provide the best treatment for cancer patients, the best education for residents, and aim to perform the following activities:

1) To provide more of the latest cutting-edge medicine to cancer patients and to further foster the next generation of skilled GI oncologists.

2) To achieve medical innovation in Japan, we aim to play a leading role in the clinical development of INDs by contributing to various types of clinical trials including FIC, FIH early trials, IITs with proof-of-concept, and international clinical trials.

3) To enhance our research activity, we will establish global research networks with cutting-edge researchers.

List of papers published in 2018

Journal

 1. Takashima A, Shitara K, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Kimura Y, Amagai K, Fujii H, Muro K, Esaki T, Choda Y, Takano T, Chin K, Sato A, Goto M, Fukushima N, Hara T, Machida N, Ohta M, Boku N, Shimura M, Morita S, Koizumi W. Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial. Gastric Cancer, 22:155-163, 2019

 2. Mehnert JM, Varga A, Brose MS, Aggarwal RR, Lin CC, Prawira A, de Braud F, Tamura K, Doi T, Piha-Paul SA, Gilbert J, Saraf S, Thanigaimani P, Cheng JD, Keam B. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer. BMC Cancer, 19:196, 2019

 3. Kawazoe A, Shitara K, Kuboki Y, Bando H, Kojima T, Yoshino T, Ohtsu A, Ochiai A, Togashi Y, Nishikawa H, Doi T, Kuwata T. Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer. Gastric Cancer, 22:69- 76, 2019

 4. Mishima S, Kawazoe A, Nakamura Y, Sasaki A, Kotani D, Kuboki Y, Bando H, Kojima T, Doi T, Ohtsu A, Yoshino T, Kuwata T, Tsuji A, Shitara K. Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer. J Immunother Cancer, 7:24, 2019

 5. Yoshino T, Portnoy DC, Obermannova R, Bodoky G, Prausova J, Garcia-Carbonero R, Ciuleanu T, Garcia-Alfonso P, Cohn AL, Van Cutsem E, Yamazaki K, Lonardi S, Muro K, Kim TW, Yamaguchi K, Grothey A, O'Connor J, Taieb J, Wijayawardana SR, Hozak RR, Nasroulah F, Tabernero J. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol, 30:124-131, 2019

 6. Nakamura Y, Yamanaka T, Chin K, Cho H, Katai H, Terashima M, Misawa K, Hirao M, Yoshida K, Oki E, Sasako M, Emi Y, Bando H, Kawashima Y, Fukunaga T, Gotoh M, Ishibashi T, Shitara K. Survival Outcomes of Two Phase 2 Studies of Adjuvant Chemotherapy with S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Patients with Gastric Cancer After D2 Gastrectomy. Ann Surg Oncol, 26:465-472, 2019

 7. Doi T, Yang JC, Shitara K, Naito Y, Cheng AL, Sarashina A, Pronk LC, Takeuchi Y, Lin CC. Phase I Study of the Focal Adhesion Kinase Inhibitor BI 853520 in Japanese and Taiwanese Patients with Advanced or Metastatic Solid Tumors. Target Oncol, 14:57- 65, 2019

 8. Nakamura Y, Yamanaka T, Shitara K. Reply to: "Multimodal Treatment of Locally Advanced Gastric Cancer: Will the West Meet the East?", by Marino, Elisabetta et al. Ann Surg Oncol, 26:919- 920, 2019

 9. Shitara K, Yamanaka T, Denda T, Tsuji Y, Shinozaki K, Komatsu Y, Kobayashi Y, Furuse J, Okuda H, Asayama M, Akiyoshi K, Kagawa Y, Kato T, Oki E, Ando T, Hagiwara Y, Ohashi Y, Yoshino T. REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients. Ann Oncol, 30:259-265, 2019

10. Shitara K, Chen X. The KEYNOTE-061 trial - Authors' reply. Lancet, 393:1099, 2019

11. Nishina T, Azuma M, Nishikawa K, Gotoh M, Bando H, Sugimoto N, Amagai K, Chin K, Niwa Y, Tsuji A, Imamura H, Tsuda M, Yasui H, Fujii H, Yamaguchi K, Yasui H, Hironaka S, Shimada K, Miwa H, Mitome T, Kageyama H, Hyodo I. Early tumor shrinkage and depth of response in patients with advanced gastric cancer: a retrospective analysis of a randomized phase III study of firstline S-1 plus oxaliplatin vs S-1 plus cisplatin. Gastric Cancer, 22:138-146, 2019

12. Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O'Neil BH, Mehnert JM, Lopez J, Doi T, van Brummelen EMJ, Cristescu R, Yang P, Emancipator K, Stein K, Ayers M, Joe AK, Lunceford JK. T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028. J Clin Oncol, 37:318-327, 2019

13. Bekaii-Saab T, Kim R, Kim TW, O'Connor JM, Strickler JH, Malka D, Sartore-Bianchi A, Bi F, Yamaguchi K, Yoshino T, Prager GW. Third- or Later-line Therapy for Metastatic Colorectal Cancer: Reviewing Best Practice. Clin Colorectal Cancer, 18:e117-e129, 2019

14. Denda T, Sakai D, Hamaguchi T, Sugimoto N, Ura T, Yamazaki K, Fujii H, Kajiwara T, Nakajima TE, Takahashi S, Otsu S, Komatsu Y, Nagashima F, Moriwaki T, Esaki T, Sato T, Itabashi M, Oki E, Sasaki T, Sunaga Y, Ziti-Ljajic S, Brillac C, Yoshino T. Phase II trial of aflibercept with FOLFIRI as a second-line treatment for Japanese patients with metastatic colorectal cancer. Cancer Sci, 110:1032-1043, 2019

15. Harada K, Okamoto W, Mimaki S, Kawamoto Y, Bando H, Yamashita R, Yuki S, Yoshino T, Komatsu Y, Ohtsu A, Sakamoto N, Tsuchihara K. Comparative sequence analysis of patient-matched primary colorectal cancer, metastatic, and recurrent metastatic tumors after adjuvant FOLFOX chemotherapy. BMC Cancer, 19:255, 2019

16. Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol, 20:420-435, 2019

17. Shimomura A, Yamamoto N, Kondo S, Fujiwara Y, Suzuki S, Yanagitani N, Horiike A, Kitazono S, Ohyanagi F, Doi T, Kuboki Y, Kawazoe A, Shitara K, Ohno I, Banerji U, Sundar R, Ohkubo S, Calleja EM, Nishio M. First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors. Mol Cancer Ther, 18:531-540, 2019

18. Oono Y, Kuwata T, Takashima K, Shinmura K, Hori K, Yoda Y, Ikematsu H, Shitara K, Kinoshita T, Yano T. Human epidermal growth factor receptor 2-, epidermal growth factor receptor-, and mesenchymal epithelial transition factor-positive sites of gastric cancer using surgical samples. Gastric Cancer, 22:335-343, 2019

19. Sawaki A, Yamada Y, Yamaguchi K, Nishina T, Doi T, Satoh T, Chin K, Boku N, Omuro Y, Komatsu Y, Hamamoto Y, Koizumi W, Saji S, Shah MA, Van Cutsem E, Kang YK, Iwasaki J, Kuriki H, Ohtsuka W, Ohtsu A. Regional differences in advanced gastric cancer: exploratory analyses of the AVAGAST placebo arm. Gastric Cancer, 21:429-438, 2018

20. Kojima T, Yamazaki K, Kato K, Muro K, Hara H, Chin K, Goddemeier T, Kuffel S, Watanabe M, Doi T. Phase I dose-escalation trial of Sym004, an anti-EGFR antibody mixture, in Japanese patients with advanced solid tumors. Cancer Sci, 109:3253-3262, 2018

21. Shitara K, Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann N Y Acad Sci, 1417:104-115, 2018

22. Matsumoto H, Sasaki A, Nakamura Y, Kawazoe A, Kuboki Y, Okinaka K, Shitara K. Tuberculous Meningitis during Chemotherapy for Advanced Gastric Cancer. Case reports in oncology, 11:228-233, 2018

23. Kuboki Y, Schatz CA, Koechert K, Schubert S, Feng J, Wittemer-Rump S, Ziegelbauer K, Krahn T, Nagatsuma AK, Ochiai A. In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients. Gastric Cancer, 21:401-412, 2018

24. Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet, 392:123- 133, 2018

25. Yoshino T, Oki E, Nozawa H, Eguchi-Nakajima T, Taniguchi H, Morita S, Takenaka N, Ozawa D, Shirao K. Rationale and design of the TRUSTY study: a randomised, multicentre, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy. ESMO open, 3:e000411, 2018

26. Nakamura Y, Yoshino T. Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer. Oncologist, 23:1310-1318, 2018

27. Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalcin S, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 19:1437-1448, 2018

28. Mishima S, Kawazoe A, Matsumoto H, Kuboki Y, Bando H, Kojima T, Doi T, Ohtsu A, Yoshino T, Nonte EM, Chintharlapalli S, Nasir A, Kuwata T, Shitara K. Efficacy and safety of ramucirumab-containing chemotherapy in patients with pretreated metastatic gastric neuroendocrine carcinoma. ESMO open, 3:e000443, 2018

29. Bando H, Okamoto W, Fukui T, Yamanaka T, Akagi K, Yoshino T. Utility of the quasi-monomorphic variation range in unresectable metastatic colorectal cancer patients. Cancer Sci, 109:3411- 3415, 2018

30. Yoshino T, Yamazaki K, Shinozaki E, Komatsu Y, Nishina T, Baba H, Tsuji A, Tsuji Y, Yamaguchi K, Sugimoto N, Denda T, Muro K, Takayama T, Esaki T, Hamamoto Y, Moriwaki T, Shimada Y, Goto M, Nakayama N, Fujii H, Tanase T, Ohtsu A. Relationship Between Thymidine Kinase 1 Expression and Trifluridine/Tipiracil Therapy in Refractory Metastatic Colorectal Cancer: A Pooled Analysis of 2 Randomized Clinical Trials. Clin Colorectal Cancer, 17:e719-e732, 2018

31. Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, Zalcberg J, Vickers MM, Wei AC, Gao Y, Tebbutt NC, Markman B, Price T, Esaki T, Koski S, Hitron M, Li W, Li Y, Magoski NM, Li CJ, Simes J, Tu D, O'Callaghan CJ. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol, 3:263-270, 2018

32. Corcoran RB, Andre T, Atreya CE, Schellens JHM, Yoshino T, Bendell JC, Hollebecque A, McRee AJ, Siena S, Middleton G, Muro K, Gordon MS, Tabernero J, Yaeger R, O'Dwyer PJ, Humblet Y, De Vos F, Jung AS, Brase JC, Jaeger S, Bettinger S, Mookerjee B, Rangwala F, Van Cutsem E. Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF(V600E)-Mutant Colorectal Cancer. Cancer Discov, 8:428-443, 2018

33. Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ, Cesari R, Chen Y, Davis CB, Huang B, Thall AD, Gopal AK. Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/ CD137 Agonist, in Patients with Advanced Cancer. Clin Cancer Res, 24:1816-1823, 2018

34. Bang YJ, Takano T, Lin CC, Fasanmade A, Yang H, Danaee H, Asato T, Kalebic T, Wang H, Doi T. TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study. Cancer Res Treat, 50:398-404, 2018

35. Grothey A, Yoshino T, Bodoky G, Ciuleanu T, Garcia-Carbonero R, Garcia-Alfonso P, Van Cutsem E, Muro K, Mytelka DS, Li L, Lipkovich O, Hsu Y, Sashegyi A, Ferry D, Nasroulah F, Tabernero J. Association of baseline absolute neutrophil counts and survival in patients with metastatic colorectal cancer treated with second-line antiangiogenic therapies: exploratory analyses of the RAISE trial and validation in an electronic medical record data set. ESMO open, 3:e000347, 2018

36. Kotaka M, Yamanaka T, Yoshino T, Manaka D, Eto T, Hasegawa J, Takagane A, Nakamura M, Kato T, Munemoto Y, Nakamura F, Bando H, Taniguchi H, Gamoh M, Shiozawa M, Saji S, Maehara Y, Mizushima T, Ohtsu A, Mori M. Safety data from the phase III Japanese ACHIEVE trial: part of an international, prospective, planned pooled analysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. ESMO open, 3:e000354, 2018

37. Shinozaki E, Yoshino T, Tsuchihara K. Reply to `Comment on `Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study''. Br J Cancer, 118:1278-1279, 2018

38. Hombu T, Yano T, Hatogai K, Kojima T, Kadota T, Onozawa M, Yoda Y, Hori K, Oono Y, Ikematsu H, Fujii S. Salvage endoscopic resection (ER) after chemoradiotherapy for esophageal squamous cell carcinoma: What are the risk factors for recurrence after salvage ER? Dig Endosc, 30:338-346, 2018

39. Sobrero A, Grothey A, Iveson T, Labianca R, Yoshino T, Taieb J, Maughan T, Buyse M, Andre T, Meyerhardt J, Shields AF, Souglakos I, Douillard JY, Cervantes A. The hard road to data interpretation: 3 or 6 months of adjuvant chemotherapy for patients with stage III colon cancer? Ann Oncol, 29:1099-1107, 2018

40. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA oncology, 4:e180013, 2018

41. Nishina T, Takahashi S, Iwasawa R, Noguchi H, Aoki M, Doi T. Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest New Drugs, 36:424-434, 2018

42. Oki E, Kato T, Bando H, Yoshino T, Muro K, Taniguchi H, Kagawa Y, Yamazaki K, Yamaguchi T, Tsuji A, Iwamoto S, Nakayama G, Emi Y, Touyama T, Nakamura M, Kotaka M, Sakisaka H, Yamanaka T, Kanazawa A. A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. Clin Colorectal Cancer, 17:147-155, 2018

43. Naito Y, Takahashi H, Shitara K, Okamoto W, Bando H, Kuwata T, Kuboki Y, Matsumoto S, Miki I, Yamanaka T, Watanabe A, Kojima M. Feasibility study of cancer genome alterations identified by next generation sequencing: ABC study. Jpn J Clin Oncol, 48:559-564, 2018

44. Kadota T, Hatogai K, Yano T, Fujita T, Kojima T, Daiko H, Fujii S. Pathological tumor regression grade of metastatic tumors in lymph node predicts prognosis in esophageal cancer patients. Cancer Sci, 109:2046-2055, 2018

45. Sunami K, Takahashi H, Tsuchihara K, Takeda M, Suzuki T, Naito Y, Sakai K, Dosaka-Akita H, Ishioka C, Kodera Y, Muto M, Wakai T, Yamazaki K, Yasui W, Bando H, Fujimoto Y, Fukuoka S, Harano K, Kawazoe A, Kimura G, Koganemaru S, Kogawa T, Kotani D, Kuboki Y, Matsumoto H, Matsumoto S, Mishima S, Nakamura Y, Sawada K, Shingaki S, Shitara K, Umemoto K, Umemura S, Yasuda K, Yoshino T, Yamamoto N, Nishio K. Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 10). Cancer Sci, 109:2980-2985, 2018

46. Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K. Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8⁺ T cells in the tumor microenvironment. J Immunother Cancer, 6:106, 2018

47. Oono Y, Kuwata T, Takashima K, Yoda Y, Ikematsu H, Shitara K, Kinoshita T, Yano T. Clinicopathological features and endoscopic findings of HER2-positive gastric cancer. Surg Endosc, 32:3964- 3971, 2018