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Mutational spectrum of TP53 gene correlates with nivolumab treatment efficacy in advanced gastric cancer (TP53MUT study)

British Journal of Cancer volume 129, pages 1032–1039 (2023)Cite this article

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Abstract

Background

Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project.

Methods

Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided.

Results

Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1–1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type.

Conclusion

Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment.

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Fig. 1: Patient flow chart.
Fig. 2: Overall survival by TP53 mutation.
Fig. 3: Progression-free survival by TP53 mutation in patients treated with nivolumab.

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Data availability

The data generated in this study are not publicly available due to information that could compromise patient privacy or consent but are available upon reasonable request from the corresponding author.

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Acknowledgements

The authors thank all of the patients and their families who participated in this study; all SCRUM-Japan GI-SCREEN and GOZILA investigators and site personnel; Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan for study management and data centre support. The authors also thank Editage for their contribution to English proofreading for this manuscript.

Funding

This work was supported by grants from JSPS KAKENHI (Grant number JP21K08735 to KA) and the Japan Agency for Medical Research and Development (no. 19ck0106445h0002 to YN).

Author information

Authors and Affiliations

  1. Department of Surgery and Science, Kyushu University, Fukuoka, Japan

    Koji Ando & Eiji Oki

  2. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura, Daisuke Kotani, Hideaki Bando & Takayuki Yoshino

  3. Department for the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan

    Yoshiaki Nakamura, Hideaki Bando & Takayuki Yoshino

  4. Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, Japan

    Hiroyuki Kitao

  5. Department of Biostatics, Yamaguchi University, Yamaguchi, Japan

    Mototsugu Shimokawa

  6. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan

    Tomohiro Nishina

  7. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan

    Takanobu Yamada

  8. Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan

    Satoshi Yuki

  9. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

    Yukiya Narita

  10. Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan

    Hiroki Hara

  11. Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan

    Takashi Ohta

  12. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Taito Esaki

  13. Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan

    Yasuo Hamamoto

  14. Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

    Ken Kato

  15. Department of Gastroenterology and Hepatology, University of Tsukuba Hospital, Tsukuba, Japan

    Yoshiyuki Yamamoto

  16. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan

    Keiko Minashi

  17. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    Koushiro Ohtsubo

  18. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan

    Naoki Izawa

  19. Department of Medical Oncology, Kindai University Hospital, Osakasayama, Japan

    Hisato Kawakami

  20. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Takeshi Kato

  21. Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan

    Taroh Satoh

  22. Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan

    Naohiro Okano

  23. Department of Clinical Oncology, Kagawa University Hospital, Kita-gun, Japan

    Akihito Tsuji

  24. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shunto-gun, Japan

    Kentaro Yamazaki

  25. Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan

    Yoshihiko Maehara

Authors
  1. Koji Ando
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  2. Yoshiaki Nakamura
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Contributions

KA, YN and HK contributed to the planning and conducting of studies, recruiting patients, acquisition of data, and writing of the manuscript. MS contributed to the analysis and interpretation of the data. DK, HB, TN, TY, SY, YN, HH, TO, TE, YH, KK, YY, KM, KO, NI, HK, TK, TS, NO and AT contributed to the recruitment of patients and acquisition of data. KY, TY, TM and EO contributed to the planning, conducting of studies and interpretation of data. All authors agree to be accountable for all aspects of the work and will ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Eiji Oki.

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Competing interests

KA, MS, KO and YM declare no conflict of interest. YN received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., Merck Biopharma, and Guardant Health AMEA and research grants from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd., Guardant Health, Genomedia, Seagen, and Roche Diagnostics. H Kitao received research funding from Taiho Pharmaceutical Co. Ltd. DK received honoraria for lectures from Takeda, Chugai, Eli Lilly, MSD, Ono, Taiho, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, Eisai, Merckbiopharma and Sysmex, and research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneos health, Cimic and Cimicshiftzero. HB received research funding from Ono, and honoraria for lectures from Ono, Taiho and Eli Lilly. TN received honoraria for lectures from Taiho Pharmaceutical, Chugai, Ono Pharmaceutical, Bristol-Meyers Squibb and Lilly; and research funding from Taiho Pharmaceutical, Chugai, Daiichi Sankyo, MSD, Ono Pharmaceutical, Bristol-Meyers Squibb, Lilly and Sumitomo Dainippon Pharma. TY received honoraria for lectures from Ono Pharmaceutical, Taiho Pharmaceutical, Johnson and Johnson, and Bristol-Myers Squibb K.K. SY received honoraria for lectures from Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., MSD K.K., Ono Phermaceutical Co., Ltd., Merck Biopharma Co., Ltd., Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Bristol-Myers Squibb K.K. YN received research funding from Chugai, MSD, Amgen, ONO Pharmaceutical, Astellas, Sanofi, Taiho, Eisai, Daiichi Sankyo, Novartis, Pfizer; Honoraria for lectures, presentations, and speakers’ bureaus from Yakult Honsha, Taiho, Eli Lilly, Daiichi Sankyo, Ono Pharma, Bristol-Mayers Squibb; Participation on an Advisory Board of Daiichi Sankyo. HH received honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Taiho, Takeda and Yakult, consulting or advisory roles Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, MSD and Ono, and research grants from ALX oncology, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Merck Biopharma, MSD, Ono and Taiho. TO received honoraria for lectures from Eli Lilly, Bristol-Myers Squibb K.K., Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., EA Pharma Co., Ltd. and Merck & Co., Inc., and research grants from Takeda Pharmaceutical Co., Ltd. TE. received honoraria for lectures from Daiichi Sankyo, Taiho and Chugai; and research funding from Novartis, Ono Pharmaceutical, Daiichi Sankyo, MSD, Astellas, Amgen Astellas BioPharma, IQVIA, Chugai, Pfyzer, Quitiles, Asahikasei Pharma and Syneos Health. YH received honoraria for lectures from Ono Pharmaceutical. KK received consulting fees from Daiichi-Sankyo, Seagen and Servier, honoraria for lectures from Ono Pharmaceutical, Bristol Myers Squibb, MSD and Taiho, research funding from Ono Pharmaceutical, Bristol Myers Squibb, MSD, Shionogi, Chugai, AstraZeneca, Janssen, Bayer, Merck Bio, Oncolys Biopharma and Beigene. YY received honoraria for lectures from Taiho Pharmaceutical, Ono Pharmaceutical, Asahi Kasei, Sanofi, Nihonkayaku, Merck Serono and Yakult, Eisai. KM received research grant from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K, Astellas, BeiGene and Daiichi Sankyo Co., Ltd. NI received honoraria for lectures from Bristol-Myers Squibb K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and MSD K.K. HK received honoraria for lectures from Bristol-Myers Squibb Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Teijin Pharma Ltd., Incyte Biosciences Japan., and Taiho Pharmaceutical Co. Ltd.; lecture fees from Glaxo Smith Kline K.K., and Otsuka Pharmaceutical Co., Ltd.; and research funding from Kobayashi Pharmaceutical. Co., Ltd., and Eisai Co. Ltd. TK received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Yakult Honsha Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and research grants from Chugai Pharmaceutical Co., Ltd. TS received honoraria for lectures from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb K.K., Taiho Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd., research grants from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb K.K., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., MSD K.K., Gilead Sciences, Inc., and Parexel International Corporation, scholarship grants from Taiho Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd., and endowed chair from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Yakult Honsha Co., Ltd. NO received honoraria for lectures from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd. Bayer Yakuhin, Ltd. and Eisai Co., Ltd; and advisory board from GlaxoSmithKline CO., Ltd. AT received speakers’ bureaux with Taiho Pharmaceutical, Chugai, Eli Lilly Japan, Merck Serono, Sanofi and Bristol-Myers Squibb; and research funding from Taiho Pharmaceutical, Sanofi and Ono Pharmaceutical. KY received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. TY received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., MSD K.K., and Ono Pharmaceutical Co., Ltd., and research grants from MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Amgen K.K., Eisai Co., Ltd., FALCO biosystems Ltd., Genomedia Inc., Molecular Health GmbH, Nippon Boehringer Ingelheim Co., Ltd., Pfizer Japan Inc., Roche Diagnostics K., Sysmex Corp., and Sysmex Corp. EO received research funding from Guardant Health, and honoraria for lectures from Ono, Takeda, Bayer, Chugai, Taiho, Eli Lilly and Bristol Myers Squibb.

Ethical approval and consent to participate

The ethical, medical, and scientific aspects of the study were reviewed and approved by the Institutional Review Board of each institution and registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000016344). This study was conducted in accordance with the Declaration of Helsinki, revised in 2000, and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects.

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Ando, K., Nakamura, Y., Kitao, H. et al. Mutational spectrum of TP53 gene correlates with nivolumab treatment efficacy in advanced gastric cancer (TP53MUT study). Br J Cancer 129, 1032–1039 (2023). https://doi.org/10.1038/s41416-023-02378-9

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  • DOI: https://doi.org/10.1038/s41416-023-02378-9

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