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Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients

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Abstract

Background

Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients.

Methods

A total of 47 patients with Stage I–III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data.

Results

CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023).

Conclusions

We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis.

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Data availability

The data will be shared on reasonable request to TW.

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Acknowledgements

We thank ClearScience (http://www.clearscience.net/) for English language editing.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Grant Number 22H03140 and 21K19522 for MN, and research funding from Denka for WT and SO.

Author information

Authors and Affiliations

  1. Department of Surgery, Division of Breast and Endocrine Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan

    Masayuki Nagahashi & Yasuo Miyoshi

  2. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan

    Masayuki Nagahashi, Chie Toshikawa, Junko Tsuchida, Kazuki Moro, Masato Nakajima, Yoshifumi Shimada, Hiroshi Ichikawa, Kazuaki Takabe & Toshifumi Wakai

  3. Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-Ku, Niigata, 951-8514, Japan

    YiWei Ling & Shujiro Okuda

  4. Medical AI Center, Niigata University School of Medicine, 2-5274 Gakkocho-dori, Chuo-Ku, Niigata, 951-8514, Japan

    YiWei Ling & Shujiro Okuda

  5. Department of Breast Surgical Oncology, St. Luke’s International Hospital, 9-1 Akashicho, Chuo-Ku, Tokyo, 104-8560, Japan

    Chie Toshikawa & Hideko Yamauchi

  6. Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan

    Tetsu Hayashida & Yuko Kitagawa

  7. Department of Breast Surgery, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan

    Manabu Futamura

  8. Division of Breast Surgical Oncology, Department of Surgery, Showa University School of Medicine, 1-5-8, Hatanodai, Shinagawa-Ku, Tokyo, 142-8666, Japan

    Takashi Kuwayama & Seigo Nakamura

  9. Division of Medical Oncology, Department of Internal Medicine, St. Luke’s International Hospital, 9-1 Akashicho, Chuo-Ku, Tokyo, 104-8560, Japan

    Teruo Yamauchi

  10. Department of Breast Oncology, Niigata Cancer Center Hospital, 15-3 Kawagishi-Cho 2-Chome, Chuo-Ku, Niigata, 951-8566, Japan

    Koji Kaneko, Chizuko Kanbayashi & Nobuaki Sato

  11. University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, 01655, USA

    Stephen Lyle

  12. Breast Surgery, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Kazuaki Takabe

  13. Department of Surgery, University at Buffalo Jacobs School of Medicine and Biosciences, The State University of New York, Buffalo, NY, 14203, USA

    Kazuaki Takabe

  14. Department of Breast Surgery and Oncology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-Ku, Tokyo, 160-8402, Japan

    Kazuaki Takabe

  15. Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan

    Kazuaki Takabe

Authors
  1. Masayuki Nagahashi
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  2. YiWei Ling
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  3. Chie Toshikawa
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  4. Tetsu Hayashida
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  5. Yuko Kitagawa
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  6. Manabu Futamura
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  7. Takashi Kuwayama
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  8. Seigo Nakamura
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  9. Hideko Yamauchi
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  10. Teruo Yamauchi
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  11. Koji Kaneko
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  12. Chizuko Kanbayashi
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  13. Nobuaki Sato
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  14. Junko Tsuchida
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  15. Kazuki Moro
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  16. Masato Nakajima
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  17. Yoshifumi Shimada
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  18. Hiroshi Ichikawa
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  19. Stephen Lyle
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  20. Yasuo Miyoshi
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  21. Kazuaki Takabe
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  22. Shujiro Okuda
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  23. Toshifumi Wakai
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Contributions

Conception and design: All authors; Administrative support: MN, YS, HI, YM, SO, TW; Collection and assembly of data: MN, YL, CT, TH, YK, MF, TK, SN, HY, TY, KK, CK, NS, JT, KM, MN; Data analysis and interpretation: MN, YL, SL, YM, KT, SO, TW; Writing the first draft of manuscript: MN, SL, YM, KT, SO, TW; Review and editing: All authors; Final approval of manuscript: All authors.

Corresponding author

Correspondence to Masayuki Nagahashi.

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Conflict of interest

M Nagahashi received honoraria from Chugai, AstraZeneca, Eli Lilly, Pfizer, Novartis, Taiho, Daiichi Sankyo, Esai, Kyowa-Kirin, and Denka. T Hayashida received research funding and honoraria from Eisai, Chugai, Eli Lilly, Pfizer, Kyowa-Kirin, Daiichi-Sankyo, Fixstars and Taiho. Y Kitagawa received grants and personal fees from ASAHI KASEI PHARMA CORPORATION, grants, personal fees and other from ONO PHARMACEUTICAL CO., LTD., grants and personal fees from Otsuka Pharmaceutical Factory, Inc., grants and personal fees from Nippon Covidien Inc., grants, personal fees and other from TAIHO PHARMACEUTICAL CO., LTD, grants, personal fees and other from CHUGAI PHARMACEUTICAL CO., LTD., grants and personal fees from KAKEN PHARMACEUTICAL CO.,LTD., personal fees from AstraZeneca K.K., personal fees from Ethicon Inc., personal fees from Olympus Corporation, personal fees from SHIONOGI & CO., LTD., personal fees and other from Bristol-Myers Squibb K.K., personal fees from MSD K.K., personal fees from Smith & Nephew KK, personal fees from ASKA Pharmaceutical Co., Ltd., personal fees from MIYARISAN PHARMACEUTICAL CO. LTD., personal fees from Toray Industries, Inc., personal fees from DAIICHI SANKYO COMPANY, LIMITED, personal fees from Chugai Foundation for Innovative Drug Discovery Science, personal fees from Nippon Kayaku Co., Ltd., grants from Yakult Honsha Co. Ltd., grants from Otsuka Pharmaceutical Co., Ltd., grants from TSUMURA & CO., grants from Sumitomo Pharma Co., Ltd., grants from EA Pharma Co., Ltd., grants from Eisai Co., Ltd., grants from Kyowa Kirin Co.,Ltd., grants from MEDICON INC., grants from Takeda Pharmaceutical Co., Ltd., grants from TEIJIN PHARMA LIMITED., outside the submitted work. H Yamauchi received research funding from AstraZeneca, and EIKEN Kagaku. N Sato received honorarium from Chugai Pharmaceutical, Kyowa Kirin Co. Ltd., Taiho Pharmaceutical, Eli Lilly, Nippon Kayaku Co., Daiichi Sankyo, and Celltrion Healthcare Japan. S Lyle is a paid consultant for KEW Inc. Y Miyoshi received research funding and honoraria from Esai, Chugai, AstraZeneca, Eli Lilly, Pfizer, MSD, Kyowa-Kirin, Daiichi-Sankyo, and Taiho. T Wakai, and S Okuda received research funding from Denka.

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Nagahashi, M., Ling, Y., Toshikawa, C. et al. Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients. Breast Cancer 30, 584–595 (2023). https://doi.org/10.1007/s12282-023-01449-2

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