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Translational Therapeutics

Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients

British Journal of Cancer volume 130, pages 1023–1035 (2024)Cite this article

Subjects

Abstract

Background

Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes.

Methods

In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses.

Results

We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort.

Conclusion

We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine.

Trial registration

The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/index-j.htm) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w.

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Fig. 1: Summary of this clinical trial.
Fig. 2: Association among observed cytokine concentrations, clinical outcomes, HRD scores, and patient ages.
Fig. 3: Cytokines correlated with clinical outcomes.
Fig. 4: Area under the curve (AUC) analysis of IL-1α, TRAIL, SCF, RANTES, and IL-16.
Fig. 5: Protein-protein interaction (PPI) network analysis.
Fig. 6: Logistic regression analysis of the patients in the eribulin-based treatment arms.

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Data availability

Clinical data and observed cytokine concentrations for all patients in the cohort at all time points for the 1st 48-plex and 40-plex measurements are given in Supplementary Table 3. Observed cytokine concentrations for all patients in the cohort at all time points for the 2nd 48-plex and 40-plex measurements are shown in Supplementary Table 4. Other raw data generated in this study are available upon request from the corresponding authors.

Code availability

All R and Python codes used in this study are available upon request.

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Acknowledgements

We gratefully acknowledge the work of the members of JBCRG and Kyoto University, who helped with this study. This study was based on a physician-led clinical trial funded by the Japan Breast Cancer Research Group and Eisai Co., Ltd.

Funding

None.

Author information

Author notes

  1. These authors contributed equally: Don Pietro Saldajeno, Shinpei Kawaoka.

Authors and Affiliations

  1. Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, 54 Kawahara-cho, Shogoin Sakyo-ku, Kyoto, 606-8507, Japan

    Don Pietro Saldajeno & Shinpei Kawaoka

  2. Mathematical Informatics Laboratory, Division of Information Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara, 630-0192, Japan

    Don Pietro Saldajeno & Kazushi Ikeda

  3. Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan

    Shinpei Kawaoka

  4. Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Norikazu Masuda

  5. Department of Breast Surgery, Kyoto University Hospital, Graduate School of Medicine, 54 Kawahara-cho, Shogoin Sakyo-ku, Kyoto, 606-8507, Japan

    Sunao Tanaka, Tomomi Nishimura, Ravindranath M. Velaga, Yukiko Fukui, Yurina Maeshima, Masahiro Takada, Kosuke Kawaguchi & Masakazu Toi

  6. Breast and Endocrine Surgery, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Hiroko Bando

  7. Department of Next-generation Clinical Genomic Medicine, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Tomomi Nishimura

  8. Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Tomomi Nishimura & Seishi Ogawa

  9. Department of Breast Surgery, Shimane University Hospital, Enyacho 89-1, Izumo, Shimane, 693-0021, Japan

    Takayuki Kadoya

  10. Department of Breast Surgery and Oncology, Kanagawa Cancer Center, 2-3-2 Nakano, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan

    Takashi Yamanaka

  11. Department of Breast Surgery, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan

    Shigeru Imoto

  12. Department of Breast and Endocrine Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Nobuko Tamura

  13. Department of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan

    Tomoyuki Aruga

  14. Department of Breast Surgery, Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminamimachi Chuo-ku, Kobe-shi, Hyogo, 650-0047, Japan

    Eiji Suzuki

  15. Breast Surgical Oncology, The Cancer Institute Hospital of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Takayuki Ueno

  16. Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Seishi Ogawa

  17. Department of Diagnostic Pathology, Kyoto University Hospital, 54 Kawahara-cho, Shogoin Sakyo-ku, Kyoto, 606-8507, Japan

    Hironori Haga

  18. Breast Oncology Center, The Cancer Institute Hospital of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Shinji Ohno

  19. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin Sakyo-ku, Kyoto, 606-8507, Japan

    Satoshi Morita

  20. Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan

    Masakazu Toi

Authors
  1. Don Pietro Saldajeno
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  2. Shinpei Kawaoka
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Contributions

KK, SK, NM and MToi designed the study. NM, HK, TY, SI, NT, TA, MTakada and ES provided specimens. KK, ST, YF, YM, TN and RMV performed sample preparation. DPS performed WGCNA statistical analyses, STRING DB analysis, and logistic regression analysis, constructed figures, and wrote the manuscript. SK, NM, TK, KI, TU, SOgawa, SOno, SM, MToi, and KK supervised the data analyses. SK and KK constructed figures and wrote the manuscript.

Corresponding authors

Correspondence to Kosuke Kawaguchi or Masakazu Toi.

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Competing interests

NM: grants from Chugai, Eli Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, MSD, Eisai, Novartis, Sanofi, Kyowa-Kirin, and Nippon-Kayaku; honoraria from Chugai, Pfizer, AstraZeneca, Eli Lilly, and Eisai; executive board and board of directors of JBCRG. TY: honoraria from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Novartis, Chugai, Eisai, Kyowa-Kirin, and Pfizer. SI: honoraria from Eisai, Taiho, Chugai, Kyowa-Kirin, Daiichi-Sankyo, and Nippon-Kayaku. NT: grant from Eisai; honoraria from Chugai, Pfizer, Eli Lilly, Novartis, Eisai, and AstraZeneca KK. TA: honoraria from Chugai, Pfizer, Eli Lilly, and AstraZeneca KK. MT: grants from Daiichi-Sankyo, AstraZeneca KK, Yakult, KBCRN, ABCSG, JBCRG and Medbis; honoraria from Chugai, Eisai, Daiichi-Sankyo, Eli Lilly, AstraZeneca, Pfizer, Nippon-Kayaku, and Mitaka Koki. TU: honoraria from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca, Novartis Pharma. SO: grants from Takeda Foundation, ChordiaTherapeutics, Inc., Sumitomo Dainippon Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd.; Royalties from ASAHI Genomics Inc, Qiagen and Cordia Therapeutics; Consulting fees from KAN Research Institute, Inc., ChordiaTherapeutics, Inc., Eisai Co., Ltd., Novartis Pharmaceuticals; honoraria from MSD Japan, Kyowa Hakko Kirin Co., Ltd., Pfizer Inc; Stock or stock options from Stock of ASAHI Genomics Inc, Stock potion of Cordia Therapeutics Inc., and Stock of Rebirthell Inc. SO: honoraria from Eli Lilly, Chugai, Pfizer, and Eisai. SM: grants from Nippon Boehringer Ingelheim, Eisai; honoraria from AstraZeneca, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Bristol Myers Squibb Co. Ltd., Novartis Pharma KK, MSD KK, Kyowa-Kirin Co. Ltd., Astellas Pharma, Pfizer Japan, Ono Pharmaceutical Co. Ltd., Eli Lilly Japan. KK: grants from TERUMO, Astellas, Eli Lilly, Kyoto Breast Cancer Research Network; consulting fees from Becton Dickinson Japan; honoraria from Eisai, Chugai, and Takeda. MT: grants from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, JBCRG Associates, Eisai, Eli Lilly, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon-Kayaku, AFI Technology, Luxonus, Shionogi, and GL Science; honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Konica Minolta, Shimadzu, Yakult, and Nippon-Kayaku; advisory board of Kyowa-Kirin, Daiichi-Sankyo, Eli Lilly, Konica Minolta, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net; board of directors of JBCRG Associates, KBCRN, OOTR; associate editor of the British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women’s Cancer, Asian Journal of Surgery, Asian Journal of Breast Surgery; deputy editor of International Journal of Oncology.

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Saldajeno, D.P., Kawaoka, S., Masuda, N. et al. Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients. Br J Cancer 130, 1023–1035 (2024). https://doi.org/10.1038/s41416-023-02527-0

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