Clinical Study

Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study

British Journal of Cancer volume 122, pages1747–1753(2020)Cite this article

Subjects

Abstract

Background

The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated.

Methods

Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate.

Results

A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4–56.7; P = 0.025).

Conclusions

The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer.

Clinical trial registration

Clinical Trial Registration: UMIN-CTR as UMIN000007074.

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Fig. 1: CONSORT diagram for this study.
Fig. 2: Distribution of the Ki-67 index.
Fig. 3: Relationship between Ki-67 reduction rate and pCR rate in each arm.

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Author information

Affiliations

  1. National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan

    Hirofumi Mukai

  2. Musashino Red Cross Hospital, Musashino, Tokyo, 180-0023, Japan

    Takeshi Yamaguchi

  3. National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido, 003-0804, Japan

    Masato Takahashi

  4. University of Tsukuba Hospital, Tsukuba, Ibaraki, 305-8576, Japan

    Yasuo Hozumi

  5. Gunma Prefectural Cancer Center, Ota, Gunma, 373-0828, Japan

    Tomomi Fujisawa

  6. National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, 791-0245, Japan

    Shozo Ohsumi

  7. Asahikawa-Kosei General Hospital, Hokkaido, Asahikawa, Japan

    Hiromitsu Akabane

  8. Kumamoto Shinto General Hospital, Chuo Ward, Kumamoto, 862-8655, Japan

    Reiki Nishimura

  9. Osaka City University Graduate School of Medicine, Sumiyoshi Ward, Osaka, 558-0022, Japan

    Tsutomu Takashima

  10. Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, 981-8558, Japan

    Youngjin Park

  11. Hakuaikai Medical Corp Sagara Hospital, Kagoshima, Japan

    Yasuaki Sagara

  12. Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, 467-8601, Japan

    Tatsuya Toyama

  13. Kyorin University Hospital, Mitaka, Tokyo, 181-8611, Japan

    Shigeru Imoto

  14. Mie University Hospital, Tsu, Mie, 514-8507, Japan

    Toshiro Mizuno

  15. National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan

    Satoshi Yamashita

  16. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, 277-8577, Japan

    Satoshi Fujii

  17. National Center for Global Health and Medicine, Tokyo, Japan

    Yukari Uemura

Authors
  1. Hirofumi Mukai
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  2. Takeshi Yamaguchi
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  3. Masato Takahashi
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  4. Yasuo Hozumi
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  5. Tomomi Fujisawa
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  6. Shozo Ohsumi
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  7. Hiromitsu Akabane
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  8. Reiki Nishimura
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  9. Tsutomu Takashima
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  10. Youngjin Park
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  11. Yasuaki Sagara
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  12. Tatsuya Toyama
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  13. Shigeru Imoto
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  14. Toshiro Mizuno
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  15. Satoshi Yamashita
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  17. Yukari Uemura
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Contributions

H.M. and T.Y. contributed to the design of the study. H.M., M.T., Y.H., T.F., S.O., H.A., R.N., T.T., Y.P., Y.S., T.T., S.I. and T.M. contributed substantially to patient recruitment. H.M., S.Y., S.F. and Y.U. contributed to data collection. H.M. contributed to data review. Y.U. contributed to data analysis. All authors contributed to data interpretation. H.M. contributed to the writing of the report. All authors contributed to review of the report and approved the final submitted version.

Corresponding author

Correspondence to Hirofumi Mukai.

Ethics declarations

Ethics approval and consent to participate

Written informed consent was obtained from each patient prior to entry into the study. The study was conducted in compliance with the principles of the declaration of Helsinki and local ethical and legal requirements. The protocol and informed consent were approved by the independent ethics committees or institutional review board of all participating sites. A full list of the ethical committees can be found in the supplementary information.

Consent to publish

None.

Data availability

The data generated and analysed during this study are available at UMIN-CTR as UMIN000007074.

Competing interests

The authors declare no competing interests.

Funding information

This study was supported by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED.

Additional information

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Mukai, H., Yamaguchi, T., Takahashi, M. et al. Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study. Br J Cancer 122, 1747–1753 (2020). https://doi.org/10.1038/s41416-020-0815-9

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