Breast Cancer Research and Treatment

, Volume 162, Issue 3, pp 501–510 | Cite as

Circulating tumor cells as a prognostic marker for efficacy in the randomized phase III JO21095 trial in Japanese patients with HER2-negative metastatic breast cancer

  • Hiroji IwataEmail author
  • Norikazu Masuda
  • Daigo Yamamoto
  • Yoshiaki Sagara
  • Nobuaki Sato
  • Yutaka Yamamoto
  • Mitsue Saito
  • Takashi Fujita
  • Shoji Oura
  • Junichiro Watanabe
  • Masami Tsukabe
  • Kazumi Horiguchi
  • Satoshi Hattori
  • Yoshimasa Matsuura
  • Katsumasa Kuroi
Clinical trial



Prognostic effects of circulating tumor cells (CTCs) have been reported in metastatic breast cancer (MBC). However, few phase III trials have investigated the potential role of CTCs in treatment selection. We explored potential relationships between CTCs, efficacy, and differential treatment effects.


Patients with HER2-negative MBC were randomized to receive either concurrent capecitabine plus docetaxel (XT) or sequential single-agent docetaxel followed by single-agent capecitabine at progression (T → X). Blood samples were collected at baseline, on day 1 of cycles 2 and 3, and at progression. CTCs were counted using the CellSearch® System. The relationship between baseline CTC count and outcomes was investigated using a pre-defined threshold of 2 CTCs/7.5 mL.


At screening, 44% of the 148 enrolled patients had positive CTC score. In multivariate analyses of pooled treatment arms, positive baseline CTC and triple-negative disease were strongly associated with worse progression-free survival (PFS) and overall survival (OS). Patients with positive CTC score at the baseline had worse OS, irrespective of change in CTC (decreased versus remaining positive) at cycle 2. The prognostic effect of baseline CTC count on OS appeared slightly less pronounced in XT-treated pts. compared with T → X.


A baseline CTC count ≥2 CTCs/7.5 mL was associated with worse prognosis. However, some improvement in PFS and OS was shown with concurrent XT, thus baseline CTC could be a predictive marker. As the current trial was not designed to evaluate a change in chemotherapy according to on-treatment CTC changes, prospective investigation is required.


Circulating tumor cells Prognostic factor HER2-negative Metastatic breast cancer Phase III trial 



The authors wish to thank the patients and their families, the study site personnel, and the study team for their participation in the trial. The JO21095 study was sponsored by Chugai Pharmaceutical. Chugai Pharmaceutical was involved in study design, statistical analyses, and data interpretation. Chugai Clinical Research Center Co., Ltd. gathered and managed data, and EPS Corporation Co., Ltd. was responsible for data monitoring. The principal investigators had full access to all study data and had final responsibility for approval and submission of the manuscript.

Compliance with ethical standards

Conflict of interest

H Iwata has received honoraria from Chugai Pharmaceutical and has served as a consultant or advisory role for Chugai Pharmaceutical; N. Masuda has received honoraria from Chugai Pharmaceutical, Astra-Zeneca, and Kyowa Hakko Kirin; S. Hattori has served as a consultant or advisory role for Chugai Pharmaceutical; D. Yamamoto, Y. Sagara, N. Sato, Y. Yamamoto, M. Saito, T. Fujita, S. Oura, J. Watanabe, M. Tsukabe, K Horiguchi, Y. Matsuura, and K. Kuroi declare that they have no conflict of interest.

Ethical approval

The ethical committee approved the study protocol and all patients provided written informed consent before entering the study.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Hiroji Iwata
    • 1
    Email author
  • Norikazu Masuda
    • 2
  • Daigo Yamamoto
    • 3
  • Yoshiaki Sagara
    • 4
  • Nobuaki Sato
    • 5
  • Yutaka Yamamoto
    • 6
  • Mitsue Saito
    • 7
  • Takashi Fujita
    • 8
  • Shoji Oura
    • 9
  • Junichiro Watanabe
    • 10
  • Masami Tsukabe
    • 11
  • Kazumi Horiguchi
    • 12
  • Satoshi Hattori
    • 13
  • Yoshimasa Matsuura
    • 14
  • Katsumasa Kuroi
    • 12
  1. 1.Department of Breast OncologyAichi Cancer Center HospitalNagoyaJapan
  2. 2.Department of Surgery, Breast OncologyNational Hospital Organization Osaka National HospitalOsakaJapan
  3. 3.Department of SurgeryKansai Medical University Medical CenterOsakaJapan
  4. 4.Department of Breast SurgerySagara HospitalKagoshimaJapan
  5. 5.Department of SurgeryNiigata Cancer Center HospitalNiigataJapan
  6. 6.Department of Breast and Endocrine Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
  7. 7.Department of Breast OncologyJuntendo University HospitalTokyoJapan
  8. 8.Department of Breast OncologyJichi Medical University HospitalTochigiJapan
  9. 9.Department of Thoracic and Cardiovascular SurgeryWakayama Medical UniversityWakayamaJapan
  10. 10.Department of Breast OncologyShizuoka Cancer CenterShizuokaJapan
  11. 11.Department of Breast SurgeryNTT West Osaka HospitalOsakaJapan
  12. 12.Department of SurgeryTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  13. 13.Biostatistics CenterKurume UniversityFukuokaJapan
  14. 14.Medical AffairsChugai Pharmaceutical CO., LTD.TokyoJapan

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